Showing posts with label biology. Show all posts
Showing posts with label biology. Show all posts
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Isotopident
Isotopident is a tool that helps you to estimate the theoretical isotopic distribution of a peptide or protein, a polynucleotide and a chemical compound from its composition (sequence of amino acids expressed in either 1-letter code, sequence of amino acids expressed in 3-letter code, sequence of nucleotides or its chemical formula). Moreover, Isotopident is capable of computing its monoisotopic mass. Finally, this tool is also able to predict the most likely isotope combination and the exact mass of the given input.
Link: http://education.expasy.org/student_projects/isotopident/htdocs/
Link: http://education.expasy.org/student_projects/isotopident/htdocs/
Insulin và công nghệ sản xuất insulin trên thế giới
Người ta đã nhận thấy rằng bệnh tiểu đường là một trong những căn bệnh đe dọa nghiêm trọng tới sức khoẻ của con người.Trên thế giới, con số những người mắc bệnh tiểu đường ước tính khoảng từ 151 triệu đến 171 triệu (năm 2000), và dự kiến con số này sẽ là 221 triệu (năm 2010), năm 2030 sẽ lên đến 366 triệu người. Và đương nhiên, việc gia tăng con số những người mắc bệnh tiểu đường sẽ kéo theo sự gia tăng các biến chứng của căn bệnh này như thần kinh, xơ vữa động mạch… Theo ước tính, số người tử vong trên thế giới do bệnh tiểu đường trong năm 2000 là 2,9 triệu và con số này sẽ còn tiếp tục gia tăng. Trong đó, tiểu đường type 2 chiếm khoảng hơn 90% tổng số ca bệnh. Điều đó đòi hỏi phải tìm ra những hướng tiệp cận mới cho việc ngăn ngừa và điều trị căn bệnh này.
Bệnh tiểu đường là một căn bệnh chịu ảnh hưởng của nhiều yếu tố. Tiểu đường gây ra do tác động phức tạp giữa gene và các yếu tố môi trường, từ đó dẫn tới sự bất bình thường trong quá trình điều hoà lượng glucose trong cơ thể liên quan tới những vấn đề về hormone insulin.
Insulin là một hormone được tiết ra bởi tế bào beta trong đảo Langerhans của tuyến tụy khi động vật tiêu ăn thức ăn, đây là hormone quan trọng nhất cho quá trình lưu trữ, sử dụng đường, acid amin và acid béo và duy trì lượng đường trong máu. Hàm lượng đường trong máu (hay còn gọi là hàm lượng glucose trong máu) là nguồn năng lượng thiết yếu cho cơ thể. Nếu lượng đường trong máu không duy trì ở mức bình thường có thể gây ra những căn bệnh nguy hiểm. Hàm lượng đường trong máu tăng có thể gây ra sự bài tiết đường qua nước tiểu, kết quả là bị mất glucose, hiện tượng này còn gọi là bệnh tiểu đường. Nếu tình trạng này tiếp diễn trong thời gian dài, sẽ gây ra những biến chứng nguy hiểm trong mô, các cơ quan của cơ thể. Mặt khác, hàm lượng đường trong máu giảm dẫn đến năng lượng cung cấp cho cơ thể bị thiếu hụt gây nguy hiểm cho sự duy trì cơ thể sống.
Hàm lượng đường trong máu được duy trì ở mức bình thường là do sự cân bằng giữa các yếu tố làm tăng lượng đường trong máu (như glucagon, hormone, cortisol, catecholamine) với các yếu tố làm giảm lượng đường trong máu. Insulin là hormone duy nhất có thể làm giảm lượng đường trong máu. Do đó, khi khả năng tiết hormone này giảm đi (do một số nguyên nhân) thì insulin không cung cấp đủ cho cơ thể gây ra bệnh tiểu đường phụ thuộc insulin (Insulin-Dependent Diabetes Mellitus - IDDM), còn gọi là tiểu đường type I. Với những bệnh nhân mắc tiểu đường type I thì insulin là phương thuốc điều trị duy nhất.
Insulin người là một polypeptide bao gồm một chuỗi A với 21 acid amin và một chuỗi B với 30 acid amin, có một cầu nối disulfur trong chuỗi A và 2 cầu nối disufur nối giữa hai chuỗi A và B. Insulin ban đầu được tổng hợp ở dạng “preproinsulin” (tiền insulin) trên ribosome trong tế bào beta trong đảo Langerhans của tuyến tụy. Preproinsulin là một phân tử dạng thẳng bao gồm: một peptide tín hiệu chứa 24 acid amin (SP), chuỗi B, peptide C với 31 acid amin (C) và chuỗi A nối với nhau theo thứ tự SP-B-C-A. Khi vận chuyển qua lưới nội chất, peptide tín hiệu bị phân cắt tạo ra proinsulin (B-C-A). Proinsulin hình thành cầu nối disulfur trong lưới nội chất, hình thành cấu trúc bậc ba. Proinsulin bị phân cắt bởi enzyme PC1/3 tại liên kết giữa chuỗi B và peptide C và sau đó bị phân cắt bởi enzyme PC2 ngay vị trí liên kết giữa chuỗi A và peptide C. Hai acid amin đầu N của peptide nối với đầu C của chuỗi B khi bị phân cắt bởi PC1/3 sẽ được phân cắt ra khỏi chuỗi B bởi enzyme carboxypeptidase H. Kết quả cuối cùng của quá trình phân cắt tạo thành insulin.
Hình 1. Cấu trúc của phân tử insulin
Trong năm 2005, nhu cầu insulin dùng trong trị bệnh tiểu đường ước tính khoảng 4.000 đến 5.000 kg và dự kiến năm 2010 là 16.000 kg. Nhu cầu về insulin của thế giới vượt qua con số vài tấn/năm và vì thế nguồn cung cấp insulin cho trị bệnh tiểu đường đang thiếu hụt. Từ những thập niên 1920 cho đến những năm đầu của thập niên 1980, insulin được tạo ra bằng cách cô lập từ tuyến tụy của động vật như heo và bò. Tuy nhiên, insulin người có sự khác biệt trong thành phần acid amin so với insulin bò (hai vị trí trong chuỗi A và một vị trí trong chuỗi B) và insulin heo (một vị trí trong chuỗi B). Do đó gây ra những tác dụng không mong muốn (như dị ứng) khi sử dụng insulin có nguồn gốc từ heo hay bò. Ngoài ra, quá trình sản xuất và tinh sạch insulin từ động vật còn gặp nhiều khó khăn. Sau đó, các phương pháp bán tổng hợp insulin người từ insulin heo và bò đã được phát triển bằng các sử dụng phản ứng chuyển peptide (transpeptidation) sử dụng trypsin. Tuy nhiên, insulin tái tổ hợp được sản xuất bằng công nghệ tái tổ hợp di truyền hiện đang được sử dụng chủ yếu do chi phí sản xuất thấp và hiệu quả sản xuất cao. Insulin người được sản xuất bằng kỹ thuật di truyền đầu tiên tạiCông ty Genetech (Hoa Kỳ) và sản phẩm này được đưa ra thị trường vào năm 1982. Trong lịch sử, đây cũng là lần đầu tiên các nhà nghiên cứu ứng dụng công nghệ sinh học vào dược phẩm thành công.
Về sau, nhiều phương pháp sản xuất insulin tái tổ hợp đã được phát triển. Ví dụ: phương pháp sản xuất của Tập đoàn Eli Lilly: phương pháp sản xuất này biểu hiện chuỗi A và chuỗi B riêng biệt bằng cách sử dụng Escherichia coli, sau đó thu chuỗi A và chuỗi B, trộn với nhau in vitro tạo cầu nối disulfur. Phương pháp này có hiệu quả sản xuất thấp. Do đó, Eli Lilly phát triển một phương pháp cải tiến hơn, phương pháp này biểu hiện proinsulin thay vì biểu hiện chuỗi A và B riêng biệt như phương pháp cũ, tạo cầu nối disulfur in vitro, sau đó phân cắt peptide C khỏi hai chuỗi A và B bằng trypsin và carboxypeptidase, tạo thành insulin.
Hình 2. Sản xuất insulin tái tổ hợp với chuỗi A và chuỗi B riêng biệt
Một phương pháp khác được phát triển bởi tập đoàn Novo Nordisk, phương pháp này biểu hiện miniproinsulin bao gồm chuỗi B và chuỗi A nối với nhau bằng 2 acid amin, được biểu hiện trong nấm men, sau đó xử lý miniproinsulin in vitro bằng trypsin tạo thành insulin. Phương pháp này có nhiều thuận lợi như cầu nối disulfur được hình thành trong quá trình biểu hiện và quá trình tiết miniproinsulin, và miniproinsulin này được tách chiết và tinh sạch dễ dàng do được tiết thẳng ra môi trường nuôi cấy.
Hiện tại, người ta vẫn tiếp tục phát triển những phương pháp sản xuất insulin tái tổ hợp. Công ty Hoechst đã đưa ra một phuơng pháp sản xuất insulin bao gồm: biểu hiện một dạng dẫn xuất mới của insulin hoặc biểu hiện preproinsulin trong E. coli; tạo các cầu nối disulfur invitro; sau đó, xử lý bằng lysylendopeptidase hoặc clostripain/carboxypeptidase B; cuối cùng tạo ra insulin.
Mới đây nhất, Công ty Bio-Technology General đã đưa ra một phương pháp mới. Trong phương pháp này, một dạng protein dung hợp (fusion protein) bao gồm superoxide dismutase (SOD) gắn với proinsulin được biểu hiện trong tế bào E. coli. Bằng cách này, hiệu suất của quá trình biểu hiện protein và hiệu quả của quá trình hình thành các cầu nốii. Sau đó, proinsulin được chuyển thành insulin nhờ xử lý với trypsin và carboxypeptidase B. Bằng những cách tương tự như thế, người ta đã đưa ra ngày càng nhiều các phuơng pháp sản xuất insulin tái tổ hợp và cải tiến nhièu hơn để nâng cao hiệu quả của các quá trình biểu hiện protein, hình thành cầu nối disulfur, chuyển proinsulin thành insulin.
Hình 3. Sản xuất insulin tái tổ hợp trên vi khuẩn
Hiện nay, hầu hết những phương pháp sản xuất insulin thương mại đều dựa trên các chủng nấm men (Saccharomyces cerevisiae) hoặc vi khuẩn (E. coli) kết hợp với các kỹ thuật gene để sản xuất insulin người tổng hợp. Người ta nuôi cấy các chủng này trên quy mô lớn, trong những bồn lên men bằng thép đặt tiền, sau đó, insulin được ly trích ra, tinh sạch để được sản phẩm cuối cùng.
Nói về các hệ thống tế bào dùng để biểu hiện insulin tái tổ hợp, người ta sử dụng rất đa dạng từ vi sinh vật tới tế bào động vật và cả thực vật. Trong số đó, tế bào vi sinh vật được sử dụng nhiều nhất do chúng dễ thao tác, dễ đưa vào áp dụng ở quy mô sản xuất công nghiệp, nhiều nhất là E. coli và nấm men. Gần đây, người ta đưa ra một hệ thống biểu hiện khác cho các loại protein tái tổ hợp – đó là Bacillus brevis.
Mục đích của những nghiên cứu, phát minh hiện tại là muốn phát triển một hệ thống biểu hiện và 1 phương pháp sản xuất insulin có năng suất cao và hiệu quả sản xuất phải ngang bằng hay vuợt trội hơn so với những hệ thống sản xuất insulin đã từ trước tới nay. Hay nói cách khác, các nghiên cứu trong giai đoạn này nhằm cải tiến phương pháp cổ điển chuyển các tiền chất của insulin thành insulin; nghiên cứu tìm ra môi trường tối ưu cho việc hình thành các cầu nối cần thiết cho việc biểu hiện hoạt tính của insulin; tìm ra một hệ thống biểu hiện insulin cho năng suất, sản luợng cao.
