Abstract
The hereditary motor neuronopathies (HMN [MIM 158590]) are heterogeneous group of disorders characterized by an exclusive involvement of the motor part of the peripheral nervous system. They are usually subdivided in proximal HMN, i.e., the classical spinal muscular atrophy syndromes and distal hereditary motor neuronopathies (distal HMN) that clinically resemble Charcot-Marie-Tooth syndromes. In this review, we concentrate on distal HMN. The distal HMN are clinically and genetically heterogeneous and were initially subdivided in seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been delineated. Since the introduction of positional cloning, 13 chromosomal loci and seven disease-associated genes have been identified for autosomaldomainant, autosomal-recessive, and X-linked recessive distal HMN. Most of the genes involved encode protein with housekeeping functions, such as RNA processing, translation synthesis, stress response, apoptosis, and others code for proteins involved in retrograde survival. Motor neurons of the anterior horn of the spinal cord seems to be vulnerable to defects in these house-keeping proteins, likely because their large axons have higher metabolic requirements for maintenance, transport over long distances and precise connectivity. Understanding the molecular pathomechanism for mutations in these genes that are ubiquitous expressed will help unravel the neuronal mechanisms that underlie motor neuropathies leading to denervation of distal limb muscles, and might generate new insights for future thera peutic strategies.
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Agarwal A. K. and Garg A. (2004) Seipin: a mysterious protein. Trends Mol. Med. 10, 440–444.
Antonellis A., Ellsworth R. E., Sambuughin N., et al. (2003) Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299.
Arlotta, P., Molyneaux, B.J., Chen J., Inoue J., Kominami R. and Macklis J. D. (2005) Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221.
Auer-Grumbach, M., Loscher, W. N., Wagner, K., et al. (2000) Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain 123, 1612–1623.
Auer-Grumbach M., Schlotter-Weigel B., Lochmuller, H., et al. (2005) Thenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann. Neurol. 57, 415–424.
Ben Hamida M., Letaief F., Hentati F., and Ben Hamida C. (1987) Morphometric study of the sensory nerve in classical (or Charcot disease) and juvenile amyotrophic lateral sclerosis. J. Neurol. Sci. 78, 313–329.
Bertini E., Gadisseux J. L., Palmieri G., et al. (1989) Distal infantile spinal muscular atrophy associated with paralysis of the dia phragm: a variant of infantile spinal muscular atrophy. Am. J. Med. Genet. 33, 328–335.
Briese M., Esmaeili B., and Sattelle D. B. (2005) Is spinal muscular atrophy the result of defects in motor neuron processes?. Bioessays 27, 946–957.
Bruijn L. I., Miller T. M., and Cleveland D. W. (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749.
Campbell L., Hunter K. M., Mohaghegh P., Tinsley J. M., Brasch M. A., and Davies K. E. (2000) Direct interaction of Smn with dp 103, a putative RNA helicase: a role for Smn in transcription regulation? Hum. Mol. Genet. 9, 1093–1100.
Carpenter S., Karpati G., Rothman S., Watters G., and Andermann F. (1978) Pathological involvement of primary sensory neurons in Werdnig-Hoffmann disease. Acta Neuropathol. (Berl.) 42, 91–97.
Chance P. F., Rabin B. A., Ryan S. G., et al. (1998) Linkage to the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am. J. Hum. Genet. 62, 640.
Charcot J. M. and Marie P. (1886) Sur une forme particulière d'atrophie musculaire progressive, souvent familiale, débutant par les pieds et les jambes et atteignant plus tard les mains. Rev. Méd. 6, 97–138.
Chen Y. Z., Bennett C. L., Huynh H. M., et al. (2004) DNA/RNA helicase gene mutations in a form of juvenile Amyotrophic Lateral Sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135.
Christodoulou K, Kyriakides T., Hristova A. H., et al. (1995) Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p. Hum. Mol. Genet. 4, 1629–1632.
Christodoulou K., Zamba E., Tsingis M. et al. (2000) A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12. Ann. Neurol. 48, 877–884.
Claes S., Devriendt K., Van Goethem G., et al. (2000) Novel syndromic form of X-linked complicated spastic paraplegia. Am. J. Med. Genet. 94, 1–4.
