Coexistence of Charcot-Marie-Tooth 1A and nondystrophic myotonia due to PMP22 duplication and SCN4A pathogenic variants: a case report

Abstract Background Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form; it is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Mutations in the transient sodium channel Nav1.4 alpha subunit (SCN4A) gene underlie a diverse group of dominantly inherited nondystrophic myotonias that run the spectrum from subclinical myopathy to severe muscle stiffness, disabling weakness, or frank episodes of paralysis. Case presentation We describe a Chinese family affected by both CMT1A and myotonia with concomitant alterations in both the PMP22 and SCN4A genes. In this family, the affected proband inherited the disease from his father in an autosomal dominant manner. Genetic analysis confirmed duplication of the PMP22 gene and a missense c.3917G > C (p. Gly1306Ala) mutation in SCN4A in both the proband and his father. The clinical phenotype in the proband showed the combined involvement of skeletal muscle and peripheral nerves. Electromyography showed myopathic changes, including myotonic discharges. MRI revealed the concurrence of neurogenic and myogenic changes in the lower leg muscles. Sural nerve biopsies revealed a chronic demyelinating and remyelinating process with onion bulb formations in the proband. The proband’s father presented with confirmed subclinical myopathy, very mild distal atrophy and proximal hypertrophy of the lower leg muscles, pes cavus, and areflexia. Conclusion This study reports the coexistence of PMP22 duplication and SCN4A mutation. The presenting features in this family suggested that both neuropathy and myopathy were inherited in an autosomal dominant manner. The proband had a typical phenotype of sodium channel myotonia (SCM) and CMT1A. However, his father with the same mutations presented a much milder clinical phenotype. Our study might expand the genetic and phenotypic spectra of neuromuscular disorders with concomitant mutations.

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Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication

Brazilian Journal of Medical and Biological Research ◽

10.1590/s0100-879x2003001000018 ◽

2003 ◽

Vol 36 (10) ◽

pp. 1403-1407 ◽

Cited By ~ 6

Author(s):

W. Marques Jr. ◽

M.G. Sweeney ◽

N.W. Wood

Keyword(s):

Amino Acid ◽

Amino Acid Substitution ◽

Clinical Phenotype ◽

Disease Type ◽

Myelin Protein ◽

Peripheral Myelin Protein 22 ◽

Peripheral Myelin Protein ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Disease

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Molecular Epidemiology of Charcot-Marie-Tooth Disease in Northern Ostrobothnia, Finland: A Population-Based Study

Neuroepidemiology ◽

10.1159/000478860 ◽

2017 ◽

Vol 49 (1-2) ◽

pp. 34-39 ◽

Cited By ~ 7

Author(s):

Maria Marttila ◽

Laura Kytövuori ◽

Seppo Helisalmi ◽

Mika Kallio ◽

Marjo Laitinen ◽

...

Keyword(s):

Point Mutations ◽

Population Based ◽

Neuromuscular Disorder ◽

Myelin Protein ◽

Hereditary Neuropathy ◽

Mitofusin 2 ◽

Peripheral Myelin Protein 22 ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Junction Protein

Background: Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder with a population prevalence of 9.7-82.3/100,000. In this study, we have estimated the prevalence of CMT and its subtypes in Finland and examined the frequency of molecular etiologies. Methods: A population-based survey included adult patients with peripheral neuropathy from the province of Northern Ostrobothnia, Finland. Secondary causes of peripheral polyneuropathy were excluded and patients with clinical and neurophysiological features pertinent with CMT were included. Molecular diagnostics was carried out when DNA was available. Results: We found 107 subjects with CMT yielding a prevalence 34.6/100,000 in Northern Ostrobothnia. The heterozygous point mutation p.His123Arg in ganglioside induced differentiation associated protein 1 (GDAP1) was found in 31.5% and peripheral myelin protein 22 (PMP22) duplication in 16.9% of the affected. Point mutations in myelin protein zero, mitofusin 2, and gap junction protein beta 1 accounted for 6.7% of the cases. In addition, 18 persons had hereditary neuropathy with liability to pressure palsies and 15 of them carried the PMP22 deletion. Conclusions: The prevalence of CMT in Northern Ostrobothnia, Finland, seems to be slightly higher than those in previous studies in European populations. Founder mutation in the GDAP1 gene accounts for a large part of the genetically defined CMT2 in Finland.

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Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation.

International Journal of Molecular Medicine ◽

10.3892/ijmm.1.2.495 ◽

1998 ◽

Author(s):

L Leonardis ◽

J Zidar ◽

A Ekici ◽

B Peterlin ◽

B Rautenstrauss

Keyword(s):

Point Mutation ◽

Autosomal Dominant ◽

Disease Type ◽

Hereditary Neuropathy ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pressure Palsies ◽

Tooth Disease

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Analysis of mutations in 17p 11.2 region in patients with Charcot-Marie-Tooth type 1 disease and patients with tomaculose neuropathy

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0204059z ◽

2002 ◽

Vol 130 (3-4) ◽

pp. 59-63

Author(s):

Natasa Zamurovic ◽

Vedrana Milic ◽

Jelena Dackovic ◽

Dragan Zamurovic ◽

Biljana Culjkovic ◽

...