T.T.T. Hằng (tổng hợp)
Nguồn:
- http://www.sembiosys.com/news2.aspx?id=5189&secId=6
- http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html
- Insulin and Insulin analogues, Philippe Cramer, MD - France Biotech, Julien Martinet, D pham - France Biotech, Text reviewed by Helen Mosnier-Pudar, MD Unité de diabétologie, hôpital Cochin, Paris
- Insulin resistance and pancreatic b cell failure, Masato Kasuga, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Tiểu đường và việc điều trị bằng insulin
Insulin là một hormon quan trọng, giúp cơ thể hấp thu glucose - một trong những thành phần chính cung cấp năng lượng cho con người.
Vai trò của Insulin
Những người bị mắc tiểu đường tuýp 1 thường không sản sinh đủ lượng insulin trong cơ thể vì vậy phải có insulin thay thế để điều trị bệnh. Nếu như không cung cấp đủ insulin thay thế thì những người mắc tiểu đường tuýp 1 sẽ bị đường trong máu cao và cơ thể chuyển sang đốt cháy các chất béo dự trữ. Trong một vài ngày liên tục như thế sẽ dẫn đến nhiễm axit tiểu đường và tính mệnh bị đe doạ.
Còn ngược lại nếu quá nhiều insulin thì sẽ khiến đường trong máu thấp, dẫn tới bệnh hypoqlycaemia (ngất xỉu, hôn mê). Triệu chứng phổ biến gồm da nhợt nhạt, hay sửng sốt bàng hoàng, run rẩy, đổ mồ hôi, nhịp tim đập nhanh, hay đói, hay lo lắng và mắt bị mờ đi. Trong một số trường hợp có thể dẫn đến mất ý thức, hôn mê, co giật.
Tiểu đường tuýp 2 thì không thiếu sự sản sinh insulin nhưng các tế bào cơ thể ngày càng đề kháng lại ảnh hưởng của insulin. Trong những năm đầu, cơ thể bù đắp được insulin đề kháng bởi sản sinh insulin từ tuyến tuỵ. Tuy nhiên, những năm tiếp theo thì tuyến tuỵ không còn khả năng bù đắp được nữa và khoảng 25% người mắc tiểu đường tuýp 2 cuối cùng vẫn cần phải điều trị bằng insulin.
Đặc điểm
Có 4 loại insulin chính dùng để tiêm và loại insulin thường dùng sẽ phụ thuộc vào sự thích nghi của từng người và lối sống của họ
- Loại insulin có tác dụng ngắn: Ví dụ loại Actrapid và Velosulin bắt đầu có hiệu quả từ 30 đến 60 phút đầu và kéo dài từ 6 đến 8 tiếng. Loại insulin aspart, insulin lispro và insulin qlulisine thì có tác dụng sau 15 phút và kéo dài trong 4 tiếng.
- Loại insulin có tác dụng trung bình: Loại này có hiệu quả sau 1 đến 2 giờ đầu và kéo dài từ 10 đến 14 tiếng như Humulin I và Insulatard.
- Insulin có tác dụng lâu: Bắt đầu có tác dụng sau 1 đến 2 tiếng và kéo dài 24 tiếng. Đó là loại insulin zinc suspension, protamine zinc insulin hoặc insulin qlarqine và insulin detemir.
- Insulin pha trộn: là loại được trộn lẫn giữa insulin có tác dụng ngắn và loại có thời gian trung bình với tỷ lệ khác nhau như 30/70 hoặc 50/50 như loại NovoMix 30, Humulin M3, Insuman comb và Humaloq Mix25.
Sản phẩm insulin nuốt khí được bắt đầu áp dụng ở Hoa Kỳ vào tháng 8 năm 2006. Nó có tác dụng ngắn, hiệu quả sau 10 đến 20 phút và kéo dài 6 tiếng.
Cách sử dụng
Có 3 chế độ:
1. Liều lượng hai lần một ngày cho loại có tác dụng ngắn và trung bình
- Dùng trước bữa ăn sáng và ăn tối
- Liều lượng insulin tác dụng ngắn có hiệu quả vào buổi sáng và tối
- Loại trung bình có hiệu quả vào buổi chiều và đêm.
- Hai loại insulin này rất thích hợp khi trộn lẫn với nhau
2. Dùng 3 lần trong một ngày
- Sử dụng loại có tác dụng ngắn và trung bình trước bữa ăn sáng
- Loại tác dụng ngắn dùng trước bữa ăn tối
- Loại tác dụng trung bình dùng trước khi đi ngủ
3. Liều lượng dùng nhiều lần trong ngày
- Loại insulin có tác dụng ngắn được sử dụng trước mỗi bữa ăn
- Loại trung bình và loại có tác dụng lâu được sử dụng trước khi đi ngủ
Có nhiều loại chế độ sử dụng khác nhau ví dụ bệnh tiểu đường đối với một số người già có thể tiêm hàng ngày loại insulin có tác dụng lâu.
Điều trị bằng truyền insulin đôi khi được sử dụng đối với người trẻ bị mắc tiểu đường.
Những loại tiêm phức tạp ngày càng được ưa sử dụng vì chúng có tính linh hoạt và giống loại insulin tự nhiên trong cơ thể
Tuy nhiên chế độ ăn uống và liều lượng sử dụng thuốc phụ thuộc vào từng cá nhân nên bạn phải cùng bác sĩ tìm ra sự kết hợp giữa thuốc và chế độ ăn để điểu chỉnh được lượng đường trong máu một cách tốt nhất.
Insulin tiêm
Insulin được khử hoạt tính bởi enzym tiêu hoá trong ruột mà không phải do tuyến nước bọt ở miệng vì vậy insulin thường được sử dụng để tiêm dưới da và thường tiêm ở bắp đùi, mông, bụng hoặc trên cánh tay. Loại kim dùng để tiêm rất nhỏ và sau khi đã quen bạn có thể tự tiêm lấy hoặc hỏi những người bị mắc tiểu đường, họ sẽ dạy bạn cách tiêm.
Lưu ý:
- Bạn nên sử dụng loại insulin có tác dụng ngắn tiêm dưới da bụng
- Loại trung bình và lâu thì tiêm ở đùi
- Loại insulin trộn lẫn có thể tiểm ở cả đùi và bụng.
- Nên luân phiên vị trí tiêm để tránh chỗ bị tiêm nhiều làm mô mỡ sẽ dầy lên gây chai cứng da và đau
- Tập thể dục sau khi tiêm có thể sẽ làm tăng tốc độ insulin chảy trong máu.
Insulin nuốt khí
Insulin nuốt khí đã được dùng để điều trị tiểu đường nhưng nó không phù hợp và phổ biến cho tất cả mọi người.
Chỉ có loại insulin tác dụng ngắn được dùng còn hầu hết những người mắc tiểu đường tuýp 1 sẽ vẫn cần phải tiêm insulin có tác dụng trung bình và lâu.
Insulin nuốt khí không thể sử dụng cho những người hút thuốc, bị bệnh về phổi như hen suyễn vì nó ảnh hưởng lâu dài đến phổi.
Viện sức khoẻ và lâm sàng quốc gia (NICE) đã khuyến cáo cho những người nào nên sử dụng loại insulin nuốt khí như những người mắc bệnh bồn chồn, ám ảnh hoặc những người mắc vấn đề dài dẳng với chỗ bị tiêm.
Mục đích điều trị insulin
Mục đích điều trị bệnh tiểu đường bằng insulin không giống nhau đối với mỗi người.
Ở những người trẻ, trung tuổi với mong muốn kéo dài tuổi thọ thì việc điều trị bệnh tiểu đường tốt sẽ làm giảm những biến chứng trong thời gian dài. Nhưng điều này đòi hỏi bác sĩ phải giám sát chặt chẽ và cơ thế có thích nghi với bệnh tiểu đường hay không.
Điều chỉnh mức độ đường glucose trong máu ở tiếu đường tuýp 1 tốt nhất ở mức từ 4mmol/l đến 7mmol/l.
Với người già hoặc những người mắc bệnh nặng có thể không thích hợp để điều trị bằng insulin thay vì vậy cần điều chỉnh các triệu chứng tiểu đường bằng cách giảm lượng đường trong máu xuống mức 10mmol/l sẽ khiến bệnh nhân không còn cảm thấy bị khát nước hoặc muốn đi tiểu.
Minh Anh
Theo Netdoctor
Việt Báo
ProtScale
ProtScale allows you to compute and represent the profile produced by any amino acid scale on a selected protein.
An amino acid scale is defined by a numerical value assigned to each type of amino acid. The most frequently used scales are the hydrophobicity or hydrophilicity scales and the secondary structure conformational parameters scales, but many other scales exist which are based on different chemical and physical properties of the amino acids. This program provides 57 predefined scales entered from the literature.
Link to ProtScale: http://www.expasy.ch/tools/protscale.html
An amino acid scale is defined by a numerical value assigned to each type of amino acid. The most frequently used scales are the hydrophobicity or hydrophilicity scales and the secondary structure conformational parameters scales, but many other scales exist which are based on different chemical and physical properties of the amino acids. This program provides 57 predefined scales entered from the literature.
Link to ProtScale: http://www.expasy.ch/tools/protscale.html
Atomic mass unit
The unified atomic mass unit (u), or dalton (Da) or, sometimes, universal mass unit, is a unit of mass used to express atomic and molecular masses. It is the approximate mass of a hydrogen atom, a proton, or a neutron.
Detail: http://en.wikipedia.org/wiki/Atomic_mass_unit
Detail: http://en.wikipedia.org/wiki/Atomic_mass_unit
Beginner’s Guide to Bioinformatics
As a computer scientist coming into Bioinformatics I was faced with the heavy task of catching up on my Biology and Chemistry (I was a Physics minor in undergrad but that wasn’t applicable to my Bioinformatics catch up). This meant two semesters of General Chemistry, a semester of Organic Chemistry and a semester of Cell Biology. Though all this course work was very educational and useful for my degree I don’t think its all that necessary for a someone who may be interested in fooling around with Bioinformatics problems on the side.
Here is a very general overview of cell biology for Non-Biologists wanting to get involved in Bioinformatics:
- Proteins are the essential part of all living organisms. Proteins have a variety of functions and are involved in every process within our cells. [Wikipedia]
- DNA is the blueprint for proteins. Segments of DNA (genes) translate into proteins. For more detail look into the Translation and Transcription of DNA to proteins.
- Cell function is determined by which proteins are expressed and their quantity. This means that some kind of gene regulation must take place. Also one can argue if you know the amount of genes expressed in a cell you can possibly infer that cells function.
For a more specific overview, the following are some of the essential key points for biology and bioinformatics:
- Genome - all the DNA in a cell.
- DNA - a string of nucleic acids (i.e. GATCACTT…ATCG).
- Gene - a substring of DNA that encodes proteins.
- Proteins - a string of amino acids (i.e. ACDEF…RSTY).
- Gene expression is regulated by the product of other genes. It is a network of interactions.
- Post-translation modifications are an important regulation mechanism for gene expression.
You may notice that the above deals quite a bit with string manipulation, hence the strong emphasis for Perl experience in Bioinformatic job postings. You will find that string manipulation is not the only driving force for computer science in Bioinformatics. I will try to explain other topics in subsequent posts.
As for Biologists wanting to do Bioinformatics I can not provide the best advice since I didn’t come into Bioinformatics from that direction but I would imagine that you may want to look into the following:
- Learn how to program. You want to know how to use a scripting language (preferably Perl) for smaller every day tasks and an object-oriented language such as C, C++, or Java for larger projects.
