Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy

doi:10.3969/j.issn.1674-8115.2022.05.008

Abstract

Abstract: Objective

·To investigate the genetic and clinical features of peripheral neuropathy patients with PMP22 gene variations and the association between genotype and clinical phenotype.

Methods

·A total of 162 patients with peripheral neuropathy who were treated in Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine from 2006 to 2022 were collected. Molecular detecting techniques including combining multiplex ligation-dependent probe amplification (MLPA), whole exon sequencing (WES) and Sanger sequencing were used to comprehensively analyze the genetic variation of 162 patients, and 26 probands with PMP22 gene variations and their 33 family members were screened out. The genetic variations included duplication, deletion and point mutations. The clinical and genetic characteristics of 26 patients with PMP22-associated peripheral neuropathy were further analyzed. The clinical characteristics included clinical demographic data, clinical manifestations, electrophysiological and pathological characteristics.

Results

·There were a total of 59 (37 male and 22 female) individuals with PMP22-associated peripheral neuropathy, among whom 46 patients in 13 families had positive family histories and 13 did not. The median age at onset of neuropathy was 34.0 (14.0, 49.5) years old. The initial symptom was limb weakness or limb numbness. There were 51 Charcot-Marie-Tooth type-1A (CMT1A) patients with PMP22 duplication, 6 hereditary neuropathy with liability to pressure palsies (HNPP) patients with PMP22 deletion and 2 Dejerine-Sottas syndrome (DSS) patients with PMP22 point mutations (p.S72L and p.G100V). Sixteen patients underwent electrophysiological detections. Compared with the 4 PMP22 deletion patients, the motor nerve conduction velocity (MCV), compound muscle action potential (CMAP) and sensory nerve conduction velocities (SCV) of 12 PMP22 duplication patients were obviously decreased (all P<0.05). Conduction block was found in both kinds of mutation types. Sural nerve biopsies were performed in 12 patients, including 8 PMP22 duplication, 3 PMP22 deletion and 1 PMP22 point mutation, and pathological changes such as thinning of myelinated nerve fibers, “onion bulbs” and decreased nerve fiber density were observed in varying degrees.

Conclusion

·PMP22 gene-associated neuropathies can be characterized by CMT1A, HNPP and DSS with high clinical heterogeneity. Patients with demyelinating manifestations on electrophysiological detections and sural nerve biopsy need genetic testing for PMP22 gene duplication, deletion and point mutation after ruling out acquired etiology. It is available to help optimize diagnosis and genetic counseling of the disease.

Key words: Charcot-Marie-Tooth type-1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas syndrome (DSS), PMP22 gene, mutation

CLC Number:

R745.4⁺9

ZHU Xiaowei, ZHAN Feixia, ZHANG Chao, LIU Shihua, ZHONG Ping, CAO Li, LUAN Xinghua. Analysis of genetic and clinical characteristics of PMP22-associated peripheral neuropathy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 609-616.

Figures/Tables 4

TrendMD

References 35

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Index	PMP22 duplication （n=12）		P value^①	PMP22 deletion （n=4）		P value^①	P value^②
Index	Left	Right	P value^①	Left	Right	P value^①	P value^②
CMAP/mV
Median nerve （wrist-APB）	3.401±1.559	3.434±1.886	0.972	6.100±2.823	7.275±1.227	0.553	0.008
Median nerve （elbow-wrist）	2.803±1.509	2.849±1.715	0.959	6.100±3.122	6.850±2.585	0.724	0.006
Ulnar nerve （wrist-ADM）	2.002±1.065	1.828±1.117	0.789	6.400±2.203	7.000±2.483	0.730	0.000
Ulnar nerve （below elbow-wrist）	1.487±1.087	1.243±0.951	0.688	6.075±2.095	6.475±2.294	0.805	0.000
Tibial nerve （ankle-AH）	16.375±1.576	16.775±3.163	0.661	39.033±0.850	37.533±2.774	0.421	0.000
Common peroneal nerve （ankle-EDB）	0.200±0.257	0.223±0.473	0.918	3.023±1.583	3.290±2.532	0.864	0.004
MCV/（m·s^-1）
Median nerve	18.943±3.114	18.529±4.095	0.835	49.65±3.074	50.525±2.344	0.765	0.000
Ulnar nerve	17.833±2.420	18.767±3.266	0.586	50.900±4.809	50.675±8.207	0.964	0.000
Tibial nerve	0.315±0.574	0.343±0.346	0.920	7.533±2.937	8.633±2.754	0.661	0.001
Common peroneal nerve	14.143±3.629	17.100±4.964	0.227	36.775±2.136	35.425±4.751	0.623	0.000
SCV/（m·s^-1）
Median nerve	12.843 （0.000， 310.200）	8.210 （0.000， 33.600）	0.548	41.575±2.990	41.475±2.666	0.962	0.000
Ulnar nerve	12.580 （0.000， 32.700）	9.060 （0.000， 39.300）	0.575	42.450±4.211	43.350±4.807	0.788	0.000
Sural nerve	9.691 （0.000， 34.600）	7.792 （0.000， 27.600）	0.717	40.850±8.009	41.575±7.374	0.898	0.000

Index	PMP22 duplication （n=12）		P value^①	PMP22 deletion （n=4）		P value^①	P value^②
Index	Left	Right	P value^①	Left	Right	P value^①	P value^②
CMAP/mV
Median nerve （wrist-APB）	3.401±1.559	3.434±1.886	0.972	6.100±2.823	7.275±1.227	0.553	0.008
Median nerve （elbow-wrist）	2.803±1.509	2.849±1.715	0.959	6.100±3.122	6.850±2.585	0.724	0.006
Ulnar nerve （wrist-ADM）	2.002±1.065	1.828±1.117	0.789	6.400±2.203	7.000±2.483	0.730	0.000
Ulnar nerve （below elbow-wrist）	1.487±1.087	1.243±0.951	0.688	6.075±2.095	6.475±2.294	0.805	0.000
Tibial nerve （ankle-AH）	16.375±1.576	16.775±3.163	0.661	39.033±0.850	37.533±2.774	0.421	0.000
Common peroneal nerve （ankle-EDB）	0.200±0.257	0.223±0.473	0.918	3.023±1.583	3.290±2.532	0.864	0.004
MCV/（m·s^-1）
Median nerve	18.943±3.114	18.529±4.095	0.835	49.65±3.074	50.525±2.344	0.765	0.000
Ulnar nerve	17.833±2.420	18.767±3.266	0.586	50.900±4.809	50.675±8.207	0.964	0.000
Tibial nerve	0.315±0.574	0.343±0.346	0.920	7.533±2.937	8.633±2.754	0.661	0.001
Common peroneal nerve	14.143±3.629	17.100±4.964	0.227	36.775±2.136	35.425±4.751	0.623	0.000
SCV/（m·s^-1）
Median nerve	12.843 （0.000， 310.200）	8.210 （0.000， 33.600）	0.548	41.575±2.990	41.475±2.666	0.962	0.000
Ulnar nerve	12.580 （0.000， 32.700）	9.060 （0.000， 39.300）	0.575	42.450±4.211	43.350±4.807	0.788	0.000
Sural nerve	9.691 （0.000， 34.600）	7.792 （0.000， 27.600）	0.717	40.850±8.009	41.575±7.374	0.898	0.000

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