MPZ-, GDAP1-, and NEFL-Related Charcot-Marie-Tooth Disease with Diverse Clinical and Electrophysiological Phenotypes

Hye Jin Kim; Hye Mi Kwon; Sang Beom Kim; Ki Wha Chung; Byung-Ok Choi

doi:10.18214/jend.2022.00143

J Electrodiagn Neuromuscul Dis > Volume 24(3); 2022 > Article

Kim, Kwon, Kim, Chung, and Choi: MPZ-, GDAP1-, and NEFL-Related Charcot-Marie-Tooth Disease with Diverse Clinical and Electrophysiological Phenotypes

Review Article

Journal of Electrodiagnosis and Neuromuscular Diseases 2022;24(3):62-69.

Published online: December 30, 2022

DOI: https://doi.org/10.18214/jend.2022.00143

MPZ-, GDAP1-, and NEFL-Related Charcot-Marie-Tooth Disease with Diverse Clinical and Electrophysiological Phenotypes

Hye Jin Kim¹

, Hye Mi Kwon¹

, Sang Beom Kim²

, Ki Wha Chung³

, Byung-Ok Choi^1,⁴

¹Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Department of Neurology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea

³Department of Biological Sciences, Kongju National University, Gongju, Korea

⁴Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Korea

Corresponding author: Byung-Ok Choi Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: +82-2-3410-1296 Fax: +82-2-3410-0052 E-mail: bochoi77@hanmail.net

Received August 8, 2022 Revised October 4, 2022 Accepted October 6, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Charcot-Marie-Tooth disease (CMT) is a spectrum of clinically and genetically heterogeneous peripheral neuropathies. CMT can be classified into demyelinating, intermediate, or axonal neuropathy based on clinical, histopathological, and electrophysiological findings. Approximately 140 genes have been reported to be associated with CMT. Mutations in the myelin protein zero (MPZ), ganglioside-induced differentiation related protein 1 (GDAP1), and neurofilament light-chain polypeptide (NEFL) genes have been reported to cause all three types of CMT, which is noteworthy because most CMT-related genes cause a single type of neuropathy (either demyelinating or axonal). In contrast, it remains unclear why these genes cause several types of CMT. CMT is presently incurable; however, ongoing attempts to treat CMT with various drugs, dietary supplements have increased the importance of an exact genetic diagnosis for precision medicine. Therefore, it is important to identify the causative mutations and compare the associated clinical characteristics. Taken together, a comparison of causative mutations and clinical features of patients with MPZ, GDAP1, and NEFL mutations will be the first step in understanding how different types of CMT are caused, and will enable a molecular genetic diagnosis. In this review, we describe the clinical, electrophysiological, and genetic characteristics of MPZ-, GDAP1-, and NEFL-related CMT.

Keywords: Charcot-Marie-Tooth disease; MPZ; GDAP1; NEFL; Phenotype

Introduction

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy that is genetically highly heterogeneous, with more than 140 different genes involved [1-3]. Classically, CMT can be divided according to clinical, histopathological, and electrophysiological findings into three types: the demyelinating type (CMT1), with a median motor nerve conduction velocity (MMNCV) below 38 m/s; axonal neuropathy (CMT2), with an MMNCV above 38 m/s; and the intermediate type (CMTDID), with an MMNCV lying between 25 and 45 m/s and nerve pathology showing axonal and/or demyelinating features [4]. Mutations in the myelin protein zero (MPZ), ganglioside-induced differentiation related protein 1 (GDAP1) and neurofilament light-chain polypeptide gene (NEFL) genes have been reported to cause all three CMT types (demyelinating, axonal, and intermediate) (Fig. 1).

Strictly expressed in myelinated Schwann cells, MPZ is a transmembrane protein that is a major component of peripheral myelin [5]. Mutations in MPZ have been reported to cause demyelinating CMT1B (MIM 118200), axonal CMT2I (MIM 607677), and intermediate CMTDID (MIM 607791) (Table 1) [6-11]. CMT1B patients generally exhibit an early onset, while CMT2I patients are characterized by a late onset [12,13]. MPZ-related CMT patients display a spectrum of diverse phenotypes, with phenotypic variations even in the same mutation. [8,14,15].