- Learn how to use databases. Bioinformatics deals with very large datasets. At some point your are going to have to deal with either retrieving information from databases or building your very own database so you might as well begin playing with them now.
- Install and run a Unix/Linux OS (Optional). This might be my personal bias but I believe if you are going to be working in Bioinformatics and its large data sets eventually you will find yourself either maintaining a server or SSHing into one so you might as well become familiar with that type of environment. At the very least XP users should install Cygwin.
Useful Links:
- Bioinformatics intro offered at my university.
- Graduate level of the Bioinformatics intro course.
- Library of videos that cover a wide range of biological topics (theoretical and practical).
- RT-PCR a common molecular biology method practiced in the lab.
- Virtual lab which provides a virtual lab for non-biologists to actually work through basic molecular biologist techniques.
Finally I must say that I am far from an expert so any constructive suggestions to help clarify or expand the above is welcomed and appreciated.
Souce: http://biowhat.com/2007/03/13/begginers-guide-to-bioinformatics/
Friedreich Ataxia
Introduction
Background
Friedreich ataxia (FA, FRDA, FRIEDREICH ATAXIA 1, OMIM# *229300) is an autosomal recessive ataxia resulting from a mutation of a gene locus on chromosome 9. It was first described in 1863 by Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany.
FA was the earliest of the inherited ataxias to be distinguished from other locomotor ataxias and is the most common of the autosomal recessive ataxias. It accounts for at least 50% of cases of hereditary ataxias in most large series. Cardinal features include progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs, and extensor plantar responses.
For related information see eMedicine articles Neuropathy of Friedreich Ataxia in Neurology and Friedreich Ataxia in Orthopedic Surgery.
Pathophysiology
The major pathophysiologic finding in Friedreich ataxia is a "dying back phenomena" of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis. The primary sites of these changes are the spinal cord and spinal roots. This results in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared.
The posterior columns and corticospinal, ventral, and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents. This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers. Overall, the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells. The posterior column degeneration accounts for the loss of position and vibration senses and the sensory ataxia. The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes.
Large neurons of the dorsal root ganglia, especially lumbosacral, and nerve cells in the Clarke column are reduced in number. The posterior roots become thin. The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size. Patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei is typical. Mild degenerative changes occur in the pontine and medullary nuclei and optic tracts. The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts and involvement of the Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways.
The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Beyond this point, the corticospinal tracts are severely degenerated, which becomes progressively more severe moving down the spinal cord. This explains the common finding of bilateral extensor plantar responses and weakness late in the disease.
Loss of cells in the nuclei of cranial nerves VII, X, and XII results in facial weakness and speech and swallowing difficulties.
Myocardial muscle fibers also show degeneration and are replaced by macrophages and fibroblasts. Essentially, chronic interstitial myocarditis occurs with hypertrophy of cardiac muscle fibers; fibers become hypertrophied and lose their striations. This is followed by swelling and vacuolation and finally interstitial fibrosis. The nuclei appear hyperchromatic and occasionally vacuolated. The cytoplasm appears granular with frequent lipofuscin depositions.
Kyphoscoliosis is likely; it is secondary to spinal muscular imbalance.
Frequency
International
Friedreich ataxia is a relatively common disorder. It is the most common autosomal recessive ataxia, accounting for approximately 50% of all cases of hereditary ataxia. Estimates of incidence range anywhere from 1 in 22,000 to 2 in 100,000, with most studies yielding an incidence among Europeans and North Americans of European descent of approximately 1.5 per 100,000 per year; a slightly higher incidence has been reported in Quebec.
Overall, the FA carrier rate has been estimated recently to be 1 in 60 to 1 in 90 with a disease prevalence of 1 per 29,000.
Mortality/Morbidity
Friedreich ataxia is a progressive disorder with significant morbidity. Loss of ambulation typically occurs 15 years after disease onset. More than 95% of patients are wheelchair bound by age 45 years.
In a series by Harding et al, the average age of death was 37.7 years±14.4 years (range, 21-69).1
Race
Friedreich ataxia is most prevalent in white populations. Most FA carriers and affected FA patients are believed to originate from a common European ancestor who lived more than 10,000 years ago. Frataxin gene expansions are therefore almost nonexistent among black African and Asian populations.
Age
* The onset of Friedreich ataxia is early; it typically presents in children aged 8-15 years and almost always presents before age 20 years.
* In a study by Harding et al, the mean onset of symptoms occurred at age 10.52±7.4 years (range, 1.5-27).1
Clinical
History
* Onset of Friedreich ataxia (FA) is early, with gait ataxia being the usual presenting symptom. Typically, both lower extremities are affected equally. Some patients may have hemiataxia initially before the symptoms become generalized. In some instances, the ataxia begins abruptly following a febrile illness in which ataxia of one lower extremity precedes that of the other.
o Gait ataxia manifests as progressively slow and clumsy walking, which often begins after normal walking has developed. The ataxia may be associated with difficulty standing and running.
o The gait ataxia is both of a sensory and cerebellar type. This combination has been referred to as a tabetocerebellar gait. Opinions are conflicting as to whether the sensory or cerebellar features predominate.
o The cerebellar features of gait ataxia in FA include a wide-based gait with constant shifting of position to maintain balance. Sitting and standing are associated with titubation.
o The sensory ataxia resulting from a loss of joint position sense contributes to the wide-based stance and gait but a steppage gait also is present, characterized by uneven and irregular striking of the floor by the bottom of the feet. Attempts to correct any imbalance typically result in abrupt and wild movements.
o As the disease progresses, ataxia affects the trunk, legs, and arms. As the arms become grossly ataxic, both action and intention tremors may develop. Titubation of the trunk may appear. Facial, buccal, and arm muscles may become tremulous and occasionally display choreiform movements. The patient may experience easy fatigability.
* Patients with advanced FA may have profound distal weakness of the legs and feet, although significant weakness of the arms is rare before the patient becomes bedridden. Eventually, the patient is unable to walk because of the progressive weakness and ataxia, becoming wheelchair bound and ultimately bedridden.
* With disease progression, dysarthria and dysphagia appear. Speech becomes slurred, slow, and eventually incomprehensible. Patients may experience mild weakening of the facial muscles with associated weakness of swallowing. Incoordination of breathing, speaking, swallowing, and laughing may result in the patient nearly choking while speaking.
* Family history
o FA is characterized by autosomal recessive inheritance. In families with one affected child, the subsequent risk of another affected child is 25%. As in most recessive disorders, the risk of developing FA is highest following birth from a consanguineous union. In North America and Europe, however, most cases are sporadic and occur in nonconsanguineous families.
o The overall risk of a patient with FA having a child with the condition is approximately 1 in 200, unless consanguinity is involved. If that same patient has a partner who is found to be a carrier of FA, then the risk becomes 1 in 2. Children descended from the unaffected sibling of a patient with FA and a nonconsanguineous spouse have a 1:1000 risk of developing FA.
o Carrier testing is available for relatives of affected patients and their partners. However, the small risk of a point mutation also must be taken into account and incorporated into genetics counseling.
o Prenatal diagnosis via direct mutation testing is also available.
Physical
See Staging for a scale used to rate functional disability in patients with Friedreich ataxia.
* The cardinal features of FA are as follows:
o Progressive limb and gait ataxia develops before the age of 30 years.
o Lower extremity tendon reflexes are absent.
o Evidence of axonal sensory neuropathy is noted.
o Dysarthria, areflexia, motor weakness of the lower extremities, extensor plantar responses, and distal loss of joint position and vibration senses are not found in all patients within the first 5 years, but are eventually universal.
o Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are other common characteristics. Clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds may be noted.
* Physical findings in patients with FA include gradual loss of vibratory and position senses from the onset, initially affecting the feet and hands. With progression, light touch, pain, and temperature sensation also may be diminished. Two-point discrimination may be affected in early cases.
* Tendon reflexes are absent in almost all cases but may be weakly present if the patient is examined early in the course of the disease. Patellar and ankle jerks are affected most profoundly. Flexor spasms are common even in the absence of tendon reflexes, indicating that the areflexia is sensory in origin. Plantar reflexes are extensor in 90% of patients and absent in the rest. Abdominal reflexes usually are retained until late in the disease process.
* Distal wasting, primarily of the upper extremities, is seen in 50% of patients. Muscle tone is usually normal or decreased. Sphincter control is usually intact but cases of urinary urgency and constipation, which are not usually severe, have occurred.
* Kyphoscoliosis is a frequent but nonspecific finding that may be severe. With early onset, severe scoliosis can produce significant cardiopulmonary morbidity and death due to restricted respiratory function. Peripheral cyanosis of the lower limbs is common.
* Foot deformities such as high plantar arches, foot inversion, and hammertoes may precede the gait ataxia. Typically, 50% of patients develop either pes cavus or varus deformities of one or both feet.
* Visual acuity rarely is affected, but optic atrophy occurs in 25% of patients with FA and has resulted in occasional blindness. Visual evoked potentials (VEP) are abnormal in two thirds of patients, typically displaying reduced amplitude and delayed latency.
* Nystagmus of various types may be found. Horizontal nystagmus, present in the primary position and increased on lateral gaze, occurs in 20% of patients with FA. Extraocular movements usually are affected and are characterized by abnormal square-wave jerks and saccadic pursuit, poor fixation, and impaired vestibulo-ocular reflexes. Pupillary reflexes are normal.
* Deafness has been noted, in some cases in association with vertigo. Brain stem auditory evoked responses (BAER) are typically consistent with central auditory pathway pathology.
* Hypertrophic cardiomyopathy develops in more than 50% of patients. Myocarditis, myocardial fibrosis, cardiac enlargement, progressive cardiac failure, tachycardias, and heart block also may be seen. Cardiac arrhythmia and congestive heart failure contribute to a significant number of deaths in patients with FA.
* Approximately 10% of patients with FA develop diabetes mellitus. An even larger percentage demonstrate impaired glucose tolerance, which has been associated with an insulin receptor abnormality.
* Mental retardation, psychosis, and dementia are uncommon, but some degree of cognitive dysfunction may occur. Emotional lability, in the presence of normal cognitive function, is frequently present.
Causes
Classic Friedreich ataxia is the result of a gene mutation at the centromeric region of chromosome 9 (9q13-21.1) at the site of the gene encoding for the 210-amino-acid protein frataxin. This mutation is characterized by an excessive number of repeats of the GAA (guanine adenine adenine) trinucleotide DNA sequence in the first intron of the gene coding for frataxin. It is the only disease known to be the result of a GAA trinucleotide repeat. This expansion alters the expression of the gene, decreasing the synthesis of frataxin protein. The expanded GAA repeat is thought to result in frataxin deficiency by interfering with transcription of the gene by adopting an unstable helical structure. The larger the number of repeats, the more profound is the reduction in frataxin expression. A recent study from Stolle and colleagues have shown that interrupted GAA repeats do not clearly impact the age of onset in FA.2
* In a normal chromosome, this trinucleotide sequence is repeated up to 50 times. In patients with FA, this sequence is repeated at least 200 times and often more than 1000 times.
* Variability in the clinical presentation of FA may be explained by the extent of this trinucleotide repeat expansion. The age of disease onset, its severity, rate of progression, and extent of neurological involvement vary with the number of repetitive GAA sequences.
o In addition, the frequency of extensor plantar responses, cardiomyopathy, leg weakness and wasting, sclerosis, and pes cavus increased with the size of the GAA expansion.
o Larger GAA expansions correlated with earlier age of onset and shorter times to loss of ambulation.
