Pragmatische Diagnostik hereditärer Neuropathien

Zusammenfassung

Hereditäre Neuropathien sind eine klinisch und genetisch heterogene Gruppe von Neuropathien. Unter den hereditären Neuropathien sind die mit sensiblen und motorischen Symptomen (Hereditäre motorische und sensible Neuropathien, HMSN -auch zusammengefasst unter Charcot-Marie-Tooth-Erkrankungen, CMT) am häufigsten. Mit einer Inzidenz von 1:2 500 gehören sie zu den seltenen Erkrankungen. In der klinischen Neurologie stellen sie die häufigste neurogenetische Erkrankung dar. Allerdings gibt es auch die rein sensiblen Formen, mit oder ohne autonomen Symptomen (HSAN) oder rein motorischen hereditären Neuropathien (dMHN) sowie die hereditäre Neuropathie mit Neigung zu Druckparesen (HNPP). In den letzten Jahren hat die molekulargenetische Diagnostik enorme Fortschritte gemacht, sodass die Gendiagnostik mittlerweile zum integralen Bestandteil der Diagnostik von Patienten mit hereditären Neuropathien gehört. Aufgrund der klinischen und genetischen Heterogenität ist die Zuordnung der hereditären Neuropathien bei über 80 potentiell krankheitsverursachenden Genen schwer. Nichts desto trotz werden über 90% aller genetisch gesicherten CMTs durch Mutationen in 4 Genen (PMP22, Cx32, MPZ und MFN2) geklärt. Wir möchten hier einen kurzen Überblick über die hereditären Neuropathien und einen pragmatischen Leitfaden für die molekulargenetische Diagnostik vorstellen. Darüber hinaus werden die Möglichkeiten der weiterführenden Diagnostik, welche in unseren Augen spezialisierten Zentren vorbehalten sein sollte, vorgestellt und diskutiert.

Abstract

Hereditary neuropathies are a clinically and genetically heterogeneous groups of neuropathies. Among the hereditary neuropathies, those forms associated with sensory and motor symptoms (hereditary sensorimotor neuropathy, and HMSN, also known as Charcot-Marie-Tooth-disease, CMT) are the most common. With an incidence of 1:2 500, they are among the group of orphan diseases. In the field of clinical neurology, they represent the most common neurogenetic disorder. However, there are also purely sensory forms, with or without autonomic symptoms (HSAN), or pure motor hereditary neuropathies (dMHN) as well as hereditary neuropathy with liability to pressure palsies (HNPP). In recent years, genetic testing has made enormous advances so that genetic testing is now an integral part of the diagnosis of patients with hereditary neuropathies. Both clinically and genetically extremely heterogeneous, the assignment of hereditary neuropathies is difficult with more than 80 potentially disease-causing genes. Nevertheless, over 90% of all genetically assured CMTs are clarified by mutations in 4 genes (PMP22, Cx32, MPZ and MFN2). We present here a brief overview of hereditary neuropathies and a pragmatic guideline for molecular genetic diagnostics. In addition, we present and discuss possibilities of further diagnostics, which we believe should be done in specialized centers.