Keyword(s):

Restriction Analysis ◽

Hereditary Neuropathy ◽

Inherited Disorders ◽

Peripheral Myelin Protein 22 ◽

Charcot Marie Tooth ◽

Standard Procedures ◽

Sporadic Cases ◽

Tooth Type ◽

Pressure Palsies

Charcot-Marie-Tooth type 1? disease (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are common inherited disorders of the peripheral nervous system associated with duplication and deletion respectively, of the 17p11.2 segment including the gene of peripheral myelin protein 22. We studied 48 subjects belonging to 29 families with clinical and electrophysiological signs of definite CMT1, 20 patients with suspected CMT phenotype, and 17 patients and healthy members of their families with HNPP. Blood sampling and DNA isolation, PCR, restriction analysis, southern blotting were performed using standard procedures. Of 48 patients with diagnosis of definite CMT1 in 25 (52%) we found a 1.5 Mb tandem duplication in chromosome 17p11.2. These duplications were not found in any of 20 sporadic cases with the clinical phenotype of CMT but without reliable electrophysiological data. Only 13 (44.8%)of 29 unrelated CMT1 patients from the first group had 17p11.2 duplications. Three of 4 sporadic cases (75%) with definite CMT1 had 17p11.2 duplications. Of 17 patients from 6 families with HNPP deletion of 17p11.2 segment was found in 15 (88.2%), as well as in 5 (83.3%) of six unrelated cases. Detection of CMT1A/HNPP recombination hotspot is a simple and reliable DNA diagnostic method, which is useful only for the patients with clinically already verified CMT1, and HNPP for further genetic counseling of patients and members of their families.

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A familial case of Syndactyly type IV due to a novel duplication of ~222.23 kb covering exons 2-17 of the LMBR1 gene: a case report

10.1101/420588 ◽

2018 ◽

Author(s):

Lijing Shi ◽

Hui Huang ◽

Qiuxia Jiang ◽

Rongsen Huang ◽

Wanyu Fu ◽

...

Keyword(s):

Autosomal Dominant ◽

Clinical Phenotype ◽

Regulatory Element ◽

Chinese Family ◽

Heterozygous Mutation ◽

Type Iv ◽

Limb Malformations ◽

Triphalangeal Thumb ◽

Generation Sequencing ◽

Syndactyly Type Iv

ABSTRACTSyndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant Syndactyly type IV (SD4) is a very rare form of syndactyly, occurring as a result of heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. The SD4 is characterized by complete cutaneous syndactyly of all fingers, cup-shaped hands due to flexion of the fingers and accompanied by polydactyly. Here, we firstly reported a big Chinese family, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). Genetically, we identified a novel duplication of ∼222.23 kb covering exons 2-17 of the LMBR1 gene in this family by next generation sequencing. This case expands our new clinical understanding of SD4 phenotype.

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Interaction between FGF23 R176W mutation and C716T nonsynonymous change (T239M, rs7955866) in FGF23 on the clinical phenotype in a family with autosomal dominant hypophosphatemic rickets

Bone Abstracts ◽

10.1530/boneabs.1.pp120 ◽

2013 ◽

Author(s):

Daniela Merlotti ◽

Domenico Rendina ◽

Luigi Gennari ◽

Teresa Esposito ◽

Sara Magliocca ◽

...

Keyword(s):

Autosomal Dominant ◽

Clinical Phenotype ◽

Hypophosphatemic Rickets ◽

Autosomal Dominant Hypophosphatemic Rickets ◽

Nonsynonymous Change

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A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

BMC Neurology ◽

10.1186/s12883-021-02256-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Nozomu Matsuda ◽

Koushi Ootsuki ◽

Shunsuke Kobayashi ◽

Ayaka Nemoto ◽

Hitoshi Kubo ◽

...

Keyword(s):

Hearing Loss ◽

Neuromuscular Disorders ◽

Whole Body ◽

Congenital Hearing Loss ◽

Severe Phenotype ◽

Demyelinating Neuropathy ◽

Magnetic Resonance Neurography ◽

Peripheral Myelin Protein 22 ◽

Hypertrophic Neuropathy

Abstract Background Hereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2. Case presentation The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2. Conclusions We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

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INF2 p.Arg214Cys mutation in a Chinese family with rapidly progressive renal failure and follow-up of renal transplantation: case report and literature review

BMC Nephrology ◽

10.1186/s12882-021-02254-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Wenbo Zhao ◽

Xinxin Ma ◽

Xiaohao Zhang ◽

Dan Luo ◽

Jun Zhang ◽

...

Keyword(s):

Renal Failure ◽

Renal Disease ◽

Autosomal Dominant ◽

Mutational Analysis ◽

Elevated Serum ◽

Chinese Family ◽

Progressive Renal Failure ◽

Rapidly Progressive Renal Failure ◽

Stage Renal Disease ◽

End Stage

Abstract Background Heterozygous mutations in the inverted formin 2 (INF2) gene are related to secondary focal segmental glomerulosclerosis (FSGS), a rare secondary disease associated with rapidly progressive renal failure. Case presentation We report a patient with familial autosomal INF2 mutation manifesting nephritic syndromes and elevated serum creatinine levels. Mutational analysis revealed an autosomal dominant (AD) inheritance pattern and a mutation in exon 4 (p.Arg214Cys) of INF2 as the likely cause, which has not been previously described in an Asian family. The patient progressed to end-stage renal disease (ESRD) and received hemodialysis. His mother had undergone renal transplant 3 years earlier, and his grandmother had carried the p.Arg214Cys mutation for more than 80 years without any sign of renal dysfunction. Conclusions This is the first report to identify an association between a familial autosomal dominant INF2 p.Arg214Cys mutation and rapidly progressive renal disease in an Asian family. INF2 mutation analysis should not be restricted to individuals without family history of FSGS, rather it should also be performed on individuals for whom drug-based therapies are not effective. In this case, kidney transplant is an effective alternative.

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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