* In a recent study by Durr et al, the large majority of patients with FA (94%) were homozygous for the GAA trinucleotide (the GAA expansion was present on both alleles of the frataxin gene). The remaining 6% were compound heterozygotes for a GAA expansion and a frataxin point mutation (one allele had a GAA expansion, and the other had a point mutation with no expansion). No patients have been described who were homozygous for a point mutation.3
* Point mutations not only reduce levels of the frataxin protein but are also responsible for the creation of abnormal protein. They also represent another source of variability in the clinical presentation of FA. Seventeen different point mutations have so far been described in FA.
o Between 1% and 5% of the point mutations are single base changes in the sequence of the FA gene causing missense, nonsense, or splicing mutations. Patients with missense mutations displayed either mild or severe symptoms, whereas splicing, nonsense, and initiation codon mutations, associated with nonfunctional frataxin, result in a severe phenotype.
o Point mutations of the frataxin gene involving the amino terminal typically present with a more benign course than those of the carboxy terminal.
o The 3 most common point mutations are the Il54F mutation among southern Italians, the ATG>ATT mutation of the start codon, and the G130V mutation. Patients with the G130V mutation tend to have slower disease progression, brisk knee reflexes, and minimal dysarthria.
* Cells and tissues of the body are differentially sensitive to frataxin deficiency. Cells normally requiring and producing greater amounts of frataxin tend to be most affected by FA. For example, sensory neurons in the dorsal root ganglion responsible for position sense highly express the frataxin gene and are affected greatly in FA. Myocardial muscle fiber also requires comparably larger amounts of frataxin than other tissues and is affected markedly in FA.
* A number of experiments have confirmed the mitochondrial subcellular localization of frataxin in mammals. Frataxin has been shown to be essential for normal mitochondrial function, both for oxidative phosphorylation and iron homeostasis. Strong evidence exists that frataxin deficiency results in iron accumulation within mitochondria of affected cells in cell culture lines. Apparently, the rate of mitochondrial export is reduced. Hearts of patients with FA have revealed mitochondrial ironlike deposits that are not present in healthy hearts.
* The excessive mitochondrial accumulation of iron affects cytosolic iron levels. Excess intracellular iron stimulates the increased generation of free radicals and mitochondrial damage. Iron excess inactivates mitochondrial enzymes essential for the production of adenosine triphosphate (ATP). Cell death, particularly of neurons of the spinal cord and peripheral nervous system, ensues. A mouse model of FA is being developed to confirm evidence of this process in living animal models.
Differential Diagnoses
Other Problems to Be Considered
Refsum disease
Abetalipoproteinemia
Ataxia with isolated vitamin E deficiency
Spinocerebellar ataxia (SCA) types 1, 2, 3
Dentatorubropallidoluysian atrophy
Hereditary motor and sensory neuropathies
Workup
Laboratory Studies
* Genetic counseling is available for prenatal diagnosis of Friedreich ataxia for parents with one affected child. Population screening for carriers of the defective gene is not practical. A specific trinucleotide repeat expansion assay is available commercially in the United States and should be performed in all suspected cases of FA.
* No evidence of CSF abnormality exists in patients with FA.
Imaging Studies
Magnetic resonance imaging (MRI) is the study of choice in the evaluation of the atrophic changes seen in Friedreich ataxia. MRI of the brain and spinal cord in patients with FA consistently shows atrophy of the cervical spinal cord with minimal evidence of cerebellar atrophy.
Other Tests
* Echocardiography reveals symmetric, concentric ventricular hypertrophy, although some have asymmetric septal hypertrophy.
* Approximately 65% of patients with FA have abnormal ECG findings. The most common findings are T-wave inversion, particularly in the inferior standard and lateral chest leads, and ventricular hypertrophy.
* Nerve conduction velocity (NCV) study findings in FA usually are normal or display only mildly reduced velocities. Sensory nerve action potentials (SNAP) are absent in greater than 90% of patients with FA. The remaining 10% display reduced-amplitude SNAPs.
* Brainstem auditory evoked responses are typically abnormal in FA, displaying absent waves III and IV with preservation of wave I. This is suggestive of involvement of central auditory pathways.
* Visual evoked potentials are abnormal in two thirds of patients with FA. Absent or delayed latency and reduced amplitude of the p100 wave are seen.
* Somatosensory evoked potentials (SSEP) reveal delayed central conduction time (N13a/N20, N13b/N20), dispersed potentials at the sensory cortex, as well as abnormal central motor conduction.
Histologic Findings
A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain). Milder involvement of spinocerebellar tracts is also present. The affected tracts show compact fibrillary gliosis on hematoxylin and eosin (H&E) stain but no breakdown products or macrophages, reflecting the very slow rate of degeneration and death of fibers. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (H&E). The posterior roots are nearly devoid of large myelinated fibers. Within the thoracic spinal cord, degeneration and loss of cells of the Clarke column are apparent.
Staging
International Cooperative Ataxia Rating Scale (World Federation of Neurology)
* Posture and gait disturbances
o Walking capacities: The patient's gait is observed during a 10-meter walking test, including a half turn, near a wall at about 1.5 meters.
+ 0 = Normal
+ 1 = Almost normal naturally, but unable to walk with feet in tandem position
+ 2 = Walking without support, but clearly abnormal and irregular
+ 3 = Walking without support, but with considerable staggering; difficulties in half turn
+ 4 = Walking with autonomous support no longer possible; the patient uses the episodic support of the wall for a 10-meter test
+ 5 = Walking possible only with 1 stick
+ 6 = Walking possible only with 2 special sticks or with a stroller
+ 7 = Walking only with accompanying person
+ 8 = Walking impossible, even with accompanying person (wheelchair)
+ Score ___
o Gait speed: Patients who scored 1-3 on the preceding test are observed for gait speed; those who scored 4 and up on the preceding test automatically score 4 in this test.
+ 0 = Normal
+ 1 = Slightly reduced
+ 2 = Markedly reduced
+ 3 = Extremely slow
+ 4 = Walking with autonomous support no longer possible
+ Score ___
o Standing capacities, eyes open: The patient is asked first to try to stand on one foot; if impossible, to stand with feet in tandem position; if impossible, to stand with feet together; for the natural position, the patient is asked to find a comfortable standing position.
+ 0 = Normal, able to stand on one foot for more than 10 seconds
+ 1 = Able to stand with feet together, but no longer able to stand on one foot for more than 10 seconds
+ 2 = Able to stand with feet together, but no longer able to stand with feet in tandem position
+ 3 = No longer able to stand with feet together, but able to stand in natural position without support, with no or moderate sway
+ 4 = Standing in a natural position without support, with considerable sway and considerable corrections
+ 5 = Unable to stand in natural position without strong support of one arm
+ 6 = Unable to stand at all, even with strong support of two arms
+ Score ___
o Spread of feet in natural position without support, eyes open: The patient is asked to find a comfortable standing position, then the distance between medial malleoli is measured.
+ 0 = Normal (spread <10 1 =" Slightly" 2 =" Clearly" 3 =" Severely">35 cm)
+ 4 = Standing in natural position impossible
+ Score ___
o Body sways with feet together, eyes open
+ 0 = Normal
+ 1 = Slight oscillations
+ 2 = Moderate oscillations (<10 3 =" Severe">10 cm at the level of head), threatening the upright position
+ 4 = Immediate falling
+ Score ___
o Body sways with feet together, eyes closed
+ 0 = Normal
+ 1 = Slight oscillations
+ 2 = Moderate oscillations (<10 3 =" Severe">10 cm at the level of head), threatening the upright position
+ 4 = Immediate falling
+ Score ___
o Quality of sitting position (thighs together, on a hard surface, arms folded)
+ 0 = Normal
+ 1 = With slight oscillations of the trunk
+ 2 = With moderate oscillations of the trunk and legs
+ 3 = With severe dysequilibrium
+ 4 = Impossible
+ Score ___
o Posture and gait score (static score) ___/34
* Kinetic functions
o Knee-tibia test (decomposition of movement and intention tremor): The test is performed in the supine position so that visual control is possible; the patient is requested to raise one leg and place the heel on the opposite knee, and then slide the heel down the anterior tibial surface toward the ankle; on reaching the ankle joint, the leg is raised again in the air to a height of approximately 40 cm and the action is repeated; at least 3 movements of each limb must be performed for proper assessment.
+ 0 = Normal
+ 1 = Lowering of the heel in continuous axis but the movement is decomposed in several phases, without real jerks, or abnormally slow
+ 2 = Lowering jerkily in the axis
+ 3 = Lowering jerkily with lateral movements
+ 4 = Lowering jerkily with extremely strong lateral movements or test impossible
+ Score right ___, Score left ___
o Action tremor in the heel-to-knee test: During the same test as the preceding one, the action tremor of the heel on the knee is observed specifically while the patient holds the heel on the knee for a few seconds before sliding it down the anterior tibial surface; visual control is required.
+ 0 = No trouble
+ 1 = Tremor stopping immediately when the heel reaches the knee
+ 2 = Tremor stopping in less than 10 seconds after reaching the knee
+ 3 = Tremor continuing for more than 10 seconds after reaching the knee
+ 4 = Uninterrupted tremor or test impossible
+ Score right ___, Score left ___
o Finger-to-nose test (decomposition and dysmetria): The subject sits in a chair; the hand is resting on the knee before the beginning of the movement; visual control is required; 3 movements of each limb must be performed for proper assessment.
+ 0 = No trouble
+ 1 = Oscillating movement without decomposition of the movement
+ 2 = Segmented movement in 2 phases and/or moderate dysmetria in reaching nose
+ 3 = Segmented movement in more than 2 phases and/or considerate dysmetria in reaching nose
+ 4 = Dysmetria preventing the patient from reaching nose
+ Score right ___, Score left ___
o Finger-to-nose test (intention tremor of the finger): The studied tremor is that appearing during the ballistic phase of the movement; the patient is sitting comfortably with the hand resting on his/her thigh; visual control is required; 3 movements of each limb must be performed for proper assessment.
+ 0 = No trouble
+ 1 = Simple swerve of the movement
+ 2 = Moderate tremor with estimated amplitude <10 3 =" Tremor" 4 =" Severe">40 cm
+ Score right ___, Score left ___
o Finger-finger test (action tremor and/or instability): The sitting patient is asked to maintain his/her index fingers pointing at each other for about 10 seconds, at a distance of 1 cm, at the level of the thorax, under visual control.
+ 0 = Normal
+ 1 = Mild instability
+ 2 = Moderate oscillations of the finger with estimated amplitude <10 3 =" Considerable" 4 =" Jerky">40 cm of amplitude
+ Score right ___, Score left ___
o Pronation-supination alternating movements: The subject, comfortably sitting on a chair, is asked to raise his/her forearm vertically and to make alternating pronating and supinating movements of the hand; each hand is moved and assessed separately.
+ 0 = Normal
+ 1 = Slightly irregular and slowed
+ 2 = Clearly irregular and slowed, but without sway of the elbow
+ 3 = Extremely irregular and slowed movements, with sway of the elbow
+ 4 = Movement completely disorganized or impossible
+ Score right ___, Score left ___
o Drawing of the Archimedes spiral on a predrawn pattern: The subject is comfortably settled in front of a table, sheet of paper being fixed to avoid artifacts; the subject is asked to perform the task without timing requirements; the same conditions of examination must be used at each examination (eg, same table, same pen); the dominant hand is examined.
+ 0 = Normal
+ 1 = Impairment and decomposition, the line quitting the pattern slightly but without hypermetric swerve
+ 2 = Line completely out of the pattern with recrossing and/or hypermetric swerves
+ 3 = Major disturbance due to hypermetria and decomposition
+ 4 = Drawing completely disorganized or impossible
+ Score ___
o Kinetic score (limb coordination) ___/52
* Speech disorders
o Dysarthria (fluency of speech): The patient is asked to repeat several times a standard sentence, always the same, for instance, "They heard him speak on the radio last night."
