Please note that I have now changed my blog site to "taratalksgnemyopathy.blogspot.com. I have changed it to more accurately name the gene (GNE) that is defective in GNE Myopathy.
In this issue of my blog I have inserted links for two articles which are quite technical in their contexts. These are only available in "abstracts" online. However, I have been fortunate enough to read and study both articles in their entirety. These articles are so important for us to understand, and I would encourage anyone who has the permission to post the complete articles online for patients. I have attempted to explain what I understand and what I find relevant for patients.
This article contains 12 pages, including tables indicating all the known 147 GNE variants as of January 2014 that were reported in literature, in addition the National Institutes of Health (NIH) found 7 more. They have identified ethnic founder mutations such as those found in Middle Eastern, Japanese, Roma Gypsies, and other ethnic groups. Additionally, there are tables indicating the various mutations and how each affects a patient in terms of "mild, medium and severe". Also mentioned by the researchers, based on their scientific calculations believe that there may be at least 40,000 patients with GNE myopathy worldwide. The estimated breakdown of patients are approximately 13,000 in Asia, of which 750 are in Japan, 4,000 in Europe, and 3,000 in North America. So far, there are only 800 reported patients. This indicates that we really need to work on bringing awareness to families, patients, and medical communities world wide.
Abstract 1
Mutation Update for GNE Gene Variants Associated with GNE Myopathy.
This second article is written by Dr. Ichizo Nishino, Dr. Carrillo-Carrasco and Dr. Zohar Argov and it contains 10 pages.
This article discusses the current update and future therapy for GNE myopathy. It further illustrates how our cells use sialic acid. It reports all the clinical trials to date done on GNE myopathy. These include IVIIG, and ManNAc, which were done at the NIH, NeuAC done in Japan, and currently SA-ER being done by Ultragenyx in the United States and Israel. Liposomal systemic GNE delivery was done on one patient of which there was minimal improvement.
Of interest to me, and I believe other patients is the discussion of "future therapeutic development", where the authors state that while they think that metabolic supplementation for GNE myopathy is promising, researchers have to consider other strategies. These strategies would include better GNE metabolites, or sialic acid compounds, drugs to block or modify the degenerative process, gene or cell based therapies. These treatments may need to be combined with supplementation therapy.
It is mentioned that at the GNE laboratory in Israel under the direction of Dr. Mitrani-Rosenbaum along with other collaborators, are studying an AAV gene mediated vector. Preliminary results with animals are promising.
I find both articles helpful in my understanding of my disease. I am encouraged by the vast amount of progress that has been made since I was diagnosed, and there is hope that one day we may be able to stop GNE myopathy. We need to spread the word around the globe for early diagnosis.
Abstract 2
http://www.ncbi.nlm.nih.gov/pubmed/25002140
In this issue of my blog I have inserted links for two articles which are quite technical in their contexts. These are only available in "abstracts" online. However, I have been fortunate enough to read and study both articles in their entirety. These articles are so important for us to understand, and I would encourage anyone who has the permission to post the complete articles online for patients. I have attempted to explain what I understand and what I find relevant for patients.
This article contains 12 pages, including tables indicating all the known 147 GNE variants as of January 2014 that were reported in literature, in addition the National Institutes of Health (NIH) found 7 more. They have identified ethnic founder mutations such as those found in Middle Eastern, Japanese, Roma Gypsies, and other ethnic groups. Additionally, there are tables indicating the various mutations and how each affects a patient in terms of "mild, medium and severe". Also mentioned by the researchers, based on their scientific calculations believe that there may be at least 40,000 patients with GNE myopathy worldwide. The estimated breakdown of patients are approximately 13,000 in Asia, of which 750 are in Japan, 4,000 in Europe, and 3,000 in North America. So far, there are only 800 reported patients. This indicates that we really need to work on bringing awareness to families, patients, and medical communities world wide.
Abstract 1
Mutation Update for GNE Gene Variants Associated with GNE Myopathy.
Celeste FV1, Vilboux T, Ciccone C, de Dios JK, Malicdan MC, Leoyklang P, McKew JC, Gahl WA, Carrillo-Carrasco N, Huizing M.
Abstract
The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ∼4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials.
Published 2014. Wiley Periodicals, Inc. **This article is a U.S. Government work and is in the public domain in the USA.
This second article is written by Dr. Ichizo Nishino, Dr. Carrillo-Carrasco and Dr. Zohar Argov and it contains 10 pages.
This article discusses the current update and future therapy for GNE myopathy. It further illustrates how our cells use sialic acid. It reports all the clinical trials to date done on GNE myopathy. These include IVIIG, and ManNAc, which were done at the NIH, NeuAC done in Japan, and currently SA-ER being done by Ultragenyx in the United States and Israel. Liposomal systemic GNE delivery was done on one patient of which there was minimal improvement.
Of interest to me, and I believe other patients is the discussion of "future therapeutic development", where the authors state that while they think that metabolic supplementation for GNE myopathy is promising, researchers have to consider other strategies. These strategies would include better GNE metabolites, or sialic acid compounds, drugs to block or modify the degenerative process, gene or cell based therapies. These treatments may need to be combined with supplementation therapy.
It is mentioned that at the GNE laboratory in Israel under the direction of Dr. Mitrani-Rosenbaum along with other collaborators, are studying an AAV gene mediated vector. Preliminary results with animals are promising.
I find both articles helpful in my understanding of my disease. I am encouraged by the vast amount of progress that has been made since I was diagnosed, and there is hope that one day we may be able to stop GNE myopathy. We need to spread the word around the globe for early diagnosis.
Abstract 2
http://www.ncbi.nlm.nih.gov/pubmed/25002140
Neurol Neurosurg Psychiatry. 2014 Jul 7. pii: jnnp-2013-307051. doi: 10.1136/jnnp-2013-307051. [Epub ahead of print]
GNE myopathy: current update and future therapy.
Abstract
GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
