腓骨肌萎缩症合并小脑性共济失调的临床及遗传学特点

doi:10.3969/j.issn.1674-8115.2023.03.011

摘要/Abstract

摘要：

腓骨肌萎缩症（Charcot-Marie-Tooth disease，CMT）是一组以周围神经病变为主的遗传性运动感觉神经病。主要临床症状包括进行性对称性肢体远端无力、萎缩、感觉障碍和腱反射减退或消失。根据神经电生理表现和病理特点，CMT可分为以脱髓鞘为主的CMT1型和轴索病变为主的CMT2型。除了周围神经系统病变外，CMT部分表型可同时累及中枢神经系统或其他脏器；其中小脑系统受累的CMT患者同时合并小脑性共济失调，可见于神经丝蛋白轻链（neurofilament light chain，NEFL）基因突变所致的CMT1F型和CMT2E型，MORC家族CW型锌指结构蛋白2（MORC family CW-type zinc finger 2，MORC2）基因突变所致的CMT2Z型，溶质载体家族25成员46（solute carrier family 25 member 46，SLC25A46）基因突变所致的伴视神经萎缩的CMT6B型，以及多核苷酸激酶3′-磷酸酶（polynucleotide kinase 3′-phosphatase，PNKP）基因突变所致的CMT2B2型等。近年来，CMT重叠表型成为研究的热点，其中CMT合并小脑性共济失调具有高度临床异质性和遗传异质性，临床上易发生误诊。该文就合并小脑性共济失调的CMT表型的临床及遗传学特点进行综述，旨在为该类患者的早期诊断和治疗提供参考。

关键词: 腓骨肌萎缩症, 小脑性共济失调, 基因突变, 神经丝蛋白轻链, MORC家族CW型锌指结构蛋白2

Abstract:

Charcot-Marie-Tooth disease (CMT) is a group of hereditary motor and sensory neuropathy predominantly with peripheral neuropathy. It is characterized by progressive symmetric distal-predominant weakness, amyotrophy, sensory loss and reduced or absent deep tendon reflexes. CMT is usually divided into CMT1 type with demyelination and CMT2 type with axonal lesions according to electrophysiological and pathological characteristics. In addition to peripheral nervous system lesions, some CMT subtypes may also involve the central nervous system or other organs. The CMT patients with cerebellar system involvement also have cerebellar ataxia which can be seen as CMT1F type and CMT2E type caused by mutations in neurofilament light chain(NEFL) gene, CMT2Z with mutations in MORC family CW-type zinc finger 2 (MORC2) gene, CMT-6B with mutations in solute carrier family 25 member 46 (SLC25A46) gene, CMT2B2 with mutations in polynucleotide kinase 3′-phosphatase (PNKP) gene and so on. In recent years, CMT overlapping phenotypes have become a hot topic of research, among which CMT with cerebellar ataxia is a clinically and genetically heterogeneous group of disorders, and is prone to misdiagnosis clinically. This article reviews the clinical and genetic characteristics of CMT with cerebellar ataxia, aiming to provide reference for the earlier recognition and therapeutic strategies.

Key words: Charcot-Marie-Tooth disease (CMT), cerebellar ataxia, gene mutation, neurofilament light chain(NEFL), MORC family CW-type zinc finger 2 (MORC2)

中图分类号:

R746.4

朱啸巍, 钟平, 曹立, 栾兴华. 腓骨肌萎缩症合并小脑性共济失调的临床及遗传学特点[J]. 上海交通大学学报（医学版）, 2023, 43(3): 350-357.

ZHU Xiaowei, ZHONG Ping, CAO Li, LUAN Xinghua. Clinical and genetic characteristics of Charcot-Marie-Tooth disease with cerebellar ataxia[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(3): 350-357.

图/表 4

图1 NEFL的结构示意图及突变分布Note： CMT1F mutations are shown in blue; CMT2E mutations are shown in green and both in orange.

