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1.

Charcot-Marie-Tooth disease axonal type 2Z

Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant axonal peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood. Rare occurrence of global developmental delay with impaired intellectual development or learning difficulties has been observed. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN), which highlights the clinical spectrum associated with MORC2 mutations and may render the classification of patients into one or the other disorder challenging (summary by Sevilla et al., 2016, Ando et al., 2017, Guillen Sacoto et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210). [from OMIM]

MedGen UID:
1800448
Concept ID:
C5569025
Disease or Syndrome
2.

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN) is a complex neurologic disorder characterized by impaired motor and intellectual development, hypotonia, poor overall growth, usually with short stature and microcephaly, and subtly dysmorphic facial features. Affected individuals have distal muscle weakness and muscle atrophy resulting in delayed acquisition of motor skills and persistent gait abnormalities. Although many patients have clinical and/or electrophysiologic features consistent with an axonal sensorimotor peripheral neuropathy, such as hyporeflexia, impaired sensation, foot drop, and pes cavus, the signs and severity are highly variable. Additional features may include hearing loss, pigmentary retinopathy, and abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN syndrome), which highlights the expanding clinical spectrum associated with MORC2 mutations and may render classification of patients into one or the other disorder challenging (summary by Guillen Sacoto et al., 2020). [from OMIM]

MedGen UID:
1765507
Concept ID:
C5436781
Disease or Syndrome
3.

Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.

Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.

Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.

There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. People with CMT2 may develop amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement.In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.

Sometimes other, historical names are used to refer to particular forms of  Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors).  Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome. [from MedlinePlus Genetics]

MedGen UID:
2980
Concept ID:
C0007959
Disease or Syndrome
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