GDAP1 is mainly expressed in neurons, is located in the outer membrane of the mitochondria, and belongs to the glutathione S-transferase family [16]. Mutations in the GDAP1 gene were reported for the first time in 2002 to cause autosomal recessive (AR) CMT4A (MIM 214400) in Tunisian families [17]. Since then, GDAP1 mutations have been reported to cause axonal forms (CMT2K; MIM 607831) [18,19], axonal forms with vocal cord paresis (MIM 607706) [18] and intermediate forms (CMTRIA; MIM 608340) of disease (Table 1) [20]. GDAP1-related patients harboring AR inheritance exhibit severe clinical features with early onset, but autosomal dominant GDAP1 mutations show mild clinical symptoms with an adult onset [17,18].

NEFL is the most abundant of the three neurofilament proteins, which are major components of the axoskeleton that provide structural support for axons and regulate axon diameter. Patients with NEFL mutations exhibit a diverse phenotypic spectrum [21]. A mutation in NEFL was first reported to cause CMT2E (MIM 607684) in 2000, and several mutations were subsequently revealed to be associated with CMT1F (MIM 607734), CMTDIG (MIM 617882) (Table 1) [21-25].

Most CMT-related genes cause one CMT neuropathy subtype—demyelinating, axonal, or intermediate neuropathy. Thus, it is noteworthy when a single gene causes multiple subtypes of CMT. In this review, we introduce the various types of CMT in a Korean cohort, caused by mutations in MPZ, GDAP1, and NEFL, and describe their clinical, electrophysiological, and genetic characteristics.

Myelin Protein Zero (MPZ)

1) Clinical diversity of MPZ-related patients

The frequency of Korean CMT families with the MPZ mutation was found to be 3.2% in all independent patients and 4.7% in CMT families without PMP22 duplicates (Table 2) [21,23,26-43]. These mutation frequencies were similar to those reported in China (3.3% and 6.4%, respectively) and Britain (3.1% and 5.1%, respectively) but lower than those reported for most other investigated ethnic groups [26,27].

The mean age at onset was 9.3 ± 10.7 years for CMT1B patients, 21.2 ± 13.7 years for CMTDID patients, and 38.7 ± 13.6 years for CMT2I patients (Table 3). The age at onset was significantly different between CMT1B and CMTDID patients (p = 0.025) or CMT2I patients (p < 0.001). However, the age at onset was not significantly different between CMTDID and CMT2I patients. Functional disability was significantly more severe in CMT1B patients than in CMT2I patients (CMT neuropathy score version 2 [CMTNS], p = 0.004, and functional disability scale [FDS], p = 0.022). The CMTNS and FDS values of the CMT1B patients were higher than those of the CMTDID patients, but the difference was not significant. When comparing the degree of disability based on CMTNS, most patients had moderate disease (53%), followed by those with severe disease (31%) and mild disease (17%) in CMT1B families. In CMTDID and CMT2I families, most patients had mild disease (75% and 80%, respectively).

2) Electrophysiological findings in MPZ-related patients

The mean MNCV of CMT1B patients was 12.2 ± 11.0 m/s, which was significantly lower than that of CMT2I patients (46.0 ± 6.6 m/s, p < 0.001) and CMTDID patients (41.3 ± 3.1 m/s, p < 0.001) (Table 3). The mean sensory nerve conduction velocity (SNCV) (7.4 ± 11.7 m/s) of CMT1B patients was significantly lower than that of CMTDID patients (18.0 ± 25.5 m/s, p = 0.021) and CMT2I patients (34.4 ± 4.3 m/s, p < 0.001). In addition, the peroneal MNCV and sural SNCV were significantly reduced in CMT1B patients compared to CMTDID or CMT2I patients. The median motor nerve compound muscle action potential (CMAP) amplitudes (6.0±5.6 mV) in the CMT1B patients were significantly lower in CMTDID (12.8±1.9 mV, p = 0.033) and CMT2I patients (13.0±4.3 mV, p = 0.011). The peroneal nerve CMAP and median and sural sensory nerve action potential (SNAP) amplitudes were also significantly lower in CMT1B patients than in CMTDID and CMT2I patients.