Fig 1 Structure diagram and mutation distribution of NEFL

图2 MORC2的结构示意图及突变分布Note： CC—coiled coil; S5—transducer S5-like domain; CW—zinc finger domain; CD—coil domain.

Fig 2 Structure diagram and mutation distribution of MORC2

图3 SLC25A46的结构示意图及突变分布Note： MC—mitochondrial carrier domain.

Fig 3 Structure diagram and mutation distribution of SLC25A46

图4 PNKP的结构示意图及突变分布Note： FHA—forkhead associated domain.

Fig 4 Structure diagram and mutation distribution of PNKP

参考文献 60

1	LAURÁ M, PIPIS M, ROSSOR A M, et al. Charcot-Marie-Tooth disease and related disorders: an evolving landscape[J]. Curr Opin Neurol, 2019, 32(5): 641-650.
2	ROSSOR A M, CARR A S, DEVINE H, et al. Peripheral neuropathy in complex inherited diseases: an approach to diagnosis[J]. J Neurol Neurosurg Psychiatry, 2017, 88(10): 846-863.
3	MERSIYANOVA I V, PEREPELOV A V, POLYAKOV A V, et al. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene[J]. Am J Hum Genet, 2000, 67(1): 37-46.
4	STONE E J, KOLB S J, BROWN A. A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L[J]. Cytoskeleton (Hoboken), 2021, 78(3): 97-110.
5	ABE A, NUMAKURA C, SAITO K, et al. Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype[J]. J Hum Genet, 2009, 54(2): 94-97.
6	ANTUNES L, FRASQUILHO S, OSTASZEWSKI M, et al. Similar α-synuclein staining in the colon mucosa in patients with Parkinson′s disease and controls[J]. Mov Disord, 2016, 31(10): 1567-1570.
7	ZHAI J B, LIN H, JULIEN J P, et al. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1[J]. Hum Mol Genet, 2007, 16(24): 3103-3116.
8	MARTIN M, IYADURAI S J, GASSMAN A, et al. Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport[J]. Mol Biol Cell, 1999, 10(11): 3717-3728.
9	YUM S W, ZHANG J X, MO K T, et al. A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy[J]. Ann Neurol, 2009, 66(6): 759-770.
10	LERAT J, MAGDELAINE C, BEAUVAIS-DZUGAN H, et al. A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next-generation sequencing and review of the literature[J]. J Peripher Nerv Syst, 2019, 24(1): 139-144.
11	GEORGIOU D M, ZIDAR J, KOROSEC M, et al. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family[J]. Neurogenetics, 2002, 4(2): 93-96.
12	FABRIZI G M, CAVALLARO T, ANGIARI C, et al. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E[J]. Neurology, 2004, 62(8): 1429-1431.
13	KIM H J, KIM S B, KIM H S, et al. Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease[J]. Mol Genet Genomic Med, 2022, 10(2): e1870.
14	LIKAR T, HASANHODŽIĆ M, TERAN N, et al. Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss[J]. PLoS One, 2018, 13(1): e0188578.
15	PISCIOTTA C, BAI Y H, BRENNAN K M, et al. Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E[J]. Neurology, 2015, 85(3): 228-234.
16	AGRAWAL P B, JOSHI M, MARINAKIS N S, et al. Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings[J]. JAMA Neurol, 2014, 71(11): 1413-1420.
17	HORGA A, LAURÀ M, JAUNMUKTANE Z, et al. Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease[J]. J Neurol Neurosurg Psychiatry, 2017, 88(7): 575-585.
18	DOPPLER K, KUNSTMANN E, KRÜGER S, et al. Painful Charcot-Marie-Tooth neuropathy type 2E/1F due to a novel NEFL mutation[J]. Muscle Nerve, 2017, 55(5): 752-755.
19	SMITH S M, JENKINSON M, JOHANSEN-BERG H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data[J]. NeuroImage, 2006, 31(4): 1487-1505.
