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

MPZ, GDAP1, and NEFL Mutations with Diverse Phenotypes

Article information

J Electrodiagn Neuromuscul Dis. 2022;24(3):62-69
Publication date (electronic) : 2022 December 30
doi : https://doi.org/10.18214/jend.2022.00143
Hye Jin Kim1orcid_icon, Hye Mi Kwon1orcid_icon, Sang Beom Kim2orcid_icon, Ki Wha Chung3orcid_icon, Byung-Ok Choi,1,4orcid_icon
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 2022 August 8; Revised 2022 October 4; Accepted 2022 October 6.

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).

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).

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].

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

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].

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

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).

Clinical and Electrophysiological Features of Korean CMT Patients with MPZ Mutations

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.

Clinical and Electrophysiological Features of Korean CMT Patients with GDAP1 Mutations

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%).

Clinical and Electrophysiological Features of Korean CMT Patients with NEFL Mutations

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.

Notes

Conflict of Interest

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

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Fig. 1.

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
Total CMT patients (%) CMT patients excluding CMT1A (%)
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
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

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 5.

Clinical and Electrophysiological Features of Korean CMT Patients with NEFL Mutations

Item CMT1F CMT2E CMTDIG p-value
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

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.