Charcot-Marie-Tooth Disease, Axonal, Type 2p

A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 2P (CMT2P) can be caused by homozygous or heterozygous mutation in the LRSAM1 gene (610933) on chromosome 9q33.

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Clinical Features

Guernsey et al. (2010) identified an extended multiply consanguineous family derived from a rural eastern Canadian isolate with 7 members affected with axonal CMT. Three further individuals were suspected to be affected. The index patient noted gradual onset of weakness around age 20, particularly affecting his distal lower extremities but also present in the hands. He noted episodic muscle cramping of extremity and trunk muscles. At the time of the examination he demonstrated bilateral pes cavus with marked wasting of distal lower extremity muscles and mild wasting of hand intrinsic muscles. Fasciculations were present in upper and lower extremity muscles. There was no gait ataxia. Upper and lower tendon reflexes were absent. He had mild loss of sensation on fingertips and severe loss of sensation in feet and legs, most markedly to vibration but also involving proprioception and pain perception. Other affected family members exhibited sensory and motor dysfunction with pes cavus. Autonomic symptoms were not consistently reported. Weakness and wasting were moderate and predominantly in distal lower extremity muscles. Onset was usually in the early adult years.

Weterman et al. (2012) reported a large 3-generation family with autosomal dominant inheritance of an axonal peripheral neuropathy consistent with CMT. Affected individuals presented in the second or third decade of life with progressive distal muscle weakness and mild sensory disturbances in the feet. Electrophysiologic studies in affected individuals revealed a severe axonal neuropathy. Sural nerve biopsy in one affected individual demonstrated severe axonal degeneration.

Nicolaou et al. (2013) reported a large 4-generation family from Sardinia with autosomal dominant axonal CMT. The proband developed distal weakness in the left lower limb and foot drop at about 34 years of age. At age 43, he showed moderate foot drop, could not stand on his heels, and had difficulty standing on his toes. There was atrophy in the lower legs and feet, as well as distal sensory loss. The upper limbs were not affected. He reported occasional cramps in the calf muscles and erectile dysfunction. Nerve conduction studies were consistent with an axonal form of CMT. Other affected family members had a similar phenotype, with onset between ages 15 and 50 years of slowly progressive distal weakness, atrophy, and multimodal hypesthesia in the lower limbs, diffusing to the upper limbs in later years. All except 1 patient remained ambulatory.

Berciano et al. (1986) described a large family of Spanish descent in which 10 members over 3 generations had a neuronal form of hereditary motor and sensory neuropathy. Peak age at onset was in the second decade. Some members showed slight slowing of conduction velocities, and 3 had normal conduction studies. Nerve biopsy showed regenerating fibers and atrophic axons, with some loss of myelinated fibers. There were several instances of male-to-male transmission. Nelis et al. (2004) presented follow-up studies on the family reported by Berciano et al. (1986). They noted that a total of 14 members of the family were affected. The age at onset ranged from 9 to 76 years (mean, 29 years), although most patients developed symptoms in the second decade. The disease presented with foot deformity and difficulty walking, with very slow progression. Ankle reflexes were absent or hypoactive in all patients, whereas knee reflexes were sometimes preserved. Mild stocking hypesthesia was present. There were normal or mildly decreased motor nerve conduction velocities (NCV) consistent with axonal CMT. Peeters et al. (2016) reported follow-up of the family reported by Berciano et al. (1986). Thirteen affected individuals spanning 3 generations had a mild, very slowly progressive or nonprogressive sensorimotor neuropathy affecting the lower limbs and resulting in difficulty walking. Affected individuals in the last generation, ranging in age from 35 to 47, were asymptomatic, but showed variable features including pes cavus, toe clawing, stocking hypoesthesia, ankle areflexia, and amyotrophy. Electrophysiologic studies showed normal or slightly decreased nerve conduction velocities and variably decreased SNAP and CMAP amplitudes. EMG studies were consistent with chronic denervation. MRI of lower limb muscles showed atrophy and fatty replacement. The findings were consistent with a length-dependent sensorimotor axonopathy affecting lumbosacral motor and sensory neurons. Several individuals previously thought to be affected in previous reports were reexamined and reclassified as being unaffected. Peeters et al. (2016) emphasized that many of the patients had very mild or even clinically asymptomatic disease, making the diagnosis difficult in the absence of electrophysiologic studies.

Inheritance

The transmission pattern of axonal CMT in the family described by Guernsey et al. (2010) was consistent with autosomal recessive inheritance. The transmission pattern in the family reported by Weterman et al. (2012) was consistent with autosomal dominant inheritance.

The transmission pattern of CMT2P in the family reported by Peeters et al. (2016) was consistent with autosomal dominant inheritance with incomplete penetrance.

Mapping

By genomewide linkage analysis of a Sardinian family with autosomal dominant axonal CMT, Nicolaou et al. (2013) found linkage to chromosome 9q33-q34 (maximum 2-point lod score of 8.06 at D9S63).

By linkage analysis in the Spanish CMT family originally reported by Berciano et al. (1986), Nelis et al. (2004) mapped the disease locus, designated CMT2G, to a 13.2-Mb (12.8-cM) region on chromosome 12q12-q13.3. However, later linkage studies by Peeters et al. (2016) reassigned the disease locus to a 23.6-Mb region on 9q31.3-q34.2 between markers D9S2026 and D9S164 (Zmax = 3.186).

Molecular Genetics

In affected members of a large consanguineous family with CMT2, Guernsey et al. (2010) found homozygosity for a splice site mutation in the LRSAM1 gene (610933.0001). Heterozygous mutation carriers were unaffected.

In affected members of a large 3-generation family with autosomal dominant axonal CMT2P, Weterman et al. (2012) identified a heterozygous frameshift mutation in the LRSAM1 gene (610933.0002). The mutation was identified by next-generation sequencing in the region of interest as determined by linkage analysis. Weterman et al. (2012) noted that zebrafish models had disturbed neurodevelopment and affected tail formation and movement.

In affected members of a large Sardinian family with autosomal dominant axonal CMT, Nicolaou et al. (2013) identified a heterozygous truncating mutation in the LRSAM1 gene (610933.0003).

In affected members of a large Spanish family with autosomal dominant CMT2P, Peeters et al. (2016) identified a heterozygous missense mutation in the LRSAM1 gene (C694Y; 610933.0004). Transcriptome analysis of patient lymphoblasts showed several misregulated transcripts, including increased levels of NEDD4L (606384), another ubiquitin ligase, and TNFRSF21 (605732), a regulator of axonal degeneration, compared to controls. TSG101 (601387) levels were unchanged in patient cells. The family was originally reported by Berciano et al. (1986) and Nelis et al. (2004) as having CMT2G.