Nonaka Myopathy is a rare, inherited neuromuscular disorder that causes the progressive weakening and wasting of skeletal muscles. It is also known as GNE Myopathy or Hereditary Inclusion Body Myopathy (hIBM). The condition is characterized by muscle atrophy that slowly progresses over decades, leading to significant disability. As a progressive disorder, it affects the muscles responsible for movement, creating challenges for mobility and daily function.
The Genetic Basis of Nonaka Myopathy
Nonaka Myopathy is caused by a mutation in the GNE gene (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This gene provides instructions for a bifunctional enzyme that performs initial steps in the body’s production of sialic acid, a sugar molecule important for maintaining the health and function of muscle cell membranes. The condition is inherited in an autosomal recessive pattern, meaning a person must inherit two mutated copies of the GNE gene, one from each parent. When the GNE enzyme is compromised, the body cannot produce sufficient sialic acid, leading to hyposialylation. This reduced level of sialic acid impairs muscle glycoproteins and glycolipids, causing muscle degeneration and atrophy.
While the enzyme’s activity is decreased, it is not completely absent, which accounts for the slow, progressive nature of the disease compared to a complete gene knockout. The exact molecular cascade that connects sialic acid deficiency to the formation of characteristic protein aggregates, known as rimmed vacuoles, inside muscle cells is still being investigated.
Identifying the Clinical Symptoms
The physical manifestations of Nonaka Myopathy typically begin in late adolescence or early adulthood, generally between 20 and 40 years of age. The first and most noticeable symptom is often bilateral foot drop, which is the inability to lift the front part of the foot due to weakness in the tibialis anterior muscle. This weakness causes a person to trip frequently and adopt a characteristic “steppage gait” as they try to clear their toes from the ground while walking.
The muscle weakness follows a distinct pattern, starting in the distal muscles of the lower legs and progressing upwards toward the center of the body. Weakness spreads from the front of the lower leg to the posterior compartment, involving the calf and hamstring muscles, and later the hip girdle. A defining feature of Nonaka Myopathy is the relative sparing of the quadriceps muscles at the front of the thighs until the disease reaches its very late stages.
As the condition advances, patients experience increasing functional limitations, such as difficulty climbing stairs or rising from a seated position. Weakness in the upper extremities usually appears five to ten years after the initial onset in the legs, affecting the hands and shoulders. The progressive muscle wasting often necessitates the use of assistive devices, with many individuals requiring a wheelchair approximately 10 to 20 years after the initial appearance of symptoms.
Supportive Care and Management Strategies
Since there is currently no approved cure for Nonaka Myopathy, management focuses entirely on supportive care aimed at preserving function and maximizing the quality of life. A multidisciplinary team, including neuromuscular specialists, physical therapists, and occupational therapists, works to address the patient’s evolving needs. Physical therapy maintains mobility and strengthens less-affected muscle groups, while occupational therapy provides strategies and adaptive devices to help with daily activities, especially as hand and arm weakness develops.
Mobility aids such as Ankle-Foot Orthoses (AFOs) are often prescribed early on to manage foot drop and reduce the risk of falls. Canes, walkers, and custom-fit wheelchairs are introduced as the disease progresses to support walking and overall mobility. Pain management addresses discomfort that can arise from muscle atrophy, joint strain, and altered gait mechanics. While the disease mechanism involves a deficiency in sialic acid, early clinical trials for sialic acid supplementation, such as aceneuramic acid extended-release, have failed to show a statistically significant clinical benefit. Research continues into other therapies, including the sialic acid precursor N-acetylmannosamine (ManNAc) and gene therapy approaches to deliver a healthy copy of the GNE gene.