GNE Myopathy

 GNE Myopathy

OVERVIEW

GNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). First signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance. 1,2

GNE myopathy is caused by changes (mutations) in the GNE gene, which encodes for an enzyme known as glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase. The enzyme is responsible for the production of sialic acid (SA), a sugar required by all cells including muscle to produce energy as well as an important component of cell membranes. The condition is inherited in an autosomal recessive manner.3

Currently, there is no cure for the disease and treatment is focused on managing the symptoms. However, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies.

The term GNE myopathy refers to a group of diseases described worldwide by different investigators and physicians over the last few decades. In 1984, Nonaka et al. were the first to describe a rare muscle disorder predominantly affecting the anterior tibialis muscles and characterized by mild serum creatine kinase (CK) elevation and muscle atrophy. Under a microscope, muscle biopsies often showed characteristic histopathological changes including rimmed vacuoles, lack of inflammation, and no evidence of regeneration. 4,5 As such, they initially termed the disease distal myopathy with rimmed vacuoles (DMRV) to describe a familial myopathy with onset in early adulthood. Reports followed by from Argov and Yarom describing a similar pathology found in Iranian Jewish families and characterized by autosomal recessive inheritance. In addition to showing the typical presence of rimmed vacuoles in muscle biopsies, these studies also suggested that the disease spared the quadriceps.3 This led the group to name the condition hereditary inclusion body myopathy (HIBM).6 Other historical names include Nonaka myopathy, inclusion body myopathy 2 (IBM2) and quadriceps sparing myopathy (QSM). Finally, the identification in the early 2000’s of GNE gene mutations being responsible for these diseases has led to a grouping of the disorders under the same name now known and commonly referred to as GNE myopathy.

SYNONYMS

hereditary Inclusion body myopathy

HIBM

h-IBM

IBM2

inclusion body myopathy, autosomal recessive

inclusion body myopathy, quadriceps-sparing

QSM

hereditary inclusion body myopathy

distal myopathy with rimmed vacuoles

DMRV

Nonaka myopathy

rimmed vacuole myopathy

quadriceps sparing myopathy

SYMPTOMS

GNE myopathy manifests between the second and third decade of life and is characterized by progressive muscle wasting often accompanied by severe incapacitation within 10 to 20 years after onset. Even at early stages of the disease, GNE myopathy patients exhibit a characteristic bilateral foot drop which is caused by weakness of the tibialis anterior muscle (one of the frontal muscles that is connected to the knee and the foot). Early stage muscle weakness in GNE myopathy patients can include disturbed gait and decreased stability, frequent falls, difficulty in climbing stairs, running and getting up from a seated position. Most patients end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first with the exception of the quadriceps which appears to be relatively spared. As the disease progresses, 5 to 10 years after the onset of symptoms, the majority of patients experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected. 1, 10, 11 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers

CAUSES

GNE myopathy is caused by mutations in the GNE gene. This gene is responsible for the production of an enzyme needed to make SA. Patients consistently express lower levels of SA as clearly demonstrated by analyses performed on muscle biopsies. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, although further studies are required to determine the specific mechanisms of action of the GNE enzyme in muscle. Mutations in GNE can occur anywhere along the sequence of the gene. The majority of mutations reported are so-called missense mutations. These are alterations of the genetic code that only produce a small change in the genetic sequence but affect the function of the GNE enzyme.

GNE myopathy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. If one parent is a carrier and the other parent has GNE myopathy, the risk to have an affected child is 50% with each pregnancy. The risk is the same for males and females.

DISORDERS WITH SIMILAR SYMPTOMS

Clinically, the diagnosis may be confused with other conditions, such as other distal myopathies, limb girdle muscular dystrophy, spinal muscular atrophy or Charcot-Marie-Tooth disease. As such, referral to a neuromuscular specialist is highly recommended.

DIAGNOSIS

Patients presenting with foot drop (young adults) and distal extremity muscle weakness (in individuals at more advance stages of the disease) are good candidates for GNE myopathy testing.

Genetic testing represents an ideal first option to assess GNE myopathy in patients. This involves the use of minimal or no invasive procedures, only requires a blood or a saliva sample and results can be obtained in a matter of hours or days. However, because missense mutations don’t necessarily imply defects in enzyme function, the genetic testing alone cannot be considered definitive to provide a diagnosis or to rule out other neuromuscular disorders. Additional testing is needed to confirm GNE myopathy, to rule out the presence of other pathologies as well as to determine the stage of the disease. Tests include a muscle biopsy, which necessitates taking a small sample of muscle using a needle. A magnetic resonance imaging (MRI) will help determine the extent of the damage to lower and upper limb muscles. Echocardiogram and pulmonary function tests are also recommended in non-ambulatory individuals.

Type of Doctor Department : Neurologist