De Jonghe P., Auer-Grumbach M., Irobi J., et al. (2002) Autosomal dominant juvenile ALS and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain 125, 1320–1325.
de Visser M., Ongerboer de V., and Verjaal M. (1988) Amyotrophy of the hands and pyramidal features of predominantly the legs segregating within one large family. J. Neurol. Sci. 88, 241–246.
Diers A., Kaczinski M., Grohmann K., Hubner C, and Stoltenburg-Didinger G. (2005) The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1). Acta Neuropathol. (Berl.) 110, 289–297.
Duquette A, Roddier K., McNabb-Baltar, J., et al. (2005) Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann. Neurol. 57, 408–414.
Dyck P. J., Chance P., Lebo, R., and Carney J. A. (1993) Hereditary motor and sensory neuropathies, in Peripheral Neuropathy, Dyck P. J., Thomas P. K., Griffin J. W., Low P. A., and Poduslo J. F., eds., W. B. Saunders Company. Philadelphia, pp. 1094–1136.
Emery A. E. H. (1971) Review: The nosology of the spinal musculartrophies. J. Med. Genet. 8, 481–495.
Evgrafov O. V., Mersiyanova I. V., Irobi, J., et al. (2004). Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat. Genet. 36, 602–606.
Fleury P. and Hageman G. (1985) A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J. Neurol. Neurosurg. Psychiatry 48, 1037–1048.
Frequin S. T., Gabreels F. J., Gabreels-Festen A. A., and Joosten E. M. (1991) Sensory axonopathy in hereditary distal spinal muscular atrophy. Clin. Neurol. Neurosurg. 93, 323–326.
Frijns C. J., Van Deutekom J., Frants R. R., and Jenekens F. G. (1994) Dominant congenital benign spinal muscularatrophy. Muscle Nerve 17, 192–197.
Grohmann K., Schuelke M., Diers A., et al. (2001) Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat. Genet. 29, 75–77.
Grohmann K., Wienker T. F., Saar K., et al. (1999) Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form is linked to chromosome 11q13-q21. Am. J. Hum. Genet. 65, 1459–1462.
Gross D. W., Rajput A. H., and Yeung M. (1998) Distal hereditary upper limb muscularatrophy. J. Neurol. Neurosurg. Psychiatry 64, 217–220.
Guenther U. P., Schuelke M., Bertini E., et al. (2004) Genomic rearrangements at the IGHMBP2 gene locus in two patients with SMARD1. Hum. Genet. 115, 319–326.
Harding A. E. (1993) Inherited neuronal atrophy and degeneration predominantly of lower motor neurons, in Peripheral Neuropathy, Dyck P. J., Thomas P. K., Griffin J. W., Low P. A. and Poduslo J. F., eds., W. B. Saunders Company, Philadelphia, pp. 1051–1064.
Harding A. E. and Thomas P. K. (1980a) Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J. Neurol. Sci. 45, 337–348.
Harding A. E. and Thomas P. K. (1980b) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103, 259–280.
Holzbaur E. L. (2004) Motor neurons rely on motor proteins. Trends Cell Biol. 14, 233–240.
Ionasescu V. V., Searby C., Sheffield V. C., et al. (1996) Autosomal dominant Charcot-Marie-Toothaxonal neuropathy mapped on chromosome 7p (CMT2D). Hum. Mol. Genet. 5, 1373–1375.
Irobi J., Tissir F., De Jonghe P. et al., (2000) A clone contig of 12q24.3 encompassing the distal hereditary motor neuropathy type II gene. Genomics 65, 34–43.
Irobi, J., Van den Bergh P., Luciano M., et al. (2004a) The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 127, 2124–2130.
Irobi J., De Jonghe P., and Timmerman V. (2004b) Molecular genetics of distal hereditary motor neuropathies. Hum. Mol. Genet. 13, 195–202.
Irobi J., Van Impe K., Seeman P., et al. (2004c) Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nature Genet. 36, 597–601.
Isozumi K., DeLong R, Kaplan J., et al. (1996) Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum. Mol. Genet. 5, 1377–1382.
Jablonka, S., Bandilla M., Wiese S., et al., (2001) Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. Hum. Mol. Genet. 10, 497–505.