Ganglioside-Induced Differentiation Related Protein 1 (GDAP1)

1) Clinical diversity of GDAP1 mutations

The GDAP1 mutation frequency rate was found to be 0.7% in all patients and 1.0% in patients negative for PMP22 duplication (Table 2). Similar frequencies have been reported in most Asian and Western countries, including Japan, China, Germany, the United States, and the United Kingdom [27-31]. However, higher frequencies of GDAP1 mutations have been reported in certain regions in Italy and Spain [32,33].

The functional disabilities and clinical characteristics were different between CMT2K and CMTRIA patients. CMT2K patients exhibited mild to moderate disabilities, with a late age at onset (19.7 ± 7.7 years), but CMTRIA patients showed severe disabilities with an early age at onset (1.7 ± 0.6 years) (Table 4). Functional disability was significantly more severe in CMTRIA patients than in CMT2K patients. The mean value of the FDS [44] was 2.3 ± 1.4 in CMT2K patients and 5.3 ± 1.2 in CMTRIA patients (p = 0.010). The mean CMTNS score [45] was 11.1±6.6 in CMT2K patients and 24.7 ± 3.2 in CMTRIA patients (p = 0.011). High values of the FDS (scores of 6-7) were observed only in CMTRIA patients. In contrast, low values of the FDS (scores < 5) were observed in CMT2K patients. All three CMTRIA patients were classified in the severe category (CMTNS ≥ 21). Foot deformities were frequent, and four patients had scoliosis. However, no wheelchair dependence, diaphragmatic weakness, vocal cord paresis, or hoarseness was observed.

2) Electrophysiological findings in GDAP1-related patients

Electrophysiological findings verified that CMTRIA patients were more severely affected than CMT2K patients. In CMT2K patients, the conduction velocity mostly did not decrease, excluding nerves with a very low amplitude. In CMTRIA patients, the decreases in CMAP and SNAP amplitudes were even more pronounced, and these parameters were not measured when nerves were explored. These results were worse in the lower extremities than in the upper extremities.

Neurofilament Light-Chain Polypeptide (NEFL)

1) Clinical diversity of NEFL mutations

The frequency of NEFL mutations was reported to range from 0.9% to 2.3% in Japanese and Chinese cohorts and in Korea (Table 2). Data on the frequency of NEFL mutations are extremely limited, though the proportion of the NEFL mutation in CMT has rarely been reported to be below 1%. Therefore, the frequency of NEFL mutations observed in East Asian countries is higher than that reported in other countries.

The prevalence of NEFL mutations was 0.44% in CMT1F patients (5/1,137), 0.35% in CMT2E patients (4/1,137), and 0.70% in CMTDIG patients (8/1,137). The age of onset was thus significantly earlier in CMT1F patients (10.2 ± 7.3 years, p = 0.013) and CMTDIG patients (12.7 ± 7.9, p = 0.007) than in CMT2E patients (24.2 ± 9.4 years) (Table 5). However, the CMTNS and FDS, as measures of disease-related disability, showed no differences among the NEFL-related CMT subtypes. Gait ataxia was identified as the most frequent symptom of NEFL-related CMT patients (78% of CMT1F patients, 50% of CMT2E patients, and 79% of CMTDIG patients). Patients were genetically tested for spinocerebellar ataxia, but no associated mutations were found. In CMT1F and CMTDIG patients, early-onset dementia was observed. Interestingly, ptosis was predominantly observed in CMT2E patients (50%).

2) Electrophysiological findings in NEFL-related patients

In CMT1F patients, the amplitudes of evoked peroneal motor responses were often markedly decreased, and the amplitudes were predominantly unrecordable in 6 of 8 patients (75%) (Table 5). However, peroneal CMAP amplitudes in CMT2E patients could not be recorded in only 1 of 4 patients (25%). Interestingly, peroneal CMAP amplitudes in CMTDIG patients (36%) occupied an intermediate position between the CMT1F and CMT2E patients. The mean MNCV of the median nerve was 16.1 ± 10.5 m/s in CMT1F patients and 47.7 ± 8.1 m/s in CMT2E patients. The mean MNCV of the median nerve was 39.6 ± 4.4 m/s in CMTDIG patients . No SNAP amplitudes of the median nerve were observed in 63% of CMT1F patients, 32% of CMTDIG patients, and 25% of CMT2E patients. Furthermore, sural SNAP amplitudes were not evoked in any of the CMT1F patients, nor were they observed in 36% of CMTDIG patients and 25% of CMT2E patients.

