Alternative titles; symbolsHMSN VHMSN5PERONEAL MUSCULAR ATROPHY WITH PYRAMIDAL FEATURES, AUTOSOMAL DOMINANTCHARCOT-MARIE-TOOTH DISEASE WITH PYRAMIDAL FEATURES, A...
Alternative titles; symbols
Cytogenetic location: 4q34.3-q35.2 Genomic coordinates (GRCh38): 4:176,600,000-190,214,555
Hereditary motor and sensory neuropathies (HMSN) are a heterogeneous group of peripheral nervous system disorders affecting motor and sensory function. HMSN I, also known as Charcot-Marie-Tooth (CMT) disease, or peroneal muscular atrophy, type 1, is a demyelinating neuropathy (see CMT1B; 118200) and HMSN II, also known as CMT type 2, is an axonal neuropathy (see CMT2A1; 118210). See also HMSN III (145900) and HMSN IV (266500).
For an autosomal recessive disorder with similarities to HMSN V, see 607731.
▼ Clinical Features
Dyck and Lambert (1968) described 8 patients in 2 kindreds in whom peroneal muscular atrophy was associated with hereditary spastic paraplegia (SPG), and classified the disorder as hereditary motor and sensory neuropathy type V (HMSN5). Harding and Thomas (1984) reported 25 cases from 15 families and referred to the disorder as 'peroneal muscular atrophy with pyramidal features.' Inheritance was autosomal dominant, and onset was usually in the first 2 decades of life with difficulty in walking. The syndrome superficially resembled HMSN types I and II (CMT1 and CMT2) with distal muscle wasting and weakness involving the legs more than the arms. Ankle reflexes were often absent, but deep tendon reflexes in the upper limbs and knees were normal or increased. In addition, extensor plantar responses were present in 22 patients and 30% of individuals had increased tone and weakness in the proximal lower limb muscles without overt spasticity. Mean motor nerve conduction velocity (MCV) was lower than normal, and two-thirds of the patients had reduced sensory nerve amplitudes. The disorder was slowly progressive. Vucic et al. (2003) noted that some of the families described by Harding and Thomas (1984) included families with sensory loss, suggestive of CMT (HMSN), and families without sensory loss, suggestive of hereditary motor neuropathy (HMN).
In a large Italian family with autosomal dominant HMSN V spanning 4 generations, Mostacciuolo et al. (2000) reported that affected members showed heterogeneous clinical signs and variable severity. Disease onset was after the third or fourth decade (average 39 years) with weakness, cramps, and pain in the legs. Some patients reported severe cramps during the night. Other features included a slow paraparetic gait, increased deep tendon reflexes, decreased sensation, and pes cavus. Two patients had EMG and sural nerve biopsy findings consistent with an axonal neuropathy. The authors noted that whereas most patients presented coexistence of the 2 syndromes, 2 had predominant pyramidal signs, and 2 had a predominant sensory neuropathy.
Passamonti et al. (2004) reported a large Italian family with autosomal dominant inheritance of distal hereditary motor neuronopathy with pyramidal features. The average age at onset was around 25 to 35 years with difficulty in walking, repeated falls, distal lower limb weakness and atrophy, and urinary urgency. Other more variable features included hyperreflexia, knee clonus, depressed ankle tendon reflexes, extensor plantar responses, and pes cavus. Although there were no prominent sensory symptoms, many had a slightly reduced vibration sense in the feet. Bulbar and upper limb involvement did not occur. Nerve conduction velocities were consistent with a motor axonal neuropathy-neuronopathy. Passamonti et al. (2004) noted the phenotypic similarities to the family with ALS4 (602433) reported by Chance et al. (1998), but excluded linkage to that region on chromosome 9q34.
Mostacciuolo et al. (2000) performed linkage analysis for markers associated with all the known loci for autosomal dominant and autosomal recessive forms of hereditary spastic paraplegia and HMSN II in a large Italian family with HMSN type V. No linkage was found, suggesting that HMSN V is both a clinically and a genetically distinct entity.
By genomewide analysis of an Italian family with distal hereditary motor neuronopathy with pyramidal features previously reported by Passamonti et al. (2004), Muglia et al. (2008) found linkage to a 26-cM region on chromosome 4q34.3-q35.2 between markers D4S1552 and D4S2930 (maximum lod score of 3.19 at D4S408). No mutations were identified in the SNX25, CASP3 (600636), or TUBB4Q genes.
The nomenclature and classification of this and related disorders remain problematic. Harding (1983) suggested that a proper classification of peroneal muscular atrophy with HSP may be within the 'complicated' forms of HSP, and Gemignani et al. (1992) stated that it may be inappropriate to allocate peroneal muscular atrophy with HSP as a unique subtype of HMSN.