Distal hereditary motor neuronopathies

Distal hereditary motor neuronopathies (distal HMN, dHMN), sometimes also called distal hereditary motor neuropathies, are a genetically and clinically heterogeneous group of motor neuron diseases that result from genetic mutations in various genes and are characterized by degeneration and loss of motor neuron cells in the anterior horn of the spinal cord and subsequent muscle atrophy.

Although they can hardly be distinguished from hereditary motor and sensory neuropathies on the clinical level, dHMNs are considered a separate class of disorders.

Classification

In 1993, A. E. Hardnig proposed to classify hereditary motor neuropathies into seven groups based on age at onset, mode of inheritance, and presence of additional features. This initial classification has since been widely adopted and expanded and currently looks as follows:^[1][2]

Type	Common name Alternate names	OMIM	Gene	Locus	Inheritance	Characteristics
HMN1	Autosomal dominant juvenile distal spinal muscular atrophy	182960	?	7q34–q36	Autosomal dominant	Juvenile-onset
HMN2A	Autosomal dominant distal spinal muscular atrophy	158590	HSPB8	12q24.23	Autosomal dominant	Adult-onset. Allelic with Charcot–Marie–Tooth disease type 2F
HMN2B		608634	HSPB1	7q11.23	Autosomal dominant	Adult-onset
HMN2C		613376	HSPB3	5q11.2	Autosomal dominant
HMN2D	Distal spinal muscular atrophy with calf predominance	615575	FBXO38	5q32	Autosomal dominant	Juvenile- or adult-onset, slowly progressive, affects both proximal and distal muscles, initially manifests with calf weakness which progresses to hands
HMN3 HMN4	Distal spinal muscular atrophy type 3	607088	?	11q13	Autosomal recessive	HMN3 – benign form: early adult onset, slowly progressive, no diaphragmatic paralysis HMN4 – severe form: juvenile-onset with diaphragmatic paralysis
HMN5A	Distal spinal muscular atrophy type VA	600794	GARS	7p14.3	Autosomal dominant	Upper limb predominance with spasticity of lower limbs Locus and phenotype overlapping with CMT-2D and SPG-17
HMN5B	Distal spinal muscular atrophy type VB	614751	REEP1	2p11.2	Autosomal dominant	Locus and phenotype overlapping with SPG-31
HMN6	Distal spinal muscular atrophy type 1 Spinal muscular atrophy with respiratory distress type 1	604320	IGHMBP2	11q13.3	Autosomal recessive	Infant-onset, severe, with diaphragmatic failure
HMN7A	Spinal muscular atrophy with vocal cord paralysis Harper–Young myopathy	158580	SLC5A7	2q12.3	Autosomal dominant	Infant-onset with vocal cord paralysis
HMN7B		607641	DCTN1	2p13.1	Autosomal dominant	Adult-onset with vocal cord paralysis and facial weakness
HMN-J	Distal spinal muscular atrophy type 2 Jerash type spinal muscular atrophy	605726	?	9p21.1–p12	Autosomal recessive	Juvenile-onset with pyramidal features

See also

• Motor neuron disease
• Hereditary motor and sensory neuropathies
• Spinal muscular atrophies
• Charcot–Marie–Tooth disease
• Hereditary spastic paraplegia

References

1. Irobi, J; De Jonghe, P; Timmerman, V (2004). "Molecular genetics of distal hereditary motor neuropathies". Human Molecular Genetics 13 (suppl 2): R195–R202. doi:10.1093/hmg/ddh226. PMID 15358725.
2. Scherer, SS (2006). "Finding the causes of inherited neuropathies". Archives of Neurology 63 (6): 812. doi:10.1001/archneur.63.6.812. PMID 16769861.