+ 0 = Normal
+ 1 = Mild modification of fluency
+ 2 = Moderate modification of fluency
+ 3 = Considerably slow and dysarthric speech
+ 4 = No speech
+ Score ___
o Dysarthria (clarity of speech)
+ 0 = Normal
+ 1 = Suggestion of slurring
+ 2 = Definite slurring, most words understandable
+ 3 = Severe slurring, speech not understandable
+ 4 = No speech
+ Score ___
o Dysarthria score ___/8
* Oculomotor disorders
o Gaze-evoked nystagmus: The subject is asked to look laterally at the finger of the examiner; the movements assessed are mainly horizontal, but they may be oblique, rotatory, or vertical.
+ 0 = Normal
+ 1 = Transient
+ 2 = Persistent but moderate
+ 3 = Persistent and severe
+ Score ___
o Abnormalities of the ocular pursuit: The subject is asked to follow the slow lateral movement performed by the finger of the examiner.
+ 0 = Normal
+ 1 = Slightly saccadic
+ 2 = Clearly saccadic
+ Score ___
o Dysmetria of the saccade: Two index fingers of the examiner are placed in each temporal visual field of the patient, whose eyes are in the primary position; the patient is then asked to look laterally at the finger, on the right and on the left; the average overshoot or undershoot of the 2 sides is then estimated.
+ 0 = Absent
+ 1 = Bilateral clear overshoot or undershoot of the saccade
+ Score ___
o Oculomotor movement score ___/6
* Total ataxia score ___/100
Treatment
Medical Care
The results of treating ataxia in Friedreich ataxia (FA) have generally been disappointing. No therapeutic measures are known to alter the natural history of the neurological disease. Standard treatment is administered for heart failure, arrhythmias, and diabetes mellitus.
High-dose propanolol has been described in a case report by Kosutic with reduction in thickness of the septal and posterior left ventricular walls and with complete normalization of diffuse electrocardiographic repolarization abnormalities.4
Li and colleagues have shown that therapeutic efforts should focus on an approach that combines iron removal from mitochondria with a treatment that increases cytosolic iron levels to maximize residual frataxin expression in patients with FA.5
The other therapies that have been used are as follows:
* 5-hydroxytryptophan
o 5-hydroxytryptophan is a serotonin precursor that has been used for a decade or more by Trouillas et al to treat various forms of ataxia with mixed results.6 This drug was known to suppress posthypoxic action myoclonus. The rationale for use of the drug in FA was that FA may in part be due to a cerebellar deficiency of serotonin.
o The results of a double-blind, cross-over study by Trouillas et al demonstrated that the levorotatory form of 5-hydroxytryptophan was able to significantly modify the cerebellar symptoms in patients with FA; however, the effect was only partial and not clinically major.6
o A study by Wessel demonstrated stabilization of posture in patients receiving long-term treatment with 5-hydroxytryptophan and a clear deterioration in patients who did not receive the treatment. This form of treatment requires further study.
* Coenzyme Q
o Coenzyme Q is an antioxidant that can buffer free radical formation that is induced by excess mitochondrial iron. A combined coenzyme Q (400 mg/d) and vitamin E (2100 IU/d) therapy has been used in a study of 10 patients with slowing of the progression of certain clinical features and a significant improvement in cardiac function.
o Experimental studies are underway to evaluate the use of coenzyme Q derivatives in limiting the toxicity of iron to mitochondrial structures.
* Idebenone: Di Prospero and colleagues have recently shown that higher doses of idebenone were generally well tolerated and associated with improvement in neurologic function and ADL in patients with FA.7 The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurologic function.
Surgical Care
Apart from surgery for scoliosis and foot deformities that may be helpful in selected cases, no significant surgical treatment is available for Friedreich ataxia. A study from Milbrandt and colleagues emphasized that in scoliosis braces were seldom effective and that segmental constructs are effective in creating substantial intraoperative correction and maintaining correction postoperatively.8
In addition, heart transplantation for FA dilated cardiomyopathy has been performed.
Consultations
Goulipian and colleagues have mentioned the role of orthopedic shoes combined with physical therapy. Their results demonstrated that orthopedic shoes improved gait disorders in a patient with Friedreich ataxia.9
Diet
No data exist to suggest that any alteration of diet would affect the onset, progression, or outcome of this disease.
Activity
No data exist to suggest that any alteration of activity level would affect the onset, progression, or outcome of this disease.
In regards to the delivery and utilization of oxygen in response to exercise, near infrared muscle spectroscopy may be an effective tool for monitoring the biochemical and functional features of FA.
Follow-up
Prognosis
* Health related quality of life (QOL) measures are potentially useful as clinical markers of disease status in Friedreich ataxia (FA).
* The prognosis of FA is poor.
* The disorder is progressive, with a mean duration of 15-20 years.
* More than 95% of patients are wheelchair bound by age 45 years.
* Commonly, patients survive to 25-30 years of age, although some patients have survived into the sixth and seventh decades, especially if they are free of heart disease and diabetes.
* QOL is significantly worse in these individuals compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, while increased disease duration was positively associated with mental QOL.10
Source: http://emedicine.medscape.com/article/1150420-overview
Background
Friedreich ataxia (FA, FRDA, FRIEDREICH ATAXIA 1, OMIM# *229300) is an autosomal recessive ataxia resulting from a mutation of a gene locus on chromosome 9. It was first described in 1863 by Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany.
FA was the earliest of the inherited ataxias to be distinguished from other locomotor ataxias and is the most common of the autosomal recessive ataxias. It accounts for at least 50% of cases of hereditary ataxias in most large series. Cardinal features include progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs, and extensor plantar responses.
For related information see eMedicine articles Neuropathy of Friedreich Ataxia in Neurology and Friedreich Ataxia in Orthopedic Surgery.
Pathophysiology
The major pathophysiologic finding in Friedreich ataxia is a "dying back phenomena" of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis. The primary sites of these changes are the spinal cord and spinal roots. This results in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared.
The posterior columns and corticospinal, ventral, and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents. This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers. Overall, the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells. The posterior column degeneration accounts for the loss of position and vibration senses and the sensory ataxia. The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes.
Large neurons of the dorsal root ganglia, especially lumbosacral, and nerve cells in the Clarke column are reduced in number. The posterior roots become thin. The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size. Patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei is typical. Mild degenerative changes occur in the pontine and medullary nuclei and optic tracts. The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts and involvement of the Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways.
The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Beyond this point, the corticospinal tracts are severely degenerated, which becomes progressively more severe moving down the spinal cord. This explains the common finding of bilateral extensor plantar responses and weakness late in the disease.
Loss of cells in the nuclei of cranial nerves VII, X, and XII results in facial weakness and speech and swallowing difficulties.
Myocardial muscle fibers also show degeneration and are replaced by macrophages and fibroblasts. Essentially, chronic interstitial myocarditis occurs with hypertrophy of cardiac muscle fibers; fibers become hypertrophied and lose their striations. This is followed by swelling and vacuolation and finally interstitial fibrosis. The nuclei appear hyperchromatic and occasionally vacuolated. The cytoplasm appears granular with frequent lipofuscin depositions.
Kyphoscoliosis is likely; it is secondary to spinal muscular imbalance.
Frequency
International
Friedreich ataxia is a relatively common disorder. It is the most common autosomal recessive ataxia, accounting for approximately 50% of all cases of hereditary ataxia. Estimates of incidence range anywhere from 1 in 22,000 to 2 in 100,000, with most studies yielding an incidence among Europeans and North Americans of European descent of approximately 1.5 per 100,000 per year; a slightly higher incidence has been reported in Quebec.
Overall, the FA carrier rate has been estimated recently to be 1 in 60 to 1 in 90 with a disease prevalence of 1 per 29,000.
Mortality/Morbidity
Friedreich ataxia is a progressive disorder with significant morbidity. Loss of ambulation typically occurs 15 years after disease onset. More than 95% of patients are wheelchair bound by age 45 years.
In a series by Harding et al, the average age of death was 37.7 years±14.4 years (range, 21-69).1
Race
Friedreich ataxia is most prevalent in white populations. Most FA carriers and affected FA patients are believed to originate from a common European ancestor who lived more than 10,000 years ago. Frataxin gene expansions are therefore almost nonexistent among black African and Asian populations.
Age
* The onset of Friedreich ataxia is early; it typically presents in children aged 8-15 years and almost always presents before age 20 years.
* In a study by Harding et al, the mean onset of symptoms occurred at age 10.52±7.4 years (range, 1.5-27).1
Clinical
History
* Onset of Friedreich ataxia (FA) is early, with gait ataxia being the usual presenting symptom. Typically, both lower extremities are affected equally. Some patients may have hemiataxia initially before the symptoms become generalized. In some instances, the ataxia begins abruptly following a febrile illness in which ataxia of one lower extremity precedes that of the other.
o Gait ataxia manifests as progressively slow and clumsy walking, which often begins after normal walking has developed. The ataxia may be associated with difficulty standing and running.
o The gait ataxia is both of a sensory and cerebellar type. This combination has been referred to as a tabetocerebellar gait. Opinions are conflicting as to whether the sensory or cerebellar features predominate.
o The cerebellar features of gait ataxia in FA include a wide-based gait with constant shifting of position to maintain balance. Sitting and standing are associated with titubation.
o The sensory ataxia resulting from a loss of joint position sense contributes to the wide-based stance and gait but a steppage gait also is present, characterized by uneven and irregular striking of the floor by the bottom of the feet. Attempts to correct any imbalance typically result in abrupt and wild movements.
o As the disease progresses, ataxia affects the trunk, legs, and arms. As the arms become grossly ataxic, both action and intention tremors may develop. Titubation of the trunk may appear. Facial, buccal, and arm muscles may become tremulous and occasionally display choreiform movements. The patient may experience easy fatigability.
* Patients with advanced FA may have profound distal weakness of the legs and feet, although significant weakness of the arms is rare before the patient becomes bedridden. Eventually, the patient is unable to walk because of the progressive weakness and ataxia, becoming wheelchair bound and ultimately bedridden.
* With disease progression, dysarthria and dysphagia appear. Speech becomes slurred, slow, and eventually incomprehensible. Patients may experience mild weakening of the facial muscles with associated weakness of swallowing. Incoordination of breathing, speaking, swallowing, and laughing may result in the patient nearly choking while speaking.
* Family history
o FA is characterized by autosomal recessive inheritance. In families with one affected child, the subsequent risk of another affected child is 25%. As in most recessive disorders, the risk of developing FA is highest following birth from a consanguineous union. In North America and Europe, however, most cases are sporadic and occur in nonconsanguineous families.
o The overall risk of a patient with FA having a child with the condition is approximately 1 in 200, unless consanguinity is involved. If that same patient has a partner who is found to be a carrier of FA, then the risk becomes 1 in 2. Children descended from the unaffected sibling of a patient with FA and a nonconsanguineous spouse have a 1:1000 risk of developing FA.
o Carrier testing is available for relatives of affected patients and their partners. However, the small risk of a point mutation also must be taken into account and incorporated into genetics counseling.
o Prenatal diagnosis via direct mutation testing is also available.
Physical
See Staging for a scale used to rate functional disability in patients with Friedreich ataxia.
* The cardinal features of FA are as follows:
o Progressive limb and gait ataxia develops before the age of 30 years.
o Lower extremity tendon reflexes are absent.
o Evidence of axonal sensory neuropathy is noted.
o Dysarthria, areflexia, motor weakness of the lower extremities, extensor plantar responses, and distal loss of joint position and vibration senses are not found in all patients within the first 5 years, but are eventually universal.
o Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are other common characteristics. Clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds may be noted.
