Abstract
In some countries with a high prevalence of consanguineous marriages, autosomal recessive inheritance is likely to account for the great majority of all forms of Charcot-Marie-Tooth (CMT) disease. As with the dominant forms, it is usual to differentiate the demyelinating forms (autosomal recessive [AR]-CMT1 or AR-CMT4) from the axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has proved to be an efficient mean of discovering novel CMT genotypes (eg, the genes GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Because of the clinical, electrophysiologic, and histologic heterogeneity of these patients, it is likely that there are numerous genes that remain to be discovered, which will probably make classification even more complex. Clinical, and especially histologic, phenotypes often lead to a suspicion that a specific gene is implicated. There is, therefore, an indication for nerve biopsy to orient diagnostic research in molecular biology, which is presently very time consuming and can only be performed in highly specialized laboratories.
Similar content being viewed by others
References and Recommended Reading
Dyck PJ, Lambert EH: Lower motor and sensory neuron diseases with peroneal muscular atrophy. 1. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol 1968, 18:603–618.
Gabreëls-Festen AA, Joosten EM, Gabreëls FJ, et al.: Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood. Brain 1991, 114:1855–1870.
Harding AE, Thomas PK: Autosomal recessive forms of hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1980, 43:667–678.
Ouvrier RA, McLeod JG, Morgan GJ, et al.: Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood. J Neurol Sci 1981, 51:181–197.
Pleasure DE: Genetics of Charcot-Marie-Tooth disease. Arch Neurol 2003, 60:481–482.
Ben Othmane K, Hentati F, Lennon F, et al.: Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 1993, 2:1625–1628.
Baxter RV, Ben Othmane K, Rochelle JM, et al.: Gangliosideinduced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002, 30:21–22. First identification of GDAP1 mutation.
Cuesta A, Pedrola L, Sevilla T, et al.: The gene encoding ganglioside-induced differentiation-associated protine 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002, 30:22–25. First identification of GDAP1 mutation.
Birouk N, Azzedine H, Dubourg O, et al.: Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in GDAP1 gene. Arch Neurol 2003, 60:598–604.
De Sandre-Giovannoli A, Chaouch M, Boccaccio I, et al.: Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies due to GDAP1 nonsense and splicing mutations. J Med Genet 2003, 40:e87.
Bolino A, Muglia M, Conforti FL, et al.: Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000, 25:17–19. irst identification of MTMR2 mutations.
Houlden H, King RH, Wood NW, et al.: Mutations in the 5′ region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. Brain 2001, 124:907–915.
Vallat JM, Gil R, Leboutet MJ, et al.: Congenital hypo- and hypermyelination neuropathy. Two cases. Acta Neuropathol 1987, 74:197–201.
Berger P, Schaffitzel C, Berger I, et al.: Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module. Proc Natl Acad Sci U S A 2003, 100:12177–12182.
Ben Othmane K, Johnson E, Menold M, et al.: Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15. Genomics 1999, 62:344–349.
Azzedine H, Bolino A, Taïeb T, et al.: Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet 2003, 72:1141–1153.
Fabrizi GM, Taioli F, Cavallaro T, et al.: Focally folded myelin in Charcot-Marie-Tooth neuropathy type 1B with Ser49Leu in the myekin protein zero. Acta Neuropathol 2000, 100:299–304.
Leguern E, Guilbot A, Kessali M, et al.: Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23q33. Hum Mol Genet 1996, 5:1685–1688.
Kessali M, Zemmouri R, Guilbot A, et al.: A clinical, electrophysiologic, neuropathologic, and genetic study of two large Algerian families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease. Neurology 1997, 48:867–873.
Gabreëls-Festen A, Van Beersum S, Eshuis L, et al.: Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33. J Neurol Neurosurg Psychiatry 1999, 66:569–574.
Tazir M, Vallat JM, Bomont P, et al.: Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1. Neuromuscul Disord 2002, 12:849–852. Nerve lesions of AR-CMT4C seem to be heterogenous. Actually, this case was shown later to be linked to a KIAA1985 mutation.
Senderek J, Bergmann C, Stendel C, et al.: Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet 2003, 73:1106–1119. First identification of mutations in an uncharacterized transcript KIAA1985 in CMT4C families.
