Hereditary peripheral neuropathies are a large group of genetic diseases with an overall prevalence of 1 in 2500; they include Charcot-Marie-Tooth (CMT) disease, hereditary sensory neuropathy, hereditary motor neuropathy, and hereditary neuropathy with liability to pressure palsies (HNPP). Here we focus on CMT disease and HNPP.
ESSENTIALS OF DIAGNOSIS AND TYPICAL FEATURES
A heterogeneous group of hereditary sensory and motor neuropathies
The most common genetic neuromuscular disorder in children
Clinically presents with distal muscle weakness and atrophy and foot deformity that is often associated with sensory loss
Medical management is primarily supportive in nature
CMT disease refers to a group of genetic disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy (HMSN). It is the most prevalent genetic neuromuscular disease in children and traditionally divided into 3 groups: demyelinating, axonal, and dominant intermediate types.
Mutations in more than 80 genes have been identified to date, with the peripheral myelin 22 (PMP22) gene duplication in CMT1A being most common, which accounts for about 50% of all CMT diseases. Inheritances of this heterogeneous group of genes range from autosomal dominant and autosomal recessive to X-linked dominant or recessive types. A gene-based classification of hereditary neuropathies was proposed in 2018 by Magy and colleagues to provide more complete and informative classification, including descriptions of mode of inheritance, neuropathy type, and causative genes.
Patients typically present with symmetric, slowly progressive distal motor neuropathy of the arms and legs that results in weakness and atrophy of the distal muscles, especially weak ankle dorsiflexion, diminished deep tendon reflexes, and feet deformities (eg, pes cavus). The majority of affected individuals have symptoms beginning in the first to second decade of life. There is often associated mild-to-moderate distal sensory loss and, in some patients, associated pain.
The demyelinating neuropathy type is typically slowly progressive with symptoms of both distal weakness and sensory loss. Foot deformities with pes cavus are common, and patients may have bilateral foot drop. About 5% of patients become wheelchair dependent, with a normal life span expected. The axonal neuropathy type presents primarily with progressive distal weakness and muscle atrophy, with typically less severe symptoms and less sensory loss compared to the demyelinating neuropathy type. It is worth noting that in the less common third group, which is the dominant intermediate type, the neuropathy varies, with some affected members of the same family being axonal and others being demyelinating.
Serum creatinine kinase levels may be normal or mildly elevated. Electromyography (EMG) and nerve conduction studies (NCSs) are abnormal with demyelinating and/or axonal neuropathic features. Demyelinating is defined as a nerve conduction velocity (NCV) less than 35 m/s, axonal is ...