Schlüsselwörter

HMSN - CMT - Neuropathie - Genetik

Keywords

HMSN - CMT - neuropathy - genetic

• Literatur

• 1 Fridman V, Bundy B, Reilly MM et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry 2015; 86: 873-878
• 2 Gess B, Schirmacher A, Boentert M et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013; 23: 647-651
• 3 Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980; 103: 259-280
• 4 Hoyer H, Braathen GJ, Busk OL et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int 2014; 210401
• 5 Pareyson D, Scaioli V, Laura M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 2006; 8: 3-22
• 6 Harel T, Lupski JR. Charcot-Marie-Tooth disease and pathways to molecular based therapies. Clin Genet 2014; 86: 422-431
• 7 Horacek O, Mazanec R, Morris CE et al. Spinal deformities in hereditary motor and sensory neuropathy: a retrospective qualitative, quantitative, genotypical, and familial analysis of 175 patients. Spine (Phila Pa 1976) 2007; 32: 2502-2508
• 8 Ushiyama T, Tanaka C, Kawasaski T et al. Hip dysplasia in Charcot-Marie-Tooth disease: report of a family. J Orthop Sci 8: 610-612
• 9 Laura M, Hutton EJ, Blake J et al. Pain and small fiber function in Charcot-Marie-Tooth disease type 1A. Muscle Nerve 2014; 50: 366-371
• 10 Jeong NY, Shin YH, Jung J. Neuropathic pain in hereditary peripheral neuropathy. J Exerc Rehabil 2013; 9: 397-399
• 11 Boentert M, Knop K, Schuhmacher C et al. Sleep disorders in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry 2014; 85: 319-325
• 12 Boentert M, Dziewas R, Heidbreder A et al. Fatigue, reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease: a web-based survey. J Neurol 2010; 257: 646-652
• 13 Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol 2009; 652: 207-224
• 14 Murphy SM, Laura M, Fawcett K et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012; 83: 706-710
• 15 Harding AE, Thomas PK. Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J Med Genet 1980; 17: 329-336
• 16 Dyck PY, Lamberteh Mulder DW. Conduction velocity of nerves in a family with Charcot-Marie-Tooth disease: detection of latent involvement. Trans Am Neurol Assoc 1961; 86: 207-208
• 17 Li J, Parker B, Martyn C et al The PMP22 gene and its related diseases. Mol Neurobiol 2013; 47: 673-698
• 18 van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY et al. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet J Rare Dis 2014; 9: 38
• 19 Chance PF. Overview of hereditary neuropathy with liability to pressure palsies. Ann N Y Acad Sci 1999; 883: 14-21
• 20 Sanmaneechai O, Feely S, Scherer SS et al. Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain 2015; 138: 3180-3192
• 21 Yger M, Stojkovic T, Tardieu S et al. Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C. J Peripher Nerv Syst 2012; 17: 112-122
• 22 Feely SM, Laura M, Siskind CE et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 2011; 76: 1690-1696
• 23 Scherer SS, Kleopa KA. X-linked Charcot-Marie-Tooth disease. J Peripher Nerv Syst 2012; (Suppl 3): 9-13
• 24 Shy ME, Siskind C, Swan ER et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology 2007; 68: 849-855
• 25 Sagnelli A, Piscosquito G, Chiapparini L et al. X-linked Charcot-Marie-Tooth type 1: stroke-like presentation of a novel GJB1 mutation. J Peripher Nerv Syst 19: 183-186
• 26 McKinney JL, De Los Reyes EC, Lo WD et al. Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease. Muscle Nerve 2014; 49: 451-454
• 27 Basri R, Yabe I, Soma H et al. X-linked Charcot-Marie-Tooth disease (CMTX) in a severely affected female patient with scattered lesions in cerebral white matter. Intern Med 2007; 46: 1023-1027
• 28 Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005; 4: 2-6
• 29 Lau KK, Lam K, Shiu KL et al. Clinical features of hereditary spinocerebellar ataxia diagnosed by molecular genetic analysis. Hong Kong Med J 2004; 10: 255-259
• 30 Graeber MB, Muller U. Recent developments in the molecular genetics of mitochondrial disorders. J Neurol Sci 1998; 153: 251-263
