GNE myopathy is a kind of distal myopathy. Its early symptoms (listed above) are, however, not unique to GNE myopathy, and other forms of distal myopathies may also show similar initial symptoms. This may lead to misdiagnosis and wrong treatment until such time that a muscle biopsy sample is taken and/or the final genetic testing is done to obtain a definitive diagnosis. It is important for patients, their families, and caregivers to be aware of some of the other distal myopathies with overlapping symptoms. Below is a brief account of some of these myopathies.
This myopathy (also called MPD1) is caused by mutations in the myosin gene, which makes the major skeletal muscle protein- myosin. It is an autosomal dominant mutation, which means that even one defective copy of the gene can cause this disease. This implies that one of the parents is most likely to be suffering from the same disease. This disorder causes progressive muscle weakness that appears in childhood (age of onset could be from birth until the 20s). The first sign of Laing Distal Myopathy is usually weakness in certain muscles in the feet and ankles, leading to tightening of the Achilles tendon, an inability to lift the first (big) toe, and foot drop. Months to years later, muscle weakness develops in the hands and wrists, which may lead to hand tremors. In addition, Laing distal myopathy causes weakness in several muscles of the neck and face. A decade or more after the onset of symptoms, mild weakness also spreads to muscles in the legs, hips, and shoulders. This myopathy progresses very gradually, and most affected people remain mobile throughout life. Life expectancy is normal with this condition.
The pathological features are variable. Rimmed vacuoles are found in a minority of patients, and are not prominent when present.
It is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States. The disease is named after the three physicians who first identified it in 1886. CMT, also known as hereditary motor and sensory neuropathy, comprises a group of disorders that affect peripheral nerves. The peripheral nerves lie outside the brain and spinal cord and supply the muscles of the limbs with sensory inputs.
CMT is caused by mutations in genes that produce proteins involved in the function of either the peripheral nerve axon or the myelin sheath. Although different proteins are abnormal in different forms of CMT disease, all of the mutations affect the normal function of the peripheral nerves. Since the nerve cells slowly degenerate and do not signal properly to the muscle cells, over a period of time muscles in the extremities become weak and start wasting (that is muscle mass starts reducing). In some cases, there is also a reduced ability to feel heat, cold, and pain.
CMT can be inherited as autosomal dominant, autosomal recessive, or in an X-linked manner. In the autosomal recessive case, both copies of the abnormal gene must be present to cause the disease. X-linked means that the abnormal gene is located on the X chromosome. In rare cases, it could also be a new mutation in the patient.
The neuropathy of CMT affects both motor and sensory nerves. A typical feature includes weakness of the foot and lower leg muscles, which may result in foot drop and a high-stepped gait with frequent tripping or falls. Foot deformities, such as high arches and hammertoes (a condition in which the middle joint of a toe bends upwards) are also characteristic due to weakness of the small muscles in the feet. Later in the disease, weakness and muscle atrophy may occur in the hands, resulting in difficulty with fine motor skills.
Onset of symptoms is most often between 15-30 years. The severity of symptoms varies from patient to patient. Progression of symptoms is gradual. Pain can range from mild to severe, and some patients may need to rely on foot or leg braces or other orthopaedic devices to maintain mobility. People with most forms of CMT have a normal life expectancy.
For details see: http://www.charcot-marie-tooth.org/
LGMDs are a heterogeneous group of diseases since they can be caused by mutations in one of several different genes. LGMD mutations of the autosomal-dominant type (where one mutated copy can cause disease) are classified as LGMD1, whereas autosomal-recessive type (where both copies must be mutated) are classified as LGMD2. LGMD is a broad group under which >25 gene defects have already been recognized, and more may be added in future.
The most common types of LGMD mutations worldwide are in the genes LGMD2A to F and LGMD2I. LGMD2A (mutation in the calpain gene) is the most frequent type in Spain, Italy, England, Turkey, Russia, China, Brazil and Australia; LGMD2B (mutation in dysferlin gene) is most common in USA, Japan and Mexico, LGMD2C-F (mutation in sarcoglycan G,A,B, or D genes respectively) and LGMD2A (calpain) are most common in India; and LGMD2I (Fukutin-related protein) in Scandinavia. LGMD is considered the second most common muscular dystrophy in England, Mexico and Turkey, after dystrophinopathies, with a disease prevalence of up to 1/14,500 and a carrier frequency of up to 1/150 (Mahmood and Jiang, Mol Med Reports, 9, 1515-1532, 2014).
LGMD is characterized by a progressive weakness of the pelvic and shoulder girdle, and trunk muscles. The hip muscles that move the thigh, the thigh adductors (muscles that draw the thigh towards the body median), and posterior compartment (backside) of the limbs are the most commonly affected. Like in GNE myopathy, facial and neck muscles, and quadriceps are usually spared. Calf hypertrophy (a feature of Duchene and Becker muscular dystrophies) is sometimes seen. Restriction of movement due to loss of joint motion is also a common feature. Rarely, there can be only distal muscle weakness (which could be confused with distal myopathy). Cardiac and respiratory involvement is seen in some types of LGMD.
The course of the disease is highly variable. Symptoms generally appear in teenage but onset could range from early (3 years of age) to mid (15-30 years) to late (> 50 years), and asymptomatic individuals. As in GNE Myopathy, climbing stairs, rising up from the chair, or getting up from the floor can progressively become difficult. The disease is invariably progressive, and loss of ambulation occurs approximately 10-30 years after the onset of symptoms. The electromyogram (EMG) pattern is typically myopathic, although a normal EMG can also be observed in presymptomatic individuals. Amongst the clinical features, involvement of the posterior compartment of the thigh is common, but it may not be present at the later stages. There is moderate to gross elevation of serum creatine kinase.
In GNE Myopathy, the anterior compartment (front side) of the limb is generally involved, while in LGMD the posterior compartment is more often involved. However, in a study of 11 GNE Myopathy patients from Korea with confirmed GNE mutations (Park Y-E et al., J. Neurol. Sci., 321, 77-81, 2012) it was reported that about half of the patients showed symptoms of LGMD rather than GNE myopathy, with relatively spared anterior muscles. Thus, considerable overlap exists in the symptoms of these myopathies, and the only confirmed diagnosis is the gene mutation, knowledge of which is important to obtain the benefit of possible future therapies.
Congenital myopathy refers to a group of muscle disorders that appear at birth or in infancy. Typically, an infant with a congenital myopathy will be "floppy," have difficulty breathing or feeding, and will lag behind other babies in meeting normal developmental milestones such as turning over or sitting up.Muscle weakness can occur for many reasons, including a problem with the muscle, a problem with the nerve that stimulates the muscle, or a problem with the brain.
There are currently seven distinct types of congenital myopathy, with some variation in symptoms, complications, treatment options, and outlook. These include Nemaline Myopathy, Myotubular Myopathy, Central Core Disease, Multi-minicore Disease, Congenital Fiber-Type Disproportion Myopathy, Centronuclear Myopathy, and Hyaline Body Myopathy. Since most of them manifest in infancy or early childhood they are less likely to be confused with GNE Myopathy.
For details see: http://www.ninds.nih.gov/disorders/myopathy_congenital/myopathy_congenital.htm