Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with NEXMIF Mutation: Case Report

The NEXMIF (KIAA2022) gene is located in the X chromosome, and hemizygous mutations in NEXMIF cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in NEXMIF also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with NEXMIF mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in NEXMIF. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with NEXMIF mutations.

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A de novo variant in the X‐linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.861 ◽

2019 ◽

Vol 7 (10) ◽

Cited By ~ 3

Author(s):

Daniel L. Polla ◽

Harriet R. Saunders ◽

Bert B. A. Vries ◽

Hans Bokhoven ◽

Arjan P. M. Brouwer

Keyword(s):

Intellectual Disability ◽

Female Patient ◽

De Novo ◽

Mild Intellectual Disability ◽

Linked Gene ◽

De Novo Variant

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Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

Frontiers in Genetics ◽

10.3389/fgene.2021.705734 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiucui Li ◽

Shijia Bao ◽

Wei Wang ◽

Xulai Shi ◽

Ying Hu ◽

...

Keyword(s):

Intellectual Disability ◽

Brain Development ◽

De Novo ◽

Basolateral Membrane ◽

Intractable Epilepsy ◽

Chinese Patient ◽

Renal Tubules ◽

Variable Degree ◽

Mild Intellectual Disability ◽

Severity Of The Disease

A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia. Cyclin M2 (CNNM2) proteins, as a member of magnesium (Mg2+) transporters, were found along the basolateral membrane of distal renal tubules and involved in the reabsorption of Mg2+. Homozygous and heterozygous variants in CNNM2 reported so far were responsible for a variable degree of hypomagnesemia, several of which also showed varying degrees of neurological phenotypes such as intellectual disability and epilepsy. Here, we report a de novo heterozygous CNNM2 variant (c.2228C > T, p.Ser743Phe) in a Chinese patient, which is the variant located in the cyclic nucleotide monophosphate-binding homology (CNBH) domain of CNNM2 proteins. The patient presented with mild intellectual disability and refractory epilepsy but without hypomagnesemia. Thus, we reviewed the literature and analyzed the phenotypes related to CNNM2 variants, and then concluded that the number of variant alleles and the changed protein domains correlates with the severity of the disease, and speculated that the CNBH domain of CNNM2 possibly plays a limited role in Mg2+ transport but a significant role in brain development. Furthermore, it can be speculated that neurological phenotypes such as intellectual disability and seizures can be purely caused by CNNM2 variants.

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A Rare, Recurrent,De Novo14q32.2q32.31 Microdeletion of 1.1 Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability

Case Reports in Genetics ◽

10.1155/2014/530134 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 4

Author(s):

Almira Zada ◽

Farmaditya E. P. Mundhofir ◽

Rolph Pfundt ◽

Nico Leijsten ◽

Willy Nillesen ◽

...

Keyword(s):

Intellectual Disability ◽

Female Patient ◽

De Novo ◽

Fragile X ◽

Genetic Diagnosis ◽

Facial Dysmorphism ◽

Feeding Problems ◽

Motor Delay ◽

Genome Wide ◽

Low Copy Repeats

We present a 20-year-old female patient from Indonesia with intellectual disability (ID), proportionate short stature, motor delay, feeding problems, microcephaly, facial dysmorphism, and precocious puberty who was previously screened normal for conventional karyotyping, fragile X testing, and subtelomeric MLPA analysis. Subsequent genome wide array analysis was performed on DNA from blood and revealed a 1.1 Mb deletion in 14q32.2q32.31 (chr14:100,388,343-101,506,214; hg19). Subsequent carrier testing in the parents by array showed that the deletion had occurredde novoin the patient and that her paternal 14q32 allele was deleted. The deleted region encompasses theDLK1/GTL2imprinted gene cluster which is consistent with the maternal UPD(14)-like phenotype of the patient. This rare, recurrent microdeletion was recently shown not to be mediated by low copy repeats, but by expanded TGG repeats, flanking the 14q32.2q32.21 deletion boundaries, a novel mechanism of recurrent genomic rearrangement. This is another example how the application of high resolution genome wide testing provides an accurate genetic diagnosis, thereby improving the care for patients and optimizing the counselling for family.

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Complex Neurological Phenotype Associated with a De Novo DHDDS Mutation in a Boy with Intellectual Disability, Refractory Epilepsy, and Movement Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1713159 ◽

2020 ◽

Author(s):

Gianluca Piccolo ◽

Elisabetta Amadori ◽

Maria Stella Vari ◽

Francesca Marchese ◽

Antonella Riva ◽

...

Keyword(s):

Intellectual Disability ◽

Movement Disorder ◽

De Novo ◽