• 31 Rossor AM, Kalmar B, Greensmith L et al The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry 2012; 83: 6-14
• 32 Pages M, Pages AM. Leber's disease with spastic paraplegia and peripheral neuropathy. Case report with nerve biopsy study. Eur Neurol 1983; 22: 181-185
• 33 Delatycki MB, Corben LA. Clinical features of Friedreich ataxia. J Child Neurol 2012; 27: 1133-1137
• 34 Homayoun H, Khavandgar S, Hoover JM et al. Novel mutation in MYH7 gene associated with distal myopathy and cardiomyopathy. Neuromuscul Disord 2011; 21: 219-222
• 35 Choi ER, Park SJ, Choe YH et al. Early detection of cardiac involvement in Miyoshi myopathy: 2D strain echocardiography and late gadolinium enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2010; 12: 31
• 36 Ishiwata S, Nishiyama S, Seki A et al. Restrictive cardiomyopathy with complete atrioventricular block and distal myopathy with rimmed vacuoles. Jpn Circ J 1993; 57: 928-933
• 37 Udd B. Distal muscular dystrophies. Handb Clin Neurol 2011; 101: 239-262
• 38 Engelhardt A. Vaskulitische Neuropathien. Theorie und Forschung Medizin. Regensburg: Roderer, S.; 1994
• 39 Ishigami N, Kondo M, Nakagawa M. [Case of Charcot-Marie-Tooth disease type 1A with increased cerebrospinal fluid proteins and nerve root hypertrophy]. Rinsho Shinkeigaku 2008; 48: 419-421
• 40 Zaidman CM, Harms MB, Pestronk A. Ultrasound of inherited vs. acquiered demyelinating polyneuropathies. J Neurol 2013; 260: 3115-3121
• 41 Kang JH, Kim HJ, Lee ER. Elektrophysiological evaluation of chronic inflammatory demyelinating polyneuropathy and charcot-marie-tooth type 1:dispersion and correlation analysis. J Phys Ther Sci 2013; 25: 1265-1268
• 42 Young P. Suralisbiopsie bei unklarer Polyneuropathie. Kontra Nervenarzt 2014; 85: 1018-1020
• 43 Stogbauer F, Halfter H, Young P et al. [Molecular biology and genetics of hereditary motor and sensory neuropathies]. Nervenarzt 1996; 67: 987-997
• 44 Sinkiewicz-Darol E, Lacerda AF, Kostera-Pruszczyk A et al. The LITAF/SIMPLE I92V sequence variant results in an earlier age of onset of CMT1A/HNPP diseases. Neurogenetics 2015; 16: 27-32
• 45 Zuchner S, De JP, Jordanova A et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006; 59: 276-281
• 46 Piscosquito G, Saveri P, Magri S et al. Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations. J Peripher Nerv Syst 2015;
• 47 Rossor AM, Polke JM, Houlden H et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol 2013; 9: 562-571
• 48 Timmerman V, Strickland AV, Zuchner S. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success. Genes (Basel) 2014; 5: 13-32
• 49 Saporta AS, Sottile SL, Miller LJ et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69: 22-33
• 50 Braathen GJ, Sand JC, Lobato A et al. Genetic epidemiology of Charcot-Marie-Tooth in the general population. Eur J Neurol 2011; 18: 39-48
• 51 Vallat JM, Mathis S, Funalot B. The various Charcot-Marie-Tooth diseases. Curr Opin Neurol 2013; 26: 473-480
• 52 Kleopa KA, Abrams CK, Scherer SS. How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease?. Brain Res 2012; 1487: 198-205
• 53 Verhoeven K, Claeys KG, Zuchner S et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 2006; 129: 2093-2102
• 54 DiVincenzo C, Elzinga CD, Medeiros AC et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med 2014; 2: 522-529
• 55 Azzedine H, Ravise N, Verny C et al. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 2006; 67: 602-606
• 56 Rankin J, Auer-Grumbach M, Bagg W et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A 2008; 146A: 1530-1542
• 57 Rankin J, Ellard S. The laminopathies: a clinical review. Clin Genet 2006; 70: 261-274
• 58 Hayashi A, Kasahara T, Iwamoto K et al. The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development. J Biol Chem 2007; 282: 34525-34534
• 59 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
• 60 Verhoeven K, De JP, Van de Putte T et al. Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. Am J Hum Genet 2003; 73: 926-932
• 61 Gonzaga-Jauregui C, Harel T, Gambin T et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep 2015; 12: 1169-1183