Conclusion

In this review, we described the clinical, electrophysiological, and genetic characteristics of various types of CMT caused by mutations in MPZ, GDAP1, and NEFL. CMT is a peripheral neuropathy with extreme clinical and genetic heterogeneity. Of the 140 causative genes for CMT and other related diseases, MPZ, GDAP1, and NEFL are the only genes that cause all three subtypes of CMT (demyelinating, axonal, and intermediate). CMT is presently incurable; however, the ongoing attempts to treat it with various drugs, dietary supplements, and increase the importance of an exact genetic diagnosis for precision medicine. Therefore, it is important to compare the genetic and clinical features of patients with MPZ, GDAP1, and NEFL mutations. Taken together, a comparison of the causative mutations and clinical features of patients with MPZ-, GDAP1-, and NEFL-related CMT will be the first step in understanding how the different types of CMT are caused, and will enable molecular genetic diagnosis.

Conflict of Interest

No potential conflict of interest relevant to this article was re¬ported.

Fig. 1.

Structure and distribution of mutations in MPZ (A), GDAP1 (B), and NEFL (C) found in Korean CMT families. Vertical arrows indicate the mutation sites. Amino acid changes are indicated in red (demyelinating), blue (axonal), and green (intermediate).

Table 1.

Diseases Caused by Mutations in the MPZ, GDAP1, and NEFL Genes

Gene	Locus	Phenotype	MIM number	Heredity
MPZ	1q23.3	CMT1B	118200	AD
		CMT2I	607677	AD
		CMTDID	607791	AD
GDAP1	8q21.11	CMT4A	214400	AR
		CMT2K	607831	AD, AR
		CMTRIA	608340	AR
NEFL	8p21.2	CMT1F	607734	AD, AR
		CMT2E	607684	AD
		CMTDIG	617882	AD

AD, autosomal dominant; AR, autosomal recessive.

Table 2.

MPZ, GDAP1, and NEFL Mutation Detection Rates in Various Populations

Gene	Population	Frequency		Reference
Gene	Population	Total CMT patients (%)	CMT patients excluding CMT1A (%)	Reference
MPZ	Korean	3.2	4.7	[34]
	Chinese	3.3	6.4	[26]
	Japanese	5.1	NA	[29]
	German	4.2	6.4	[31]
	British	3.1	5.1	[27]
	American	4.1	6.5	[35]
	Spanish	4.3	7.5	[32]
	Italian	4.3	12.3	[33]
	Hungarian	4.5	7.5	[36]
	Norwegian	6.0	NA	[37]
	Russian	3.5	5.2	[21]
	Finnish	5.2	NA	[38]
	Austrian	4.0	NA	[39]
GDAP1	Korean	0.7	1.0	[40]
	Chinese	NA	1.6	[30]
	Japanese	NA	0.9	[29]
	British	0.5	0.8	[27]
	American	0.7	1.6	[28]
	Spanish	11.1	20.7	[32]
	Italian	5.4	11.0	[33]
NEFL	Korean	1.5	2.1	[41]
	Chinese	1.9	3.7	[26]
	Japanese	0.9	NA	[29]
		2.3	2.7	[23]
	German	0.0	0.0	[31]
		0.1	0.1	[42]
	British	0.2	0.2	[27]
	American	0.7	1.6	[28]
		0.7	1.1	[35]
		0.5	0.8	[43]
	Spanish	0.9	1.6	[32]
	Italian	0.6	1.8	[33]
	Norwegian	0.7	NA	[37]

CMT, Charcot-Marie-Tooth disease; NA, not available.

Table 3.