20	HWANG S, PARK C H, KIM R E, et al. Cerebellar white matter abnormalities in Charcot-Marie-Tooth Disease: a combined volumetry and diffusion tensor imaging analysis[J]. J Clin Med, 2021, 10(21): 4945.
21	ANDO M, OKAMOTO Y, YOSHIMURA A, et al. Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan[J]. Eur J Neurol, 2017, 24(10): 1274-1282.
22	PAREYSON D, SAVERI P, PISCIOTTA C. New developments in Charcot-Marie-Tooth neuropathy and related diseases[J]. Curr Opin Neurol, 2017, 30(5): 471-480.
23	GUILLEN SACOTO M J, TCHASOVNIKAROVA I A, TORTI E, et al. De novo variants in the ATPase module of MORC2 cause a neurodevelopmental disorder with growth retardation and variable craniofacial dysmorphism[J]. Am J Hum Genet, 2020, 107(2): 352-363.
24	SANCHO P, BARTESAGHI L, MIOSSEC O, et al. Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations[J]. Hum Mol Genet, 2019, 28(10): 1629-1644.
25	SEVILLA T, LUPO V, MARTÍNEZ-RUBIO D, et al. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease[J]. Brain, 2016, 139(Pt 1): 62-72.
26	WANG G L, WANG C Y, CAI X Z, et al. Identification and expression analysis of a novel CW-type zinc finger protein MORC2 in cancer cells[J]. Anat Rec (Hoboken), 2010, 293(6): 1002-1009.
27	TCHASOVNIKAROVA I A, TIMMS R T, DOUSE C H, et al. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2[J]. Nat Genet, 2017, 49(7): 1035-1044.
28	LI D Q, NAIR S S, OHSHIRO K, et al. MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response[J]. Cell Rep, 2012, 2(6): 1657-1669.
29	DOUSE C H, BLOOR S, LIU Y C, et al. Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms[J]. Nat Commun, 2018, 9(1): 651.
30	SÁNCHEZ-SOLANA B, LI D Q, KUMAR R. Cytosolic functions of MORC2 in lipogenesis and adipogenesis[J]. Biochim Biophys Acta, 2014, 1843(2): 316-326.
31	SHAO Y G, LI Y, ZHANG J, et al. Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase Ⅸ[J]. Nucleic Acids Res, 2010, 38(9): 2813-2824.
32	CESTRA G, TOOMRE D, CHANG S, et al. The Abl/Arg substrate ArgBP2/nArgBP2 coordinates the function of multiple regulatory mechanisms converging on the actin cytoskeleton[J]. Proc Natl Acad Sci U S A, 2005, 102(5): 1731-1736.
33	ZANNI G, NARDELLA M, BARRESI S, et al. De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia, axonal polyneuropathy and nocturnal hypoventilation[J]. Brain, 2017, 140(6): e34.
34	SCHOTTMANN G, WAGNER C, SEIFERT F, et al. MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy, and diaphragmatic paralysis[J]. Brain, 2016, 139(Pt 12): e70.
35	HYUN Y S, HONG Y B, CHOI B O, et al. Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations[J]. Brain, 2016, 139(Pt 7): e40.
36	SIVERA R, LUPO V, FRASQUET M, et al. Charcot-Marie-Tooth disease due to MORC2 mutations in Spain[J]. Eur J Neurol, 2021, 28(9): 3001-3011.
37	RAJU S, MEDARAMETLA S, BORAIAH N. Dystonia and hereditary motor sensory neuropathy 6B due to SLC25A46 gene mutations[J]. Mov Disord Clin Pract, 2021, 8(3): 480-482.
38	ABRAMS A J, HUFNAGEL R B, REBELO A, et al. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder[J]. Nat Genet, 2015, 47(8): 926-932.
39	PERIVOLIDI V I, VIOLITZI F, IOANNIDOU E, et al. Proteomic identification of the SLC25A46 interactome in transgenic mice expressing SLC25A46-FLAG[J]. J Proteome Res, 2022, 21(2): 375-394.
40	WAN J J, STEFFEN J, YOURSHAW M, et al. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia[J]. Brain, 2016, 139(11): 2877-2890.
