Hereditary motor and sensory neuropathy type V or complicated form of spastic paraplegia?

Abstract

Hereditary motor and sensory neuropathies (HMSN) are a heterogeneous group of peripheral nervous system disorders affecting motor and sensory function. HMSN type V is characterized by the combination of peroneal muscular atrophy with pyramidal features. Inheritance is mostly autosomal dominant but autosomal recessive forms have been described as well. However, no gene responsible for the disease has been identified so far. In complicated forms of Hereditary Spastic Paraplegia (HSP) pyramidal tract dysfunction can be accompagnied by peripheral neuropathy as well as other neurological or non-neurological deficits. Genetics of HSP is heterogeneous, to date 31 genetic loci, termed SPG1–31 have been described. Differentiation between HMSN V and complicated forms of hereditary spastic paraplegia (HSP) is therefore ambiguous and no clinical or electrophysiological diagnostic criteria have been established so far. We performed molecular genetic analysis in 10 families with the combination of motor and sensory neuropathy and pyramidal tract dysfunction. Inheritance was autosomal dominant in 9 families and autosomal recessive in 1 pedigree. In the latter MRI revealed additional atrophy of the corpus callosum. Haplotype analysis mapped the autosomal recessive pedigree to SPG11. No mutations in Atlastin (SPG3) or Spastin (SPG4), responsible for about 50% of autosomal dominant HSP, were found in the remaining 9 families with dominant disease. A novel mutation in the neuronal kinesin heavy chain gene KIF5A (SPG10) was identified in one family. Sequencing of the BSCL2 gene (SPG17) is on-going. Muscular atrophy and peripheral neuropathy in addition to lower limb spasticity are observed in several forms of HSP, including SPG10/17/19 (autosomal dominant) as well as SPG11/14/20/26 (autosomal recessive). We identified SPG10 and SPG11 in families with a HMSN V phenotype. It is likely that most families described in the literature as HMSN type V carry mutations in one of these genes. To prevent further confusion the term HMSN type V should no longer be used. This study and further molecular genetic analyses suggest that families with the HMSN V phenotype should be subsumed under the complicated forms of HSP.