Clinical and Electrophysiological Features of Korean CMT Patients with MPZ Mutations

Item	CMT1B	CMT2I	CMTDID	p-value
Item	CMT1B	CMT2I	CMTDID	1B vs. 2I	1B vs. DID	2I vs. DID	ANOVA
Patient number	48	7	5
Female ratio (%)	54	14	20
Examined age (y)	26.4 ± 19.6	51.1 ± 11.7	40.8 ± 23.3	0.002	0.129	0.332	0.005
Onset age (y)	9.3 ± 10.7	38.7 ± 13.6	21.2 ± 13.7	< 0.001	0.025	0.053	< 0.001
Disability score
CMTNS	16.0 ± 7.4	8.0 ± 3.2	9.8 ± 1.0	0.004	0.102	0.326	0.023
FDS	2.8 ± 1.3	1.3 ± 0.5	1.8 ± 0.4	0.022	0.092	0.092	0.004
Nerve conduction studies
Patient number	38	5	4
Median motor nerve
CMAP (mV)	6.0 ± 5.6	13.0 ± 4.3	12.8 ± 1.9	0.011	0.033	0.915	0.006
MNCV (m/s)	12.2 ± 11.0	46.0 ± 6.6	41.3 ± 3.1	< 0.001	< 0.001	0.431	< 0.001
Peroneal nerve
CMAP (mV)	0.9 ± 2.0	2.1 ± 2.8	4.0 ± 3.1	0.231	0.001	0.132	0.002
MNCV (m/s)	5.1 ± 9.0	20.4 ± 19.4	25.7 ± 17.2	0.004	< 0.001	0.278	< 0.001
Median sensory nerve
SNAP (μV)	2.3 ± 4.7	15.6 ± 12.5	10.8 ± 15.3	< 0.001	< 0.001	0.718	< 0.001
SNCV (m/s)	7.4 ± 11.7	34.4 ± 4.3	18.0 ± 25.5	< 0.001	0.021	0.78	< 0.001
Sural nerve
SNAP (μV)	1.1 ± 3.5	5.4 ± 5.9	6.9 ± 9.7	0.059	0.001	0.346	0.002
SNCV (m/s)	3.4 ± 9.0	17.2 ± 14.9	13.3 ± 18.7	0.02	0.016	0.643	0.007

All data are expressed as the mean ± standard deviation. Normal nerve conduction velocity values: motor median nerve ≥ 50.5 m/s; sensory median nerve ≥ 39.3 m/s; sural nerve ≥ 32.1 m/s. Normal amplitude values: motor median nerve ≥ 6 mV; sensory median nerve ≥ 8.8 μV; sural nerve ≥ 6.0 μV.

CMT, Charcot-Marie-Tooth disease; ANOVA, analysis of variance; CMTNS, CMT neuropathy score; FDS, functional disability scale; CMAP, compound muscle action potential; MNCV, motor nerve conduction velocity; SNAP, sensory nerve action potential; SNCV, sensory nerve conduction velocity.

Table 4.

Clinical and Electrophysiological Features of Korean CMT Patients with GDAP1 Mutations

Item	CMT2K	CMTRIA	p-value
Patient number	7	3
Female ratio (%)	29	67
Examined age (y)	42.6 ± 15.7	9.7 ± 4.2	0.009
Onset age (y)	19.7 ± 7.7	1.7 ± 0.6	0.004
Disability score
CMTNS	11.1 ± 6.6	24.7 ± 3.2	0.011
FDS	2.3 ± 1.4	5.3 ± 1.2	0.010
Nerve conduction studies
Patient number	7	3
Median motor nerve
CMAP (mV)	11.2 ± 5.8	1.4 ± 1.2	0.024
MNCV (m/s)	52.0 ± 5.8	32.3 ± 28.0	0.092
Peroneal nerve
CMAP (mV)	1.8 ± 1.8	0.0 ± 0.1	0.127
MNCV (m/s)	21.7 ± 20.4	0.0 ± 0.0	0.113
Median sensory nerve
SNAP (μV)	6.3 ± 3.0	0.9 ± 1.3	0.051
SNCV (m/s)	38.2 ± 1.2	12.5 ± 17.7	0.005
Sural nerve
SNAP (μV)	0.2 ± 0.6	0.0 ± 0.0	0.604
SNCV (m/s)	4.8 ± 11.8	0.0 ± 0.0	0.604

Table 5.

