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DNM2-related intermediate Charcot-Marie-Tooth neuropathy(DI-CMTB)

MedGen UID:
338346
Concept ID:
C1847902
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth disease dominant intermediate 1; Charcot-Marie-Tooth disease dominant intermediate I; CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B; CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE B; CMT DI1; DI-CMTB
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
892334
Concept ID:
CN000007
Functional Concept
Source: HPO
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): DNM2 (19p13.2)
OMIM®: 606482

Disease characteristics

DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity, depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss. Age of onset varies greatly among affected individuals and ranges from age two to 50 years. It is unusual for individuals with DI-CMTB to become wheelchair bound. Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years). [from GeneReviews]
Authors:
Stephan Züchner  |  Feifei Tao   view full author information

Additional descriptions

From OMIM
Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Classification CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by Salisachs (1974) and Davis et al. (1978). Davis et al. (1978) proposed that this form be designated 'intermediate' CMT. Claeys et al. (2009) stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). Genetic Heterogeneity of Autosomal Dominant Intermediate CMT In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIC (608323), caused by mutation in the YARS gene (603623) on chromosome 1p35-p34l; CMTDID (607791), caused by mutation in the MPZ gene (159440) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; 614455), caused by mutation in the INF2 gene (610982) on chromosome 14q; and CMTDIF (615185), caused by mutation in the GNB4 gene (610863) on chromosome 3q26. CMTDIA (606483) has been mapped to chromosome 10q24.1-q25.1.  http://www.omim.org/entry/606482
From GHR
Charcot-Marie-Tooth disease is a group of progressive disorders that affect 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 can result in 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, even among members of the same family. Some people never realize they have the disorder, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in 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 involve balance difficulties, clumsiness, and muscle weakness 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 (or gait) and increase the risk of ankle injuries and tripping.As the disease progresses, 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 this disorder typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In some cases, affected individuals experience gradual hearing loss, deafness, or loss of vision.There are several types of Charcot-Marie-Tooth disease. Type 1 Charcot-Marie-Tooth disease (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to conduct nerve impulses. These abnormalities slow the transmission of nerve impulses. Type 2 Charcot-Marie-Tooth disease (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body and transmits nerve impulses. These abnormalities reduce the strength of the nerve impulse. Type 4 Charcot-Marie-Tooth disease (CMT4) affects either the axon or myelin and is distinguished from the other types by its pattern of inheritance. In intermediate forms of Charcot-Marie-Tooth disease, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both axons and myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in a gene 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) are distinguished by the specific gene that is altered.Sometimes other, more historical names are used to describe this disorder. For example, Roussy-Levy syndrome is a form of Charcot-Marie-Tooth disease defined by 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 Charcot-Marie-Tooth disease 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. Some researchers believe that this condition is not actually a form of Charcot-Marie-Tooth disease. Instead, they classify it as a separate disorder characterized by peripheral nerve problems, deafness, and vision loss.  https://ghr.nlm.nih.gov/condition/charcot-marie-tooth-disease

Clinical features

Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Absent tendon reflex
MedGen UID:
548673
Concept ID:
C0278124
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Segmental peripheral demyelination/remyelination
MedGen UID:
335873
Concept ID:
C1843077
Finding
A segmental pattern of demyelination and regeneration (remyelination) affecting peripheral nerves.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Onion bulb formation
MedGen UID:
376237
Concept ID:
C1847906
Finding
Repeated episodes of segmental demyelination and remyelination lead to the accumulation of supernumerary Schwann cells around axons, which is referred to as onion bulb formation. This finding affects peripheral nerves.
Decreased number of peripheral myelinated nerve fibers
MedGen UID:
346872
Concept ID:
C1858285
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
Segmental peripheral demyelination
MedGen UID:
870491
Concept ID:
C4024938
Finding
A loss of myelin from the internode regions along myelinated nerve fibers from segments of the peripheral nervous system.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Finding
Muscular atrophy affecting muscles in the distal portions of the extremities.

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