GNE Myopathy - Causes, Diagnosis,Treatment, and Prognosis.

Introduction:

GNE myopathy is a very rare autoimmune recessive genetic disorder characterized by slow to moderate progressive skeletal atrophy (skeletal muscle wasting), and weakness preferentially affects the tibialis anterior and is characterized by early adult onset.

Previously, it was also known as:

• Hereditary inclusion body myopathy (HIBM).

• Inclusion body myopathy type 2 (IBM2).

• Nonaka myopathy.

• Quadriceps-sparing myopathy (QSM).

• Distal myopathy with rimmed vacuoles.

• Hereditary inclusion body myopathy-type 2 (HIBM2).

GNE myopathy is a slow, progressive skeletal muscle disease that presents between the ages of 20 and 40 years. It can start as early as the age of ten years too. It occurs from the early teenage to the 50s. The symptoms include foot drops caused by anterior tibialis weakness and difficulty walking. The disease slowly progresses to other muscles of extremities like the thighs, arms, and legs. The shoulder girdle muscle and neck flexor muscles are subsequently affected.

In the later stages of the disease, the respiratory muscles are affected. The condition worsens, and individuals suffering from GNE myopathy use a wheelchair one or two decades later, and a few may need assistance in their daily routine activities, too. The ocular, pharyngeal, and cardiac muscles are spared. Usually, the facial muscles are not involved, and there is no alteration in cognition in individuals with GNE myopathy.

Is GNE Myopathy a Hereditary Disorder?

GNE myopathy is a hereditary disease that involves the autosomal recessive pattern. It is caused by a defect in the GNE gene.

What Are the Clinical Manifestations of GNE Myopathy?

The characteristic clinical manifestations of GNE myopathy include:

• GNE myopathy typically presents in early adulthood, between the ages of 20 and 40.

• Distal muscle weakness in the legs, also known as foot drop.

• Slowly progressive muscle weakness that affects the upper and lower extremities.

• The distinct feature of GNE myopathy is that it involves the tibialis anterior and typically does not involve the quadriceps.

• Gait disturbance.

• Inability to lift toes.

• Decreased balance.

• Increased risk of falling or increased tripping.

• It does not involve the facial muscles.

• In the later stages, it involves the respiratory muscles.

• Cardiac involvement is also reported.

• Thrombocytopenia is reported in a small number of individuals with GNE myopathy disorder.

• Difficulty in climbing stairs and getting up from a seated position.

• Weakness in hands and shoulders.

• Fatigue with exertion.

• Lack of energy.

• Muscle stiffness, cramps, and spasms.

What Causes GNE Myopathy?

GNE myopathy is caused by a genetic defect of biallelic mutations (about both alleles of a single gene of paternal and maternal) in the GNE gene. The genetic defect disrupts the functioning of the sialic acid metabolic pathway and interferes with normal muscle function, resulting in skeletal muscle atrophy. There is an increased attachment of sialic acid groups to skeletal muscle cells.

What Are the Symptoms of GNE Myopathy?

The symptoms of GNE myopathy begin in young adults between 20 and 40 years of age, and the expected initial symptoms are:

• Tripping frequently.

• Foot drop.

• Change in gait.

• Difficulty in climbing stairs.

• Difficulty in running.

• Difficulty getting up from a seated position.

• Loss of balance and

• Weakness in hands and shoulders.

How Is GNE Myopathy Diagnosed?

The GNE myopathy is diagnosed in the following ways:

• The clinical presentation of bilateral foot drop and distal extremity muscle weakness in early adulthood should be considered a potential diagnosis of GNE myopathy.

• The typical distinctive feature of GNE myopathy is the involvement of the anterior tibialis muscle and the exclusion of muscle weakness in the quadriceps. Thus, this characteristic clinical sign enables clinicians to diagnose GNE myopathy.

• Currently, GNE myopathy is diagnosed based on clinical and muscle pathology findings, which are validated by discovering biallelic mutations in the GNE gene.

• Numerous factors could contribute to the delay in diagnosing this rare disease. The clinical manifestations of the condition are nonspecific in the early stages, and the typical clinical sign, sparing of the quadriceps, does not appear until late in the disease.

• There is no regular laboratory test that indicates the existence of GNE myopathy. Serum creatine phosphokinase (CPK) levels can be elevated (typically less than 1000 mcg per liter) or normal.

• Electromyograms (EMGs) and nerve conduction analyses may be nonspecific and make little difference in the diagnosis.

• T1-weighted muscle magnetic resonance imaging (MRI) demonstrates the fatty-fibrous replacement of affected muscles and may help determine the location of a muscle biopsy.

• However, more patients are being recognized by neuromuscular genetic testing that includes GNE or next-generation (including exome) sequencing; genetic testing is nearly impossible until clinical suspicion exists.

• Muscle histology - Muscle biopsy of the affected muscles reveals the presence of rimmed vacuoles, variation in muscle fiber size, and atrophic fibers, usually angular and clustered. Muscle biopsy also shows fiber size variation (with atrophy).

• Evident family history as GNE myopathy is an autosomal recessive inherited disease.

• Blood tests show a modest elevation of serum creatine kinase.

• Presence of congophilic protein aggregates.

• Electromyography (EMG) helps to assess the type and degree of muscle damage.

What Is the Treatment for GNE Myopathy?

There is no specific treatment approved for GNE myopathy. However, various research has enabled clinicians to provide targeted treatment based on the underlying strategies for the disease condition, such as:

• Maintaining precursors of the sialic acid biosynthetic pathway (sialylation-increasing therapies).

• Reestablishing UDP-GlcNAc 2-epimerase and ManNAc kinase enzymatic activities by gene or cell therapy approaches.

• Supportive therapy includes continued physical activity, which includes regular exercise (except for lifting weights), as tolerated and should be encouraged in patients with GNE myopathy.

• Clinical trials for ManNAc N-acetyl-D-mannosamine have shown promising results as the cure for GNE myopathy.

What Is the Differential Diagnosis for GNE Myopathy?

Differential diagnosis includes:

• Other adult-onset distal myopathies.

• Rimmed vacuolar pathology (distal myopathy, Welander type; tibial muscular dystrophy; adult-onset distal myopathy due to VCP mutation; and vocal cord and distal pharyngeal myopathy).

• Myofibrillar myopathies.

• GNE myopathy.

• Laing early-onset distal myopathy.

• Muscular dystrophies and other inherited myopathies.

• Complex neuromyopathy disorders.

• Congenital myopathies.

• Markesberry-Griggs myopathy.

• Welander’s myopathy.

• Udd’s myopathy.

• Miyoshi’s myopathy.

• Laing’s myopathy.

What Is the Prognosis of GNE Myopathy?

Most patients become wheelchair-bound after one or two decades of the onset of the disease. About five percent of patients have atypical early involvement of the quadriceps muscle, resulting in earlier non-ambulation.

How to Know Whether the Individual Is a Carrier?

GNE myopathy is an autosomal recessive disorder in which the carriers are not affected by the disease and, therefore, do not show symptoms of the disease. However, when two carriers have a child, there is a 25% chance with each pregnancy of having a child who has GNE myopathy, a 50% chance that each child will be a carrier like his or her parents, and a 25% chance that each child will not carry any mutation for the disease.

Conclusion:

GNE myopathy is a very autoimmune recessive hereditary genetic disorder that primarily affects the skeletal muscles. It is characterized by muscle weakness, foot drops, and difficulty in walking. There is no specific treatment approach established yet, but the clinicians are providing targeted treatment based on the underlying strategies for the disease condition.