Kalaydjieva L, Morar B, Gresham D, et al.: Social and biological history on the Roma (Gypsies). Acta Myol 2001, XX:181–187. Identification and interesting description of a novel demyelinating recessive neuropathy in the Roma (ie, CMT4D).
Butinar D, Starr A: Auditory neuropathy in HMSN-Lom. Acta Myol 2001, XX:220–225.
King RH, Tournev I, Colomer J, et al.: Ultrastructural changes in peripheral nerve in hereditary motor and sensory neuropathy-Lom. Neuropathol Appl Neurobiol 1999, 25:306–312.
Navarro C, Teijeira S: Neuromuscular disorders in the Gypsy ethnic group. A short review. Acta Myologica 2003, XXII:11–14.
Colomer J, Iturriaga C, Kalydjieva L, et al.: Hereditary motor and sensory neuropathy-Lom (HMSNL) in a Spanish family: clinical, electrophysiological, pathological and genetic studies. Neuromuscul Disord 2000, 10:573–583.
Thomas PK, Kalaydjieva L, Youl B, et al.: Hereditary motor and sensory neuropathy-Russe: new autosomal recessive neuropathy in Balkan Gypsies. Ann Neurol 2001, 50:452–457.
Warner LE, Svaren J, Milbrandt J, Lupski JR: Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Gen 1999, 8:1245–1251.
Roa BB, Garcia CA, Pentao L, et al.: Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nat Genet 1993, 5:189–194.
Nelis E, Holmberg B, Adolfsson R, et al.: PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism? Nat Genet 1997, 15:13–14.
Naef R, Suter U: Impaired intracellular trafficking is a common disease mechanism of PMP22 point mutations in peripheral neuropathies. Neurobiol Dis 1999, 6:1–14.
Numakura C, Lin C, Oka N, et al.: Hemizygous mutation of the peripheral myelin protein 22 gene associated with Charcot-Marie-Tooth disease type 1. Ann Neurol 2000, 47:101–103.
Parman Y, Planté-Bordeneuve V, Guiochon-Mantel A, et al.: Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. Ann Neurol 1999, 45:518–522.
Takashima H, Boerkoel CF, De Jonghe P, et al.: Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann Neurol 2002, 51:709–715.
Delague V, Bareil C, Tuffery S, et al.: Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am J Hum Genet 2000, 67:236–243.
Bouhouche A, Benomar A, Birouk N, et al.: A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am J Hum Genet 1999, 65:722–727.
Barhoumi C, Amouri R, Ben Hamida C, et al.: Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooch disease to chromosome 8q21.3. Neuromuscul Disord 2001, 11:27–34.
De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al.: Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002, 70:726–736. This is first reported evidence that mutation in lamin A/C gene may induce AR-CMT2. No other gene that might induce cases of AR-CMT2 is known at the present time.
Thomas PK, Claus D, King RH: Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy. J Neurol 1999, 246:107–112.
Tazir M, Azzedine H, Assami S, et al.: Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain 2003, 127:154–163. Description of the clinical, electrophysiologic, and histologic phenotypes of AR-CMT2 due to a unique mutation in lamin A/C gene.
Muchir A, Bonne G, Van Der Kooi AJ, et al.: Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000, 9:1453–1459.
Di Barletta MR, Ricci E, Galluzzi G, et al.: Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2000, 66:1407–1412.
Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000, 9:109–112.
Novelli G, Muchir A, Sangiuolo F, et al.: Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002, 71:426–431.
Van der KooiAJ, Bonne G, Eymard B, et al.: Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Neurology 2002, 59:620–623.
Sevillano Fernandez JA, Paz Fraile A, Cano Ballesteros JC, et al.: Charcot-Marie-Tooth disease, dilated myocardiopathy and cardiac conduction disorders. Ann Intern Med 1994, 11:455–456.
Enzi G, Anglini C, Negrin P, et al.: Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis. Medicine 1985, 64:388–393.
Becane HM, Bonne G, Varnous S, et al.: High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000, 23:1661–1666.
Goizet C, Yaou RB, Demay L, et al.: A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia. J Med Genet 2004, 41:e29. Mutations of the lamin A/C gene may also be encountered in AD-CMT.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vallat, J.M., Grid, D., Magdelaine, C. et al. Autosomal recessive forms of Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep 4, 413–419 (2004). https://doi.org/10.1007/s11910-004-0089-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11910-004-0089-2