Jablonka S., Wiese S., and Sendtner M. (2004a) Axonal defects in mouse models of motoneuron disease. J. Neurobiol. 58, 272–286.
Jablonka S., Wiese S., and Sendtner M. (2004b) Axonal defects in mouse models of motoneuron disease. J. Neurobiol. 58, 272–286.
Jones E. G., Schreyer D. J., and Wise S. P. (1982) Growth and maturation of the rat corticospinal tract. Prog. Brain Res. 57, 361–379.
Jordanova, A., Irobi, J., Thomas F. P., et al. (2006) Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase associated with dominant intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38, 197–202.
LaMonte B. H., Wallace K. E., Holloway B.A., et al. (2002) Disruption of dynein/ dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34, 715–727.
Lander C. M., Eadie M. J., and Tyrer J. H. (1976) Hereditary motor peripheral neuropathy predominantly affecting the arms. J. Neurol. Sci. 28, 389–394.
Lefebvre S., Burglen L., Reboullet S., et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165.
Magre, J., Delepine, M., Khallouf E., et al. (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat. Genet. 28, 365–370.
McEntagart M., Dunstan M., Bell C., et al. (2002) Clinical and genetic heterogeneity in peroneal muscular atrophy associated with vocal cord weakness. J. Neurol. Neurosurg. Psychiatry 73, 762–765.
McEntagart M., Norton N., Williams H., et al. (2001) Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am. J. Hum. Genet. 68, 1270–1276.
McLeod J. G. (1995) Investigation of peripheral neuropathy. J Neurol. Neurosurg. Psychiatry 58, 274–283.
McLeod J. G. and Prineas J. W. (1971) Distal type of chronic spinal muscular atrophy. Clinical, electrophysiological and pathological studies. Brain 94, 703–714.
Mehlen P., Preville X., Chareyron P., Briolay J., Klemenz R., and Arrigo A. P. (1995) Constitutive expression of human hsp27, Drosophila hsp27, or human alpha B-crystallin confers resistance to TNF- and oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts. J. Immunol. 154, 363–374.
Meister G., Buhler D., Laggerbauer B., Zobawa M., Lottspeich F., and Fischer U. (2000) Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. Hum. Mol. Genet. 9, 1977–1986.
Miao M., Chan S. L., Fletcher G. L., and Hew C. L. (2000) The rat ortholog of the presumptive flounder antifreeze enhancer-binding protein is a helicase domain-containing protein. Eur. J. Biochem. 267, 7237–7246.
Middleton L. T., Christodoulou K., Mubaidin A., et al. (1999) Distal hereditary motor neuronopathy of the Jerash type. Ann. NY Acad. Sci. 883, 65–68.
Moreira M. C., Klur S., Watanabe M., et al. (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nature Genet. 36, 225–227.
Munch C., Sedlmeier R., Meyer T., et al. (2004) Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 63, 724–726.
Myrianthopoulos N. C., Lane M. H., Silberberg D. H., and Vincent B. L. (1964) Nerve conduction and other studies in families with Charcot-Marie-Tooth disease. Brain 87, 589–610.
Nelson J. N. and Amick L. D. (1966) Heredofamilial progressive spinal muscular atrophy: a clinical and electromyographic study of a kinship. Neurology 16, 306.
Ogino S., Wilson R. B., and Gold B. (2004) New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations. Eur. J. Hum. Genet. 12, 1015–1023.
Patel H., Hart P. E., Warner T. T., et al. (2001) The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12–q14, with evidence for genetic heterogeneity within this subtype. Am. J. Hum. Genet. 69, 209–215.
Pearn J. and Hudgson P. (1979) Distal spinal muscular atrophy. A clinical and genetic study in 8 kindreds. J. Neurol. Sci. 43, 183–191.
Pellizzoni L., Charroux B., Rappsilber J., Mann M., and Dreyfuss G. (2001) A functional interaction between the survival motor neuron complex and RNA polymerase II. J. Cell Biol. 152, 75–85.
Perng M. D., Cairns L., van den Ijssel P., et al. (1999) Intermediate filament interactions can be altered by HSP27 and alpha B-crystallin. J. Cell Sci. 112, 2099–2112.
