Clinical And Genetic Study Of Charcot-marie-tooth Disease And Distal Hereditary Motor Neuropathy

Objective:Both Charcot-Marie-Tooth disease(CMT)and distal hereditary motor neuropathy(d HMN)are groups of single-gene peripheral neuropathy,with high clinical and genetic heterogeneity.In this study,we summarized the clinical characteristics and gene distribution of a group of CMT and d HMN patients,and tried a new gene identification method to improve the genetic diagnosis rate and expand the clinical and genetic spectrum of hereditary peripheral neuropathy.Materials and Methods:Patients with a clinical diagnosis of CMT or d HMN who visited the Department of Neurology at the First Affiliated Hospital of Nanchang University from September2017 to March 2023 were collected.Clinical data were collected,standardized neuroelectrophysiological examination was performed,the pathogenic genes were identified by whole exon sequencing(WES)or targeted gene panel sequencing,and dynamic mutations of NOTCH2 NLC gene were screened by repeat-primed polymerase chain reaction(RP-PCR)for patients with negative conventional gene screening.Results:1、Basic information: a total of 52 cases of CMT/d HMN were collected,including37 CMT cases and 15 d HMN cases.The male to female ratio in CMT was 26:11.The inheritance patterns included autosomal dominant inheritance(43.24%,16/37),autosomal recessive inheritance(18.92%,7/37),X-chromosome linked inheritance(8.11%,3/37)and sporadic inheritance(29.73%,11/37).The median age of onset(Inter Quartile Range,IQR)was 28 years old,the median age(IQR)of seeing a doctor was37(33)years old,and the median course of disease was 5 years(2 days to 26 years).The male-female ratio of d HMN patients was 3:2,with autosomal dominant inheritance(33.3%,5/15),autosomal recessive inheritance(26.67%,4/15),X-linked inheritance(6.67%,1/15)and sporadic inheritance(33.33%,5/15).The mean age of onset(IQR)was 30(39)years old,the mean age(IQR)of going to the hospital was 36(29)years old,and the median course of disease was 3 years(3 months to 25 years).2、Clinical characteristics: 72.97% of CMT and 93.33% of d HMN patients started with symptoms of lower extremity weakness;24.32% of CMT and 33.33% of d HMN patients were asymmetrically involved early in the course of disease.67.57% of CMT patients and 66.67% of d HMN patients had muscular atrophy.Among the special signs,37.84% of CMT and 6.67% of d HMN patients had pes cavus,8.11% of CMT and 20.00%of d HMN patients had foot drop,2.7% of CMT and 20.00% of d HMN patients had crane leg,3 CMT patients had hammer toe,and 2 CMT patients had thoracic scoliosis.Tendon reflex decreased/disappeared in 83.78% of CMT and 73.33% of d HMN patients.CMT patients may have other system involvement,including tremor(10.81%),cranial nerve involvement(8.11%),mental retardation(8.11%),pyramidal sign(5.41%),dry cough(5.41%),paroxysmal vomiting/abdominal pain(5.41%),retinitis pigmentosa(2.70%),and ataxia(2.70%).26.67% of d HMN patients were accompanied with other system symptoms,including diaphragmatic weakness,tremor,pyramidal sign and ataxia.3、Electrophysiological features: 31 CMT and 10 d HMN patients had complete electrophysiological data,with 7 cases being CMT1,14 cases being I-CMT,and 10 cases being CMT2.83.87 % of CMT and 90.00% of d HMN patients showed neurogenic damage.CMT1 patients have the most severe demyelination and axonal degeneration in the upper and lower limbs,while only mild reductions in median motor nerve conduction velocity(MNCV)and compound muscle action potential(CMAP)in I-CMT.Most sensory nerves in CMT1 and I-CMT are no response to electrical stimulations,and the electrophysiological parameters of CMT2 and d HMN showed a decrease in CMAP in the common peroneal nerve.The electrophysiological correlation analysis showed that MNCV and CMAP of median nerve in CMT1 patients were significantly negatively correlated with the age of onset.CMAP of median nerve in ICMT patients was moderately negatively correlated with onset age.Distal motor latency(DML)of median nerve in d HMN patients was significantly positively correlated with the age of onset and negatively correlated with the course of disease.Median nerve CMAP was positively correlated with the course of disease.4 、 A total of 50 CMT/d HMN patients underwent WES or targeted panel sequencing.30 pathogenic/likely pathogenic variations were found,including 23 in the CMT group and 7 in the d HMN group,among which 21 were unreported.5 of 7 CMT1 patients had PMP22 repeat variants and 2 with MPZ variants.The most common causative gene for I-CMT was GJB1(25.00%),followed by GGC repeat in the 5’untranslated region(5’ UTR)of NOTCH2 NLC gene(12.67%),while SACS,SH3TC2,MME and HARS1 mutations accounted for 11.11% respectively;GDAP1,BICD2 mutation and NOTCH2 NLC gene repeat were detected in 3 CMT2 patients,respectively,and in the 5 patients that could not be classified,there were PMP22 repeat,MPV17,GJB1,MME and TRPV4 gene mutations.7 d HMN patients had SH3TC2,SOD1,HSPB1,REEP1,MFN2,SORD and GNE as the causative genes in sequence,respectively.The detection rate of CMT gene was 65.71%: 100.00% for CMT1,75.00%for I-CMT,and only 30.00% for CMT2;the detection rate of d HMN gene was 46.67%.5、Phenotype-genotype correlation: PMP22 duplication variants are related to sensory symptoms,median age of onset was 29 years old.GJB1 gene variants are more common in males and may present with central nervous system involvement;NOTCH2NLC gene duplication amplification usually combined with multisystem involvement symptoms,such as tremor,dry cough and abdominal pain/vomit;MME gene related CMT may overlap with the phenotype of spinocerebellar ataxia.Conclusion:1、Both CMT and d HMN patients are more common in men,and the inheritance mode is mainly autosomal dominant inheritance.The median age of onset of CMT and d HMN patients in our cohort is 28 years and 30 years old respectively.2、The majority of CMT and d HMN patients presented with weakness of lower limbs as the onset symptom.Some patients may have other system symptoms outside the peripheral neuropathy,such as pyramidal sign,tremor,dry cough and abdominal pain,suggesting high clinical heterogeneity.3、Neuro-electrophysiology: the MNCV and CMAP values of median nerve in CMT patients are suggestive of CMT classification,and are related to the onset age or course of disease.The DML and CMAP values of median nerve were related to the onset age or course of d HMN.4、In the CMT group,the diagnosis rate of CMT1 and I-CMT was higher,while CMT2 was lower.There are various pathogenic genes of CMT,among which PMP22,MPZ and GJB1 are common.For CMT patients with negative conventional genetic results and external peripheral neuropathy,screening for NOTCH2 NLC gene should be considered.5、The common pathogenic genes of d HMN patients were HSPB1,SH3TC2,MFN2,REEP1,SOD1,SORD and GNE.6、The symptoms of other systems in CMT/d HMN patients may suggest some special pathogenic genes,such as NOTCH2 NLC gene.