Clinical and Electrophysiological Features of Korean CMT Patients with NEFL Mutations

Item	CMT1F	CMT2E	CMTDIG	p-value
Item	CMT1F	CMT2E	CMTDIG	1B vs. 2I	1B vs. DIG	2I vs. DIG	ANOVA
Patient number	9	4	24
Female ratio (%)	44	25	50
Examined age (y)	32.4 ± 16.8	42.7 ± 6.9	37.3 ± 16.3	0.271	0.453	0.524	0.536
Onset age (y)	10.2 ± 7.3	24.2 ± 9.4	12.1 ± 7.4	0.013	0.523	0.007	0.011
Disability score
CMTNS	24.1 ± 5.1	16.2 ± 12.3	18.4 ± 7.9	0.136	0.071	0.641	0.169
FDS	4.9 ± 1.9	3.2 ± 3.0	3.4 ± 2.0	0.243	0.055	0.914	0.165
Nerve conduction studies
Patient number	8	4	22
Median motor nerve
CMAP (mV)	3.1 ± 4.3	8.7 ± 5.2	9.6 ± 3.5	0.075	< 0.001	0.666	0.001
MNCV (m/s)	16.1 ± 10.5	47.7 ± 8.1	39.6 ± 4.4	< 0.001	< 0.001	0.007	< 0.001
Peroneal nerve
CMAP (mV)	0.5 ± 1.0	3.1 ± 4.0	1.7 ± 2.0	0.104	0.122	0.298	0.148
MNCV (m/s)	6.4 ± 12.2	26.3 ± 18.9	21.2 ± 17.1	0.049	0.033	0.591	0.066
Median sensory nerve
SNAP (μV)	4.6 ± 7.8	9.7 ± 15.4	5.0 ± 6.0	0.449	0.877	0.275	0.509
SNCV (m/s)	13.0 ± 18.5	29.0 ± 19.4	23.7 ± 17	0.194	0.146	0.581	0.246
Sural nerve
SNAP (μV)	0.0 ± 0.0	6.0 ± 9.0	2.5 ± 2.6	0.073	0.011	0.119	0.028
SNCV (m/s)	0.0 ± 0.0	23.4 ± 16.4	18.2 ± 14.6	0.002	0.002	0.522	0.004

References

1. Madrid R, Bradley WG, Davis CJ: The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. Part 2. Observations on pathological changes in sural nerve biopsies. J Neurol Sci 1977;32:91-122.

2. Cortese A, Wilcox JE, Polke JM, Poh R, Skorupinska M, Rossor AM, et al: Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology 2020;94:e51-e61.

3. Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, et al: Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep 2015;12:1169-1183.

4. Rossor AM, Polke JM, Houlden H, Reilly MM: Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol 2013;9:562-571.

5. Lemke G, Axel R: Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 1985;40:501-508.

6. De Jonghe P, Timmerman V, Ceuterick C, Nelis E, De Vriendt E, Löfgren A, et al: The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. Brain 1999;122(Pt 2):281-290.

7. Hayasaka K, Himoro M, Sato W, Takada G, Uyemura K, Shimizu N, et al: Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet 1993;5:31-34.

8. Kochański A: Mutations in the Myelin Protein Zero result in a spectrum of Charcot-Marie-Tooth phenotypes. Acta Myol 2004;23:6-9.

9. Mastaglia FL, Nowak KJ, Stell R, Phillips BA, Edmondston JE, Dorosz SM, et al: Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1999;67:174-179.

10. Sanmaneechai O, Feely S, Scherer SS, Herrmann DN, Burns J, Muntoni F, et al: Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain 2015;138(Pt 11):3180-3192.

11. Senderek J, Hermanns B, Lehmann U, Bergmann C, Marx G, Kabus C, et al: Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible “hotspot” on Thr124Met. Brain Pathol 2000;10:235-248.

12. Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, et al: Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 2003;126(Pt 1):134-151.

13. Shy ME, Jáni A, Krajewski K, Grandis M, Lewis RA, Li J, et al: Phenotypic clustering in MPZ mutations. Brain 2004;127(Pt 2):371-384.

14. Mazzeo A, Muglia M, Rodolico C, Toscano A, Patitucci A, Quattrone A, et al: Charcot-Marie-Tooth disease type 1B: marked phenotypic variation of the Ser78Leu mutation in five Italian families. Acta Neurol Scand 2008;118:328-332.

15. Senderek J, Ramaekers VT, Zerres K, Rudnik-Schöneborn S, Schröder JM, Bergmann C: Phenotypic variation of a novel nonsense mutation in the P0 intracellular domain. J Neurol Sci 2001;192:49-51.

