The typical presenting symptom is difficulty walking or running, due to weakness of the distal leg muscles. CMT1A usually presents as the вЂњclassical CMTвЂќ phenotype. Late onset at 76В years is mentioned and a case report describing siblings diagnosed at age 69 and 65В years. Exceptions occur as onset at birth as a floppy infant or with congenital foot deformities. The age of onset of CMT1A is mainly in the first two decades and most frequently in the first 10В years of life. Epidemiological studies show that 19.6% to 64.7% of CMT patients carry the PMP22 duplication, which gives calculated prevalences of CMT1A in the range of 1:3,800 to 1:12,500. Several more recent epidemiological studies reported prevalences of CMT ranging from 1:1,214 (in Norway) to 1:6,500 (in the United Kingdom). Overall prevalence of CMT is usually reported as 1:2,500. This autosomal dominantly inherited demyelinating form of CMT is caused by a 1.5В Mb duplication on chromosome 17p11.2, containing the gene coding for peripheral myelin protein 22 (PMP22) and thus leading to three copies of the PMP22 gene.

CMT1A is the most common subtype of CMT1. Further subclassification is based on the underlying genetic cause. However, nowadays, a nerve biopsy for diagnosis is considered to be obsolete. Previously, histopathological features were also applied to distinguish demyelinating from axonal neuropathy. CMT can be inherited in an autosomal dominant, autosomal recessive and X-linked manner. It has been used in individuals with a MCV between 30 and 40В m/s, in individuals with clinical and histopathological evidence of both abnormal myelin and axon abnormalities and in families in which members have either a demyelinating phenotype or an axonal phenotype, like families with X-linked CMT due to GJB1-mutations, with male members showing a demyelinating type and female an axonal type. Several definitions exist for the term вЂњintermediateвЂќ. The existence of the latter is a controversial topic. the demyelinating type (CMT1) defined by a motor conduction velocity (MCV) of the median or ulnar nerve of less than 38В m/s, the axonal type (CMT2) with MCV above 38В m/s, and an intermediate type. Based on neurophysiologic findings three different subtypes are distinguished, i.e. Classification is based on a combination of neurophysiologic characteristics, inheritance pattern, and underlying genetic cause. Despite the genetic heterogeneity, the clinical phenotype is relatively homogeneous. More than 45 causative genes have been identified. CMT is the commonest inherited neuromuscular disorder. The disease was first described in 1886 by Charcot and Marie in France and independently by Tooth in Great Britain and was named after them. DefinitionД¬harcot-Marie-Tooth disease (CMT), also known as Hereditary Motor and Sensory Neuropathy (HMSN), encompasses a clinically and genetically heterogeneous group of disorders characterized by predominantly distal muscle weakness and atrophy, and sensory loss. Synonyms: Hereditary Motor and Sensory Neuropathy type Ia (HMSN Ia). Life expectancy is normal.Д¬harcot-Marie-Tooth disease type 1A (CMT1A). Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing.

Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Prenatal testing is possible requests for prenatal testing are not common. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. The mode of inheritance is autosomal dominant and de novo mutations occur. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation.

Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. CMT1A usually presents in the first two decades with difficulty walking or running. The prevalence of HNPP is not well known. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes.

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