* Physical findings in patients with FA include gradual loss of vibratory and position senses from the onset, initially affecting the feet and hands. With progression, light touch, pain, and temperature sensation also may be diminished. Two-point discrimination may be affected in early cases.
* Tendon reflexes are absent in almost all cases but may be weakly present if the patient is examined early in the course of the disease. Patellar and ankle jerks are affected most profoundly. Flexor spasms are common even in the absence of tendon reflexes, indicating that the areflexia is sensory in origin. Plantar reflexes are extensor in 90% of patients and absent in the rest. Abdominal reflexes usually are retained until late in the disease process.
* Distal wasting, primarily of the upper extremities, is seen in 50% of patients. Muscle tone is usually normal or decreased. Sphincter control is usually intact but cases of urinary urgency and constipation, which are not usually severe, have occurred.
* Kyphoscoliosis is a frequent but nonspecific finding that may be severe. With early onset, severe scoliosis can produce significant cardiopulmonary morbidity and death due to restricted respiratory function. Peripheral cyanosis of the lower limbs is common.
* Foot deformities such as high plantar arches, foot inversion, and hammertoes may precede the gait ataxia. Typically, 50% of patients develop either pes cavus or varus deformities of one or both feet.
* Visual acuity rarely is affected, but optic atrophy occurs in 25% of patients with FA and has resulted in occasional blindness. Visual evoked potentials (VEP) are abnormal in two thirds of patients, typically displaying reduced amplitude and delayed latency.
* Nystagmus of various types may be found. Horizontal nystagmus, present in the primary position and increased on lateral gaze, occurs in 20% of patients with FA. Extraocular movements usually are affected and are characterized by abnormal square-wave jerks and saccadic pursuit, poor fixation, and impaired vestibulo-ocular reflexes. Pupillary reflexes are normal.
* Deafness has been noted, in some cases in association with vertigo. Brain stem auditory evoked responses (BAER) are typically consistent with central auditory pathway pathology.
* Hypertrophic cardiomyopathy develops in more than 50% of patients. Myocarditis, myocardial fibrosis, cardiac enlargement, progressive cardiac failure, tachycardias, and heart block also may be seen. Cardiac arrhythmia and congestive heart failure contribute to a significant number of deaths in patients with FA.
* Approximately 10% of patients with FA develop diabetes mellitus. An even larger percentage demonstrate impaired glucose tolerance, which has been associated with an insulin receptor abnormality.
* Mental retardation, psychosis, and dementia are uncommon, but some degree of cognitive dysfunction may occur. Emotional lability, in the presence of normal cognitive function, is frequently present.
Causes
Classic Friedreich ataxia is the result of a gene mutation at the centromeric region of chromosome 9 (9q13-21.1) at the site of the gene encoding for the 210-amino-acid protein frataxin. This mutation is characterized by an excessive number of repeats of the GAA (guanine adenine adenine) trinucleotide DNA sequence in the first intron of the gene coding for frataxin. It is the only disease known to be the result of a GAA trinucleotide repeat. This expansion alters the expression of the gene, decreasing the synthesis of frataxin protein. The expanded GAA repeat is thought to result in frataxin deficiency by interfering with transcription of the gene by adopting an unstable helical structure. The larger the number of repeats, the more profound is the reduction in frataxin expression. A recent study from Stolle and colleagues have shown that interrupted GAA repeats do not clearly impact the age of onset in FA.2
* In a normal chromosome, this trinucleotide sequence is repeated up to 50 times. In patients with FA, this sequence is repeated at least 200 times and often more than 1000 times.
* Variability in the clinical presentation of FA may be explained by the extent of this trinucleotide repeat expansion. The age of disease onset, its severity, rate of progression, and extent of neurological involvement vary with the number of repetitive GAA sequences.
o In addition, the frequency of extensor plantar responses, cardiomyopathy, leg weakness and wasting, sclerosis, and pes cavus increased with the size of the GAA expansion.
o Larger GAA expansions correlated with earlier age of onset and shorter times to loss of ambulation.
* In a recent study by Durr et al, the large majority of patients with FA (94%) were homozygous for the GAA trinucleotide (the GAA expansion was present on both alleles of the frataxin gene). The remaining 6% were compound heterozygotes for a GAA expansion and a frataxin point mutation (one allele had a GAA expansion, and the other had a point mutation with no expansion). No patients have been described who were homozygous for a point mutation.3
* Point mutations not only reduce levels of the frataxin protein but are also responsible for the creation of abnormal protein. They also represent another source of variability in the clinical presentation of FA. Seventeen different point mutations have so far been described in FA.
o Between 1% and 5% of the point mutations are single base changes in the sequence of the FA gene causing missense, nonsense, or splicing mutations. Patients with missense mutations displayed either mild or severe symptoms, whereas splicing, nonsense, and initiation codon mutations, associated with nonfunctional frataxin, result in a severe phenotype.
o Point mutations of the frataxin gene involving the amino terminal typically present with a more benign course than those of the carboxy terminal.
o The 3 most common point mutations are the Il54F mutation among southern Italians, the ATG>ATT mutation of the start codon, and the G130V mutation. Patients with the G130V mutation tend to have slower disease progression, brisk knee reflexes, and minimal dysarthria.
* Cells and tissues of the body are differentially sensitive to frataxin deficiency. Cells normally requiring and producing greater amounts of frataxin tend to be most affected by FA. For example, sensory neurons in the dorsal root ganglion responsible for position sense highly express the frataxin gene and are affected greatly in FA. Myocardial muscle fiber also requires comparably larger amounts of frataxin than other tissues and is affected markedly in FA.
* A number of experiments have confirmed the mitochondrial subcellular localization of frataxin in mammals. Frataxin has been shown to be essential for normal mitochondrial function, both for oxidative phosphorylation and iron homeostasis. Strong evidence exists that frataxin deficiency results in iron accumulation within mitochondria of affected cells in cell culture lines. Apparently, the rate of mitochondrial export is reduced. Hearts of patients with FA have revealed mitochondrial ironlike deposits that are not present in healthy hearts.
* The excessive mitochondrial accumulation of iron affects cytosolic iron levels. Excess intracellular iron stimulates the increased generation of free radicals and mitochondrial damage. Iron excess inactivates mitochondrial enzymes essential for the production of adenosine triphosphate (ATP). Cell death, particularly of neurons of the spinal cord and peripheral nervous system, ensues. A mouse model of FA is being developed to confirm evidence of this process in living animal models.
Differential Diagnoses
Other Problems to Be Considered
Refsum disease
Abetalipoproteinemia
Ataxia with isolated vitamin E deficiency
Spinocerebellar ataxia (SCA) types 1, 2, 3
Dentatorubropallidoluysian atrophy
Hereditary motor and sensory neuropathies
Workup
Laboratory Studies
* Genetic counseling is available for prenatal diagnosis of Friedreich ataxia for parents with one affected child. Population screening for carriers of the defective gene is not practical. A specific trinucleotide repeat expansion assay is available commercially in the United States and should be performed in all suspected cases of FA.
* No evidence of CSF abnormality exists in patients with FA.
Imaging Studies
Magnetic resonance imaging (MRI) is the study of choice in the evaluation of the atrophic changes seen in Friedreich ataxia. MRI of the brain and spinal cord in patients with FA consistently shows atrophy of the cervical spinal cord with minimal evidence of cerebellar atrophy.
Other Tests
* Echocardiography reveals symmetric, concentric ventricular hypertrophy, although some have asymmetric septal hypertrophy.
* Approximately 65% of patients with FA have abnormal ECG findings. The most common findings are T-wave inversion, particularly in the inferior standard and lateral chest leads, and ventricular hypertrophy.
* Nerve conduction velocity (NCV) study findings in FA usually are normal or display only mildly reduced velocities. Sensory nerve action potentials (SNAP) are absent in greater than 90% of patients with FA. The remaining 10% display reduced-amplitude SNAPs.
* Brainstem auditory evoked responses are typically abnormal in FA, displaying absent waves III and IV with preservation of wave I. This is suggestive of involvement of central auditory pathways.
* Visual evoked potentials are abnormal in two thirds of patients with FA. Absent or delayed latency and reduced amplitude of the p100 wave are seen.
* Somatosensory evoked potentials (SSEP) reveal delayed central conduction time (N13a/N20, N13b/N20), dispersed potentials at the sensory cortex, as well as abnormal central motor conduction.
Histologic Findings
A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain). Milder involvement of spinocerebellar tracts is also present. The affected tracts show compact fibrillary gliosis on hematoxylin and eosin (H&E) stain but no breakdown products or macrophages, reflecting the very slow rate of degeneration and death of fibers. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (H&E). The posterior roots are nearly devoid of large myelinated fibers. Within the thoracic spinal cord, degeneration and loss of cells of the Clarke column are apparent.
Staging
International Cooperative Ataxia Rating Scale (World Federation of Neurology)
* Posture and gait disturbances
o Walking capacities: The patient's gait is observed during a 10-meter walking test, including a half turn, near a wall at about 1.5 meters.
+ 0 = Normal
+ 1 = Almost normal naturally, but unable to walk with feet in tandem position
+ 2 = Walking without support, but clearly abnormal and irregular
+ 3 = Walking without support, but with considerable staggering; difficulties in half turn
+ 4 = Walking with autonomous support no longer possible; the patient uses the episodic support of the wall for a 10-meter test
+ 5 = Walking possible only with 1 stick
+ 6 = Walking possible only with 2 special sticks or with a stroller
+ 7 = Walking only with accompanying person
+ 8 = Walking impossible, even with accompanying person (wheelchair)
+ Score ___
o Gait speed: Patients who scored 1-3 on the preceding test are observed for gait speed; those who scored 4 and up on the preceding test automatically score 4 in this test.
+ 0 = Normal
+ 1 = Slightly reduced
+ 2 = Markedly reduced
+ 3 = Extremely slow
+ 4 = Walking with autonomous support no longer possible
+ Score ___
o Standing capacities, eyes open: The patient is asked first to try to stand on one foot; if impossible, to stand with feet in tandem position; if impossible, to stand with feet together; for the natural position, the patient is asked to find a comfortable standing position.
+ 0 = Normal, able to stand on one foot for more than 10 seconds
+ 1 = Able to stand with feet together, but no longer able to stand on one foot for more than 10 seconds
+ 2 = Able to stand with feet together, but no longer able to stand with feet in tandem position
+ 3 = No longer able to stand with feet together, but able to stand in natural position without support, with no or moderate sway
+ 4 = Standing in a natural position without support, with considerable sway and considerable corrections
+ 5 = Unable to stand in natural position without strong support of one arm
+ 6 = Unable to stand at all, even with strong support of two arms
+ Score ___
o Spread of feet in natural position without support, eyes open: The patient is asked to find a comfortable standing position, then the distance between medial malleoli is measured.
+ 0 = Normal (spread <10 1 =" Slightly" 2 =" Clearly" 3 =" Severely">35 cm)
+ 4 = Standing in natural position impossible
+ Score ___
o Body sways with feet together, eyes open
+ 0 = Normal
+ 1 = Slight oscillations
+ 2 = Moderate oscillations (<10 3 =" Severe">10 cm at the level of head), threatening the upright position
+ 4 = Immediate falling
+ Score ___
o Body sways with feet together, eyes closed
+ 0 = Normal
+ 1 = Slight oscillations
+ 2 = Moderate oscillations (<10 3 =" Severe">10 cm at the level of head), threatening the upright position
+ 4 = Immediate falling
+ Score ___
o Quality of sitting position (thighs together, on a hard surface, arms folded)
+ 0 = Normal
+ 1 = With slight oscillations of the trunk
+ 2 = With moderate oscillations of the trunk and legs
+ 3 = With severe dysequilibrium
+ 4 = Impossible
+ Score ___
o Posture and gait score (static score) ___/34
* Kinetic functions
o Knee-tibia test (decomposition of movement and intention tremor): The test is performed in the supine position so that visual control is possible; the patient is requested to raise one leg and place the heel on the opposite knee, and then slide the heel down the anterior tibial surface toward the ankle; on reaching the ankle joint, the leg is raised again in the air to a height of approximately 40 cm and the action is repeated; at least 3 movements of each limb must be performed for proper assessment.
