Some science behind the scenes

Charcot-Marie-Tooth disease

Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Tooth neuropathy, and peroneal muscular atrophy is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterised by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, and affects approximately 1 in 2,500 people. CMT was previously classified as a subtype of muscular dystrophy.

Symptoms

Symptoms of CMT usually begin in early childhood or early adulthood, but can begin earlier. Some people do not experience symptoms until their early thirties or forties. Usually, the initial symptom is foot drop early in the course of the disease. This can also cause hammer toe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses.

Loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms occur with various types of the disease. Early and late onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. High arched feet (pes cavus) or flat arched feet (pes planus) are classically associated with the disorder.

Sensory and proprioceptive nerves in the hands and feet are often damaged, while pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.

Symptoms and progression of the disease can vary. Involuntary grinding of teeth as well as squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some; so can hearing, vision, as well as the neck and shoulder muscles. Scoliosis is common, causing hunching and loss of height. Hip sockets can be malformed.

Gastrointestinal problems can be part of CMT, as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords).

A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as extreme emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.

Pain due to postural changes, skeletal deformations, muscular fatigue and cramping is fairly common in people with CMT.

Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity varies from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies, as well as Postherpetic neuralgia and Complex regional pain syndrome, among other diseases.

Causes

Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

The most common cause of CMT (70-80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein. Cells contain separate sets of genes in their nucleus and in their mitochondria. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning.

Inherited peripheral neuropathies are among the most common genetic neuromuscular disorders worldwide. However, their diagnosis can be challenging due to genotypic and phenotypic variability. Charcot-Marie-Tooth disease (CMT), the most common form, is associated with mutations or copy-number variations in over 70 genes, representing proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Other genetic peripheral neuropathies are associated with multisystem manifestations, including familial amyloid neuropathy and neuropathies associated with metabolic or other genetic syndromes.  PMID:  25299278

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inherited diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.

References

Continuum (Minneap Minn). 2014 Oct;2015 Peripheral Nervous System Disorders:1208-25. doi: 10.1212/01.CON.0000455885.37169.4c.  Charcot-Marie-Tooth disease and other inherited neuropathies.  Saporta MA.

Observations

For iPad/iPhone users: tap letter twice to get list of items.