16. Estela A, Pla-Martín D, Sánchez-Piris M, Sesaki H, Palau F: Charcot-Marie-Tooth-related gene GDAP1 complements cell cycle delay at G2/M phase in Saccharomyces cerevisiae fis1 gene-defective cells. J Biol Chem 2011;286:36777-36786.

17. Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, et al: Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002;30:21-22.

18. Cuesta A, Pedrola L, Sevilla T, García-Planells J, Chumillas MJ, Mayordomo F, et al: The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002;30:22-25.

19. Claramunt R, Pedrola L, Sevilla T, López de Munain A, Berciano J, Cuesta A, et al: Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 2005;42:358-365.

20. Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A, et al: Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 2003;126(Pt 3):642-649.

21. Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, et al: A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet 2000;67:37-46.

22. Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, et al: Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 2003;126(Pt 3):590-597.

23. Abe A, Numakura C, Saito K, Koide H, Oka N, Honma A, et al: Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. J Hum Genet 2009;54:94-97.

24. Yum SW, Zhang J, Mo K, Li J, Scherer SS: A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol 2009;66:759-770.

25. Berciano J, García A, Peeters K, Gallardo E, De Vriendt E, Pelayo-Negro AL, et al: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype. J Neurol 2015;262:1289-1300.

26. Hsu YH, Lin KP, Guo YC, Tsai YS, Liao YC, Lee YC: Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. Ann Clin Transl Neurol 2019;6:1090-1101.

27. Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL, et al: Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012;83:706-710.

28. DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, 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.

29. Yoshimura A, Yuan JH, Hashiguchi A, Ando M, Higuchi Y, Nakamura T, et al: Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan. J Neurol Neurosurg Psychiatry 2019;90:195-202.

30. Pakhrin PS, Xie Y, Hu Z, Li X, Liu L, Huang S, et al: Genotype-phenotype correlation and frequency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations. J Neurol 2018;265:637-646.

31. Gess B, Schirmacher A, Boentert M, Young P: Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. Neuromuscul Disord 2013;23:647-651.

32. Sivera R, Sevilla T, Vílchez JJ, Martínez-Rubio D, Chumillas MJ, Vázquez JF, et al: Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series. Neurology 2013;81:1617-1625.

33. Sadjadi R, Reilly MM, Shy ME, Pareyson D, Laura M, Murphy S, et al: Psychometrics evaluation of Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) second version, using Rasch analysis. J Peripher Nerv Syst 2014;19:192-196.

34. Kim HJ, Nam SH, Kwon HM, Lim SO, Park JH, Kim HS, et al: Genetic and clinical spectrums in Korean Charcot-Marie-Tooth disease patients with myelin protein zero mutations. Mol Genet Genomic Med 2021;9:e1678.

35. Fridman V, Bundy B, Reilly MM, Pareyson D, Bacon C, Burns J, 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.

36. Milley GM, Varga ET, Grosz Z, Nemes C, Arányi Z, Boczán J, et al: Genotypic and phenotypic spectrum of the most common causative genes of Charcot-Marie-Tooth disease in Hungarian patients. Neuromuscul Disord 2018;28:38-43.

37. Østern R, Fagerheim T, Hjellnes H, Nygård B, Mellgren SI, Nilssen Ø: Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies. BMC Med Genet 2013;14:94.

38. Silander K, Meretoja P, Juvonen V, Ignatius J, Pihko H, Saarinen A, et al: Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies. Hum Mutat 1998;12:59-68.

39. Miltenberger-Miltenyi G, Schwarzbraun T, Löscher WN, Wanschitz J, Windpassinger C, Duba HC, et al: Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. Eur J Hum Genet 2009;17:1154-1159.

40. Kim HS, Kim HJ, Nam SH, Kim SB, Choi YJ, Lee KS, et al: Clinical and neuroimaging features in Charcot-Marie-Tooth patients with GDAP1 mutations. J Clin Neurol 2021;17:52-62.

41. Kim HJ, Kim SB, Kim HS, Kwon HM, Park JH, Lee AJ, et al: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease. Mol Genet Genomic Med 2022;10:e1870.

42. Rudnik-Schöneborn S, Tölle D, Senderek J, Eggermann K, Elbracht M, Kornak U, et al: Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet 2016;89:34-43.

43. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME: Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011;69:22-33.