+ 0 = Normal
+ 1 = Lowering of the heel in continuous axis but the movement is decomposed in several phases, without real jerks, or abnormally slow
+ 2 = Lowering jerkily in the axis
+ 3 = Lowering jerkily with lateral movements
+ 4 = Lowering jerkily with extremely strong lateral movements or test impossible
+ Score right ___, Score left ___
o Action tremor in the heel-to-knee test: During the same test as the preceding one, the action tremor of the heel on the knee is observed specifically while the patient holds the heel on the knee for a few seconds before sliding it down the anterior tibial surface; visual control is required.
+ 0 = No trouble
+ 1 = Tremor stopping immediately when the heel reaches the knee
+ 2 = Tremor stopping in less than 10 seconds after reaching the knee
+ 3 = Tremor continuing for more than 10 seconds after reaching the knee
+ 4 = Uninterrupted tremor or test impossible
+ Score right ___, Score left ___
o Finger-to-nose test (decomposition and dysmetria): The subject sits in a chair; the hand is resting on the knee before the beginning of the movement; visual control is required; 3 movements of each limb must be performed for proper assessment.
+ 0 = No trouble
+ 1 = Oscillating movement without decomposition of the movement
+ 2 = Segmented movement in 2 phases and/or moderate dysmetria in reaching nose
+ 3 = Segmented movement in more than 2 phases and/or considerate dysmetria in reaching nose
+ 4 = Dysmetria preventing the patient from reaching nose
+ Score right ___, Score left ___
o Finger-to-nose test (intention tremor of the finger): The studied tremor is that appearing during the ballistic phase of the movement; the patient is sitting comfortably with the hand resting on his/her thigh; visual control is required; 3 movements of each limb must be performed for proper assessment.
+ 0 = No trouble
+ 1 = Simple swerve of the movement
+ 2 = Moderate tremor with estimated amplitude <10 3 =" Tremor" 4 =" Severe">40 cm
+ Score right ___, Score left ___
o Finger-finger test (action tremor and/or instability): The sitting patient is asked to maintain his/her index fingers pointing at each other for about 10 seconds, at a distance of 1 cm, at the level of the thorax, under visual control.
+ 0 = Normal
+ 1 = Mild instability
+ 2 = Moderate oscillations of the finger with estimated amplitude <10 3 =" Considerable" 4 =" Jerky">40 cm of amplitude
+ Score right ___, Score left ___
o Pronation-supination alternating movements: The subject, comfortably sitting on a chair, is asked to raise his/her forearm vertically and to make alternating pronating and supinating movements of the hand; each hand is moved and assessed separately.
+ 0 = Normal
+ 1 = Slightly irregular and slowed
+ 2 = Clearly irregular and slowed, but without sway of the elbow
+ 3 = Extremely irregular and slowed movements, with sway of the elbow
+ 4 = Movement completely disorganized or impossible
+ Score right ___, Score left ___
o Drawing of the Archimedes spiral on a predrawn pattern: The subject is comfortably settled in front of a table, sheet of paper being fixed to avoid artifacts; the subject is asked to perform the task without timing requirements; the same conditions of examination must be used at each examination (eg, same table, same pen); the dominant hand is examined.
+ 0 = Normal
+ 1 = Impairment and decomposition, the line quitting the pattern slightly but without hypermetric swerve
+ 2 = Line completely out of the pattern with recrossing and/or hypermetric swerves
+ 3 = Major disturbance due to hypermetria and decomposition
+ 4 = Drawing completely disorganized or impossible
+ Score ___
o Kinetic score (limb coordination) ___/52
* Speech disorders
o Dysarthria (fluency of speech): The patient is asked to repeat several times a standard sentence, always the same, for instance, "They heard him speak on the radio last night."
+ 0 = Normal
+ 1 = Mild modification of fluency
+ 2 = Moderate modification of fluency
+ 3 = Considerably slow and dysarthric speech
+ 4 = No speech
+ Score ___
o Dysarthria (clarity of speech)
+ 0 = Normal
+ 1 = Suggestion of slurring
+ 2 = Definite slurring, most words understandable
+ 3 = Severe slurring, speech not understandable
+ 4 = No speech
+ Score ___
o Dysarthria score ___/8
* Oculomotor disorders
o Gaze-evoked nystagmus: The subject is asked to look laterally at the finger of the examiner; the movements assessed are mainly horizontal, but they may be oblique, rotatory, or vertical.
+ 0 = Normal
+ 1 = Transient
+ 2 = Persistent but moderate
+ 3 = Persistent and severe
+ Score ___
o Abnormalities of the ocular pursuit: The subject is asked to follow the slow lateral movement performed by the finger of the examiner.
+ 0 = Normal
+ 1 = Slightly saccadic
+ 2 = Clearly saccadic
+ Score ___
o Dysmetria of the saccade: Two index fingers of the examiner are placed in each temporal visual field of the patient, whose eyes are in the primary position; the patient is then asked to look laterally at the finger, on the right and on the left; the average overshoot or undershoot of the 2 sides is then estimated.
+ 0 = Absent
+ 1 = Bilateral clear overshoot or undershoot of the saccade
+ Score ___
o Oculomotor movement score ___/6
* Total ataxia score ___/100
Treatment
Medical Care
The results of treating ataxia in Friedreich ataxia (FA) have generally been disappointing. No therapeutic measures are known to alter the natural history of the neurological disease. Standard treatment is administered for heart failure, arrhythmias, and diabetes mellitus.
High-dose propanolol has been described in a case report by Kosutic with reduction in thickness of the septal and posterior left ventricular walls and with complete normalization of diffuse electrocardiographic repolarization abnormalities.4
Li and colleagues have shown that therapeutic efforts should focus on an approach that combines iron removal from mitochondria with a treatment that increases cytosolic iron levels to maximize residual frataxin expression in patients with FA.5
The other therapies that have been used are as follows:
* 5-hydroxytryptophan
o 5-hydroxytryptophan is a serotonin precursor that has been used for a decade or more by Trouillas et al to treat various forms of ataxia with mixed results.6 This drug was known to suppress posthypoxic action myoclonus. The rationale for use of the drug in FA was that FA may in part be due to a cerebellar deficiency of serotonin.
o The results of a double-blind, cross-over study by Trouillas et al demonstrated that the levorotatory form of 5-hydroxytryptophan was able to significantly modify the cerebellar symptoms in patients with FA; however, the effect was only partial and not clinically major.6
o A study by Wessel demonstrated stabilization of posture in patients receiving long-term treatment with 5-hydroxytryptophan and a clear deterioration in patients who did not receive the treatment. This form of treatment requires further study.
* Coenzyme Q
o Coenzyme Q is an antioxidant that can buffer free radical formation that is induced by excess mitochondrial iron. A combined coenzyme Q (400 mg/d) and vitamin E (2100 IU/d) therapy has been used in a study of 10 patients with slowing of the progression of certain clinical features and a significant improvement in cardiac function.
o Experimental studies are underway to evaluate the use of coenzyme Q derivatives in limiting the toxicity of iron to mitochondrial structures.
* Idebenone: Di Prospero and colleagues have recently shown that higher doses of idebenone were generally well tolerated and associated with improvement in neurologic function and ADL in patients with FA.7 The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurologic function.
Surgical Care
Apart from surgery for scoliosis and foot deformities that may be helpful in selected cases, no significant surgical treatment is available for Friedreich ataxia. A study from Milbrandt and colleagues emphasized that in scoliosis braces were seldom effective and that segmental constructs are effective in creating substantial intraoperative correction and maintaining correction postoperatively.8
In addition, heart transplantation for FA dilated cardiomyopathy has been performed.
Consultations
Goulipian and colleagues have mentioned the role of orthopedic shoes combined with physical therapy. Their results demonstrated that orthopedic shoes improved gait disorders in a patient with Friedreich ataxia.9
Diet
No data exist to suggest that any alteration of diet would affect the onset, progression, or outcome of this disease.
Activity
No data exist to suggest that any alteration of activity level would affect the onset, progression, or outcome of this disease.
In regards to the delivery and utilization of oxygen in response to exercise, near infrared muscle spectroscopy may be an effective tool for monitoring the biochemical and functional features of FA.
Follow-up
Prognosis
* Health related quality of life (QOL) measures are potentially useful as clinical markers of disease status in Friedreich ataxia (FA).
* The prognosis of FA is poor.
* The disorder is progressive, with a mean duration of 15-20 years.
* More than 95% of patients are wheelchair bound by age 45 years.
* Commonly, patients survive to 25-30 years of age, although some patients have survived into the sixth and seventh decades, especially if they are free of heart disease and diabetes.
* QOL is significantly worse in these individuals compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, while increased disease duration was positively associated with mental QOL.10
Source: http://emedicine.medscape.com/article/1150420-overview
Friedreich Ataxia
Discussion of what Friedreich Ataxia is,how it impacts the lives of those who have it, what can be done to improve quality of life and how important more research is to find a cure.
One Gene, Many Proteins
We humans have approximately 30,000 genes that carry within them the instructions for making proteins. There is good evidence for 26,383 protein-coding genes, according to J. Craig Venter and colleagues at Celera Genomics. Based on a combination of computer data and human analysis, there is some evidence that the genome may contain another 12,731 or so genes, but it is too early to know for sure; some of the predicted genes may be overestimates.
Venter is the lead author on a landmark paper that appears in the February 16 issue of Science. Scientists participating in the Human Genome Project, partially funded by the U.S. National Institutes of Health, estimate the number of human genes to be between 30,000 and 40,000. They chose to publish their data in the British journal Nature, which is also out this week.
What does this mean? It means that the old paradigm that one gene makes one protein is clearly in need of revision. Through mechanisms that include "alternative splicing," one gene can direct the synthesis of many proteins. Victor A. McKusick, of the Johns Hopkins University School of Medicine, says, "It seems to be a matter of five or six proteins, on average, from one gene." McKusick, who is a co-author of the Science paper, suggests that people who now claim that the number of human genes is much higher, may be looking at and counting separate messenger RNAs—the molecules that take information from genes and direct the production of proteins. That being likely, mRNAs will now have to be reexamined against the human genome sequence.
Nobel laureate Richard J. Roberts, Research Director at New England Biolabs, Beverly, MA, who is also a co-author of the Science paper, says, "Since genes are [now] easy to discover by sequencing, and the transcriptional splicing variants are much more difficult to discover and characterize properly, it means that much work lies ahead." Or, as the Science paper says, "As was true at the beginning of genome sequencing, ultimately it will be necessary to measure mRNA in specific cell types to demonstrate the presence of a gene."
The finding that one gene makes many proteins also confirms (if confirmation were needed), that future research in drug discovery and medicine will rely heavily on an integration of genomics and proteomics, a newly coined word for the study of proteins and their biological interactions. Proteins are sensitive markers of early onset of disease, and of obvious importance to diagnosis. Proteins are equally vital to prognosis and treatment; it is proteins, for instance, that are the targets of most drugs and other therapeutic agents. Detailed understanding of proteins and the genes from which they come is the next frontier.
Small gene number was predicted ages ago.
