[GNE myopathy]. / Myopathie GNE.

GNE myopathy is a rare neuromuscular disease whose description is fairly recent. It predominantly affects the adult population and is an inherited autosomal recessive disorder. Although universal and ubiquitous, GNE myopathy prevails in the Jewish community of Persian origin, living in Iran, Israel or in the United States. This condition has also been reported in great number in populations of far-East Asia (Japan and neighboring countries) and, closer to France, in Bulgaria. GNE myopathy causes muscle weakness in the extremities (distal myopathy), affecting initially and predominantly foot flexor muscles. The generic term of GNE myopathy is now fully accepted and encompasses two previously described entities: the quadriceps sparing myopathy, (also referred to as the autosomal recessive form of inclusion body myopathy (hIBM) and the Nonaka type distal myopathy (or distal myopathy with rimmed vacuoles DMRV). This myopathy is due to mutations in the GNE gene encoding a bifunctional enzyme, the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. This enzyme plays a role at two levels in the metabolic pathway leading to the synthesis of sialic acid. Sialic acid, also known as N-acetylneuraminic acid (Neu5Ac or NANA), is a monosaccharide essential to other protein or lipid molecules requiring sugar residues on their surface in order to function efficiently. GNE myopathy is characterized by histological lesions (rimmed vacuoles) within muscle fibers. They are fairly typical in a suggestive context, but non-specific and inconsistent from one muscle to another. The diagnosis of GNE myopathy is essentially based on clinical clues, including muscle imaging, and is confirmed by genetic studies. If promising therapeutic trials are being developed to compensate for this recently unveiled metabolic defect, the treatment of this myopathy remains purely supportive to date.

GNE myopathy in Roma patients homozygous for the p.I618T founder mutation.

GNE myopathy is an autosomal-recessive disorder caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase. We studied 50 Bulgarian Roma patients homozygous for p.I618T, an ancient founder mutation in the kinase domain of the GNE gene, dating before the Gypsy exodus from North West India. The clinical features in the Bulgarian GNE group can be described with disease onset mostly in the third decade, but in individual cases, onset was as early as 10 years of age. The majority of patients had foot drop as the first symptom, but three patients developed hand weakness first. Muscle weakness was early and severe for the tibialis anterior, and minimal or late for quadriceps femoris, and respiratory muscles were only subclinically affected even in the advanced stages of the disease. During a 15-year follow-up period, 32 patients became non-ambulant. The average period between disease onset and loss of ambulation was 10.34 ± 4.31 years, ranging from 3 to 20 years. Our analysis of affected sib pairs suggested a possible role of genetic modifying factors, accounting for significant variation in disease severity.

Mutation update for GNE gene variants associated with GNE myopathy.

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.

Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family.

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype.

Dysferlin mutation in a Chinese pedigree with Miyoshi myopathy.

OBJECTIVES: Mutations in the dysferlin gene cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. The purpose of this study was to diagnose a Chinese pedigree with the autosomal recessive form of muscular dystrophy and conduct mutational screening. METHODS: The pedigree was diagnosed accurately by using two-point linkage analysis and multi-Western blot analysis. Mutations were determined by reverse transcriptase polymerase chain reaction (RT-PCR) followed by DNA sequencing. RESULTS: Two-point linkage analysis showed significant LOD scores with makers from chromosome 2p13. Multi-Western blot analysis confirmed dysferlin deficiency of muscle specimen from the propositus. Mutation analysis of the dysferlin gene revealed a novel mutation, 6429delG, on exon 53. CONCLUSIONS: We identified an inbred Chinese pedigree with Miyoshi myopathy caused by the 6429delG mutation in the dysferlin gene. This mutation is predicted to result in premature termination of translation contributing to Miyoshi myopathy.