Pridmore C., Baraitser M., Brett E. M., and Harding A. E. (1992) Distal spinal muscular atrophy with vocal cord paralysis. J. Med. Genet. 29, 197–199.
Puls I., Jonnakuty C., LaMonte B. H., et al. (2003) Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456.
Puls I., Oh S. J., Summer C. J., et al. (2005) Distal spinal and bulbar muscular atrophy caused by dynactin mutation. Ann. Neurol. 57, 687–694.
Rabin B. A., Griffin J. W., Crain B. J., Scavina M., Chance P. F., and Cornblath D. R. (1999) Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 122, 1539–1550.
Sambuughin N., Sivakumar K., Selenge B., et al. (1998) Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. J. Neurol. Sci. 161, 23–28.
Silver J. R. (1966) Familial spastic paraplegia with amyotrophy of the hands. J. Neurol. Neurosurg. Psychiatry 29, 135–144.
Sivakumar K., Kyriakides T., Puls I., et al. (2005) Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain 128, 2304–2314.
Takata R. I., Martins C. E. S., Passosbueno M. R., et al. (2004) A new locus for recessive distal spinal muscular atrophy at Xq13.1–q21. J. Med. Genet. 41, 224–229.
Tang B., Liu X., Zhao G., et al. (2005a) Mutationa analysis of the small heat shock protein 27 gene in chinese patients with Charcot-Marie-Tooth disease. Arch. Neurol. 62, 1201–1207.
Tang B. S., Luo W., Xia K., et al. (2004) A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum. Genet. 114, 527–533.
Tang B. S., Zhao G. H., Luo W., et al. (2005b) Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum. Genet. 116, 222–224.
Terashima T. (1995) Anatomy, development and lesion-induced plasticity of rodent corticospinal tract. Neurosci. Res. 22, 139–161.
Timmerman V., De Jonghe P., Simokovic S., et al. (1996) Distal hereditary motor neuropathy type II (distal HMN II): mapping of a locus to chromosome 12q24. Hum. Mol. Genet. 5, 1065–1069.
Timmerman V., Raeymaekers P., Nelis E., et al. (1992) Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree. J. Neurol. Sci. 109, 41–48.
Tooth H. H. (1886) The peroneal type of progressive muscular atrophy. H. K. Lewis and Co., London.
van der Vleuten A. J. W., van Ravenswaaij-Arts C. M. A., Frijns C. J. M., et al. (1998) Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23–q24. Eur. J. Hum. Genet. 6, 376–382.
van Gent E. M., Hoogland R. A., and Jennekens F. G. (1985) Distal amyotrophy of predominantly the upper limbs with pyramidal features in a large kinship. J. Neurol. Neurosurg. Psychiatry 48, 266–269.
Viollet L., Zarhrate M., Maystadt I., and Munnich A. (2003) Refinement of the Chronic Distal Spinal Muscular Atrophy (Chronic DSMA) locus on chromosome 11q13.3 and evidence of a founder haplotype in the European population. Am. J. Hum. Genet. 73, 480.
Viollet L., Barois A., Rebeiz J. G., et al. (2002) Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13. Ann. Neurol. 51, 585–592.
Viollet L., Zarhrate M., Maystadt I., et al. (2004) Refined genetic mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.3 and evidence of linkage disequilibrium in European families. Eur. J. Hum. Genet. 12, 483–488.
Williams K. L., Rahimtula M., and Mearow K. M. (2005) Hsp27 and axonal growth in adult sensory neurons in vitro. BMC. Neurosci. 6, 24.
Windpassinger C., Auer-Grumbach M., Irobi J., et al. (2004) Heterozygous missense mutations in the BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature Genet. 36, 271–276.
Young I. D. and Harper P. S. (1980) Hereditary distal spinal muscular atrophy with vocal cord paralysis. J. Neurol. Neurosurg. Psychiatry 43, 413–508.
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Irobi, J., Dierick, I., Jordanova, A. et al. Unraveling the genetics of distal hereditary motor neuronopathies. Neuromol Med 8, 131–146 (2006). https://doi.org/10.1385/NMM:8:1-2:131
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DOI: https://doi.org/10.1385/NMM:8:1-2:131