For the past quarter century, estimates of the number of genes in the human genome have generally ranged between 80,000 and 150,000, so the much smaller number comes as an apparent surprise, though perhaps it should not. As early as 1937, the famed biologist J.B.S. Haldane speculated that if the number of genes in an organism becomes too large, deleterious mutations could drive it to extinction. In the 1960's, human geneticist James F. Crow and colleagues hypothesized (correctly) that human beings have about 30,000 genes.
The newly published human genome sequence, Venter and colleagues note, "provides the framework upon which all the genetics, biochemistry, physiology, and ultimately, phenotype depend.... Now we know what we have to explain."
Source: http://www.genomenewsnetwork.org/articles/02_01/One_gene.shtml
From the Genome to the Proteome
Cells are the fundamental working units of every living system. All the instructions needed to direct their activities are contained within the chemical DNA (deoxyribonucleic acid).
DNA from all organisms is made up of the same chemical and physical components. The DNA sequence is the particular side-by-side arrangement of bases along the DNA strand (e.g., ATTCCGGA). This order spells out the exact instructions required to create a particular organism with its own unique traits.
The genome is an organism’s complete set of DNA. Genomes vary widely in size: the smallest known genome for a free-living organism (a bacterium) contains about 600,000 DNA base pairs, while human and mouse genomes have some 3 billion. Except for mature red blood cells, all human cells contain a complete genome.
DNA in the human genome is arranged into 24 distinct chromosomes--physically separate molecules that range in length from about 50 million to 250 million base pairs. A few types of major chromosomal abnormalities, including missing or extra copies or gross breaks and rejoinings (translocations), can be detected by microscopic examination. Most changes in DNA, however, are more subtle and require a closer analysis of the DNA molecule to find perhaps single-base differences.
Each chromosome contains many genes, the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions on how to make proteins. Genes comprise only about 2% of the human genome; the remainder consists of noncoding regions, whose functions may include providing chromosomal structural integrity and regulating where, when, and in what quantity proteins are made. The human genome is estimated to contain 20,000-25,000 genes.
Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures. Proteins are large, complex molecules made up of smaller subunits called amino acids. Chemical properties that distinguish the 20 different amino acids cause the protein chains to fold up into specific three-dimensional structures that define their particular functions in the cell.
The constellation of all proteins in a cell is called its proteome. Unlike the relatively unchanging genome, the dynamic proteome changes from minute to minute in response to tens of thousands of intra- and extracellular environmental signals. A protein’s chemistry and behavior are specified by the gene sequence and by the number and identities of other proteins made in the same cell at the same time and with which it associates and reacts. Studies to explore protein structure and activities, known as proteomics, will be the focus of much research for decades to come and will help elucidate the molecular basis of health and disease.
Source: http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml
Trisomy 13 syndrome
Trisomy 13 syndrome is a disorder of human chromosomes which occurs in approximately 1 in 10,000 live born infants. Trisomy 13 is due to the presence of an extra #13 chromosome. Approximately 80% of infants with Trisomy 13 syndrome will have a full trisomy while the remainder will have a trisomy due to a rearrangement called a translocation or have mosaicism (two different cell lines).
Infants born with Trisomy 13 have a recognizable pattern of physical features that often allow the health professional to make the diagnosis of the syndrome. Notable physical birth defects and sometimes, anatomic changes of internal organs are present. Findings of significance include small head size (microcephaly); small eyes (microphthalmia) or sometimes absent eye or faulty development of the retina. Cleft lip or cleft palate or both occur in about 60% of children. In addition, there are a number of less medically significant physical findings that are helpful in diagnosis. These include variations of ear shape, changes on the palm of the hand, and extra fingers and toes. Changes in foot development, including changes to the heel, the so-called rocker bottom foot, can occur.
Heart Defects
About 80% of children with Trisomy 13 will have a congenital heart defect. These can include: ventricular septal defect – an opening between the lower chambers of the heart which prevents the heart from pumping blood correctly (a heart murmur is generally heard from this finding); atrial septal defect – an opening between the two upper chambers of the heart making it difficult for the heart to pump sufficient oxygen rich blood to body tissues (a heart murmur is often heard); patent ductus arteriosis – a defect involving the lack of closure of the channel that usually closes near the time of birth; dextrocardia – location of the heart on the right side of the chest; on occasion more medically serious heart defects can occur in Trisomy 13.
Synonyms: Trisomy 13
Patau Syndrome
Trisomy 13-15
D Trisomy Syndrome
(these last two terms are usually not used at the present time)
Medical Problems
The major implications of Trisomy 13 involve a predisposition to congenital malformations (birth defects) mentioned above, an increased mortality in infancy, and a developmental disability in older children. In addition, older infants can have visual difficulties because of the findings mentioned above and a hearing loss. The increased mortality is related to difficulties with breathing due to either interrupted breathing (apnea), or problems of lung development. In addition, gastroesophageal reflux and feeding problems can occur and predispose to aspiration adding to this risk. Usually the heart defects are not serious enough to be a major health threat in the newborn period.
Important and Common Birth Defects in Trisomy 13
* Omphalocele 10%
* Holoprosencephaly 60% (an anatomic defect of the brain involving failure of the forebrain to divide properly)
* Kidney defects 30%
* Skin defects of the scalp 20%
Common Disorders in infants and young children with Trisomy 13
* feeding difficulties
* gastroesophageal reflux
* slow post natal growth
* apnea
* seizures
* hypertension
* kidney defects
* developmental disabilities
* scoliosis
Routine follow-up care of infants with Trisomy 13
* Routine child care/anticipatory guidance
* Cardiac evaluation
* Eye evaluation
* Hearing test
* Referral for Infant pre-school/ early intervention program
* Ongoing Support
* Scoliosis check through childhood
* Routine immunization including chicken pox
Source: http://www.trisomy.org/trisomy13.php
Infants born with Trisomy 13 have a recognizable pattern of physical features that often allow the health professional to make the diagnosis of the syndrome. Notable physical birth defects and sometimes, anatomic changes of internal organs are present. Findings of significance include small head size (microcephaly); small eyes (microphthalmia) or sometimes absent eye or faulty development of the retina. Cleft lip or cleft palate or both occur in about 60% of children. In addition, there are a number of less medically significant physical findings that are helpful in diagnosis. These include variations of ear shape, changes on the palm of the hand, and extra fingers and toes. Changes in foot development, including changes to the heel, the so-called rocker bottom foot, can occur.
Heart Defects
About 80% of children with Trisomy 13 will have a congenital heart defect. These can include: ventricular septal defect – an opening between the lower chambers of the heart which prevents the heart from pumping blood correctly (a heart murmur is generally heard from this finding); atrial septal defect – an opening between the two upper chambers of the heart making it difficult for the heart to pump sufficient oxygen rich blood to body tissues (a heart murmur is often heard); patent ductus arteriosis – a defect involving the lack of closure of the channel that usually closes near the time of birth; dextrocardia – location of the heart on the right side of the chest; on occasion more medically serious heart defects can occur in Trisomy 13.
Synonyms: Trisomy 13
Patau Syndrome
Trisomy 13-15
D Trisomy Syndrome
(these last two terms are usually not used at the present time)
Medical Problems
The major implications of Trisomy 13 involve a predisposition to congenital malformations (birth defects) mentioned above, an increased mortality in infancy, and a developmental disability in older children. In addition, older infants can have visual difficulties because of the findings mentioned above and a hearing loss. The increased mortality is related to difficulties with breathing due to either interrupted breathing (apnea), or problems of lung development. In addition, gastroesophageal reflux and feeding problems can occur and predispose to aspiration adding to this risk. Usually the heart defects are not serious enough to be a major health threat in the newborn period.
Important and Common Birth Defects in Trisomy 13
* Omphalocele 10%
* Holoprosencephaly 60% (an anatomic defect of the brain involving failure of the forebrain to divide properly)
* Kidney defects 30%
* Skin defects of the scalp 20%
Common Disorders in infants and young children with Trisomy 13
* feeding difficulties
* gastroesophageal reflux
* slow post natal growth
* apnea
* seizures
* hypertension
* kidney defects
* developmental disabilities
* scoliosis
Routine follow-up care of infants with Trisomy 13
* Routine child care/anticipatory guidance
* Cardiac evaluation
* Eye evaluation
* Hearing test
* Referral for Infant pre-school/ early intervention program
* Ongoing Support
* Scoliosis check through childhood
* Routine immunization including chicken pox
Source: http://www.trisomy.org/trisomy13.php
How do chromosome abnormalities happen?
Chromosome abnormalities usually occur when there is an error in cell division. There are two kinds of cell division.
- Mitosis results in two cells that are duplicates of the original cell. In other words, one cell with 46 chromosomes becomes two cells with 46 chromosomes each. This kind of cell division occurs throughout the body, except in the reproductive organs. This is how most of the cells that make up our body are made and replaced.
- Meiosis results in cells with half the number of chromosomes, 23 instead of the normal 46. These are the eggs and sperm.
In both processes, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division can result in cells with too few or too may copies of a chromosome. Errors can also occur when the chromosomes are being duplicated.
Other factors that can increase the risk of chromosome abnormalities are:
- Maternal Age: Women are born with all the eggs they will ever have. Therefore, when a woman is 30 years old, so are her eggs. Some researchers believe that errors can crop up in the eggs' genetic material as they age over time. Therefore, older women are more at risk of giving birth to babies with chromosome abnormalities than younger women. Since men produce new sperm throughout their life, paternal age does not increase risk of chromosome abnormalities.
- Environment: Although there is no conclusive evidence that specific environmental factors cause chromosome abnormalities, it is still a possibility that the environment may play a role in the occurance of genetic errors.
Source: http://www.genome.gov/11508982
Edwards' syndrome
This rare genetic chromosomal disorder occurs when a child is born with three copies of chromosome 18, rather than the usual two. It's also known as trisomy 18.
What are the symptoms?
The features and problems that develop in children with Edwards' syndrome vary from child to child.
Typically, a child will have a small head with characteristic facial features including a small jaw and mouth, upturned nose, widely spaced small eyes with narrow eyelid folds and drooping of the upper eyelids, and low-set, malformed ears.
The hands may be clenched, with the second and fifth fingers overlapping the other fingers, and the thumbs may be underdeveloped or absent. Webbing of the second and third toes may also occur.
In addition to these features, all systems of the body may be affected. Structural malformations of the heart, kidneys, brain, digestive tract and genitals may be present and cause the child difficulties. For example, children with the syndrome often have trouble feeding and breathing, and experience delay in growth and development. Infections of the lungs and urinary system are also common.
Who's affected?
Edwards' syndrome occurs in around one in 6,000 live births and around 80 per cent of those affected are female. However, the majority of babies with the syndrome die before birth.
It affects people from all cultural backgrounds and becomes more likely with increasing maternal age.
How is it diagnosed?
At birth, if physical characteristics suggest the possibility of Edwards' syndrome, this can be confirmed with genetic testing.
An ultrasound during pregnancy can often identify foetal abnormalities, providing the opportunity for genetic testing by amniocentesis.
What's the treatment?
There's no cure for Edwards' syndrome, but medical treatment of symptoms is provided as required.
Treatment focuses on providing good nutrition, tackling infections - which arise frequently - and helping the heart to function better.
Many babies with Edwards' syndrome have difficulties with feeding, so food may be given via a nasogastric tube or directly into the stomach through a gastrostomy. Where limb abnormalities affect movement, physiotherapy and occupational therapy can help.
Emotional support for parents and other members of the family is vital, as babies with Edwards' syndrome have a shortened life expectancy. Few survive beyond their first year.
Source: http://www.bbc.co.uk/health/conditions/edwardssyndrome2.shtml
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