scholarly journals A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bianca R. Grosz ◽  
Natasha B. Golovchenko ◽  
Melina Ellis ◽  
Kishore Kumar ◽  
Garth A. Nicholson ◽  
...  
Keyword(s):  
In Silico ◽  
De Novo ◽  
Age Of Onset ◽  
Nerve Biopsy ◽  
Enhancer Element ◽  
Peripheral Myelin Protein 22 ◽  
Charcot Marie Tooth ◽  
Electrophysiological Examination ◽  
Congenital Hypomyelinating Neuropathy ◽  
Type 3

AbstractEGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.

scholarly journals Clinical and Neuroimaging Features in Charcot–Marie–Tooth Patients with GNB4 Mutations

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 494
Author(s):  
Hye Mi Kwon ◽  
Hyun Su Kim ◽  
Sang Beom Kim ◽  
Jae Hong Park ◽  
Da Eun Nam ◽  
...  
Keyword(s):  
De Novo ◽  
Motor Nerve ◽  
Nerve Biopsy ◽  
Sural Nerve Biopsy ◽  
Motor Nerve Conduction Velocity ◽  
De Novo Mutation ◽  
Intermediate Type ◽  
Demyelinating Neuropathy ◽  
Charcot Marie Tooth ◽  
Pmp22 Duplication

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Towards the de novo design of DNA based catalytic sites using a combined NMR and in silico approach

2014 ◽  
Author(s):  
Dieter Buyst ◽  
V. Gheerardijn ◽  
J. Van Den Begin ◽  
A. Madder ◽  
J. C. Martins
Keyword(s):  
In Silico ◽  
De Novo ◽  
De Novo Design ◽  
Catalytic Sites

scholarly journals Mutation-dependent alteration in cellular distribution of peripheral myelin protein 22 in nerve biopsies from Charcot–Marie–Tooth type 1A

Brain ◽  
2000 ◽  
Vol 123 (5) ◽  
pp. 1001-1006 ◽  
Author(s):  
C. Oliver Hanemann ◽  
Donatella D'Urso ◽  
Anneke A. W. M. Gabreëls-Festen ◽  
Hans W. Müller
Keyword(s):  
Myelin Protein ◽  
Cellular Distribution ◽  
Peripheral Myelin Protein 22 ◽  
Peripheral Myelin Protein ◽  
Charcot Marie Tooth ◽  
Tooth Type

Confirmation of the GNB4 gene as causal for Charcot–Marie–Tooth disease by a novel de novo mutation in a Czech patient

2017 ◽  
Vol 27 (1) ◽  
pp. 57-60 ◽  
Author(s):  
Petra Laššuthová ◽  
Dana Šafka Brožková ◽  
Jana Neupauerová ◽  
Marcela Krůtová ◽  
Radim Mazanec ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Czech Patient ◽  
Tooth Disease

Variability in nerve biopsy findings in a kinship with dominantly inherited charcot-marie-tooth disease

1982 ◽  
Vol 5 (3) ◽  
pp. 185-196 ◽  
Author(s):  
Tiemen W. van Weerden ◽  
Hendrik Jan Houthoff ◽  
Onggie Sie ◽  
Jan M. Minderhoud
Keyword(s):  
Nerve Biopsy ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance

2021 ◽  
Vol 9 ◽  
Author(s):  
Han Zhang ◽  
Ye Wu ◽  
Yuwu Jiang
Keyword(s):  
De Novo ◽  
Serum Magnesium ◽  
Brain Magnetic Resonance Imaging ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
Domain Variations ◽  
Type 3

CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with CNNM2 novel de novo pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with CNNM2-related disorders have been reported. We combined all 23 cases to analyze the features of CNNM2-related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of CNNM2-related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of CNNM2 variants and classified the phenotypes of CNNM2-related disorders into three types. We found that DUF21 domain variations were most associated with CNNM2-related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. These results provide important clues for further functional studies of CNNM2 and provide basic foundations for more accurate genetic counseling.

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