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Worldwide prevalence is estimated at 1/1,000,000, however it is more frequent in populations of Persian Jewish and Japanese ethnicity.

The disease usually starts during the third decade of life (but the onset may range from the early teens to the 5th decade). Typically, distal weakness in the legs with foot drop is the first sign, followed by (usually) slow progression to the proximal muscles (thigh) and the upper limbs (hand muscles). Shoulder girdle muscles are subsequently involved, with relative sparing of the triceps. Neck flexor muscles are also commonly affected. A unique clinical pattern of this myopathy is sparing of quadriceps in spite of major involvement of other thigh muscles. Unusual patterns of onset in proximal lower limb musculature and even in the upper limbs have been observed. Ocular, pharyngeal, and cardiac muscles are usually spared. Respiratory muscles are generally not affected until the very late stages in wheelchair-bound patients. Occasionally, affected individuals may present facial weakness.

GNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3) which encodes a bi-functional enzyme involved in the sialic acid biosynthetic pathway. Mutations in this gene result in a 30-60% decrease in enzyme activity leading to a decreased sialylation of glycoproteins and glycolipids. Hyposialylation appears to be involved in disease pathogenesis, but the process by which a defect in GNEleads to muscle disease is still elusive. With increasing number of patients, genotype-phenotype correlations are currently emerging.

Diagnosis is suspected in individuals with early-onset foot drop, negative dominant family history, sustained quadriceps sparing despite marked weakness of all other thigh muscles, modest elevation of serum creatine kinase (2-5x), muscle biopsy showing fiber size variation (with atrophy) and presence of rimmed vacuoles and congophilic protein aggregates. MRI reveals a characteristic pattern of muscle involvement with (from the early stages of the disease) severe fatty-fibrous replacement of the biceps femoris short head muscles, accompanied by less severe involvement of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis muscles. Genetic screening revealing pathogenic variants in GNE confirms the diagnosis.

Differential diagnosis includes other adult-onset distal myopathies with rimmed vacuolar pathology (i.e. distal myopathy, Welander type; tibial muscular dystrophy; adult-onset distal myopathy due to VCP mutation; and vocal cord and pharyngeal distal myopathy), myofibrillar myopathies, and Laing early-onset distal myopathy.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.

In the absence of a proven effective therapy, management remains mainly supportive. Metabolic supplementation with sialic acid or a precursor of sialic acid, as well as gene therapy, are under investigation.

Most patients become wheelchair-bound after 15-20 years of disease onset. About 5% of patients have atypical early involvement of the quadriceps muscle resulting in earlier non-ambulation.