41	GAO L, WANG M, LIAO L F, et al. A Slc25a46 mouse model simulating age-associated motor deficit, redox imbalance, and mitochondria dysfunction[J]. J Gerontol A Biol Sci Med Sci, 2021, 76(3): 440-447.
42	LI Z, PENG Y Y, HUFNAGEL R B, et al. Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice[J]. Hum Mol Genet, 2017, 26(19): 3776-3791.
43	NGUYEN M, BOESTEN I, HELLEBREKERS D M, et al. Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder[J]. Clin Genet, 2017, 91(1): 121-125.
44	ABRAMS A J, FONTANESI F, TAN N B L, et al. Insights into the genotype-phenotype correlation and molecular function of SLC25A46[J]. Hum Mutat, 2018, 39(12): 1995-2007.
45	BRAUNISCH M C, GALLWITZ H, ABICHT A, et al. Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type Ⅰ[J]. Clin Genet, 2018, 93(2): 255-265.
46	CHARLESWORTH G, BALINT B, MENCACCI N E, et al. SLC25A46 mutations underlie progressive myoclonic ataxia with optic atrophy and neuropathy[J]. Mov Disord, 2016, 31(8): 1249-1251.
47	LEAL A, BOGANTES-LEDEZMA S, EKICI A B, et al. The polynucleotide kinase 3′-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25[J]. Neurogenetics, 2018, 19(4): 215-225.
48	LEAL A, MORERA B, DEL VALLEG, et al. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3[J]. Am J Hum Genet, 2001, 68(1): 269-274.
49	JILANI A, RAMOTAR D, SLACK C, et al. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3′-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage[J]. J Biol Chem, 1999, 274(34): 24176-24186.
50	BERNSTEIN N K, WILLIAMS R S, RAKOVSZKY M L, et al. The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase[J]. Mol Cell, 2005, 17(5): 657-670.
51	TSUKADA K, MATSUMOTO Y, SHIMADA M. Linker region is required for efficient nuclear localization of polynucleotide kinase phosphatase[J]. PLoS One, 2020, 15(9): e0239404.
52	MCKINNON P J. DNA repair deficiency and neurological disease[J]. Nat Rev Neurosci, 2009, 10(2): 100-112.
53	PEDROSO J L, ROCHA C R, MACEDO-SOUZA L I, et al. Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease[J]. Neurol Genet, 2015, 1(4): e30.
54	BERGHOFF C, BERGHOFF M, LEAL A, et al. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3[J]. Neuromuscul Disord, 2004, 14(5): 301-306.
55	BRAS J, ALONSO I, BARBOT C, et al. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4[J]. Am J Hum Genet, 2015, 96(3): 474-479.
56	DJORDJEVIC D, PINARD M, GAUTHIER M S, et al. De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy[J]. Am J Hum Genet, 2022, 109(4): 759-763.
57	HYUN Y S, PARK H J, HEO S H, et al. Rare variants in methionyl- and tyrosyl-tRNA synthetase genes in late-onset autosomal dominant Charcot-Marie-Tooth neuropathy[J]. Clin Genet, 2014, 86(6): 592-594.
58	CORTESE A, SIMONE R, SULLIVAN R, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia[J]. Nat Genet, 2019, 51(4): 649-658.
59	李资益, 田沃土, 沈隽逸, 等. 非典型Charlevoix-Saguenay常染色体隐性遗传痉挛性共济失调二家系[J]. 中国神经精神疾病杂志, 2021, 47(8): 509-512.
	LI Z Y, TIAN W T, SHEN J Y, et al. Atypical autosomal recessive spastic ataxia of Charlevoix-Saguenay: a report of two families[J]. Chinese Journal of Nervous and Mental Diseases, 2021, 47(8): 509-512.
60	ECHANIZ-LAGUNA A, GHEZZI D, CHASSAGNE M, et al. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease[J]. Neurology, 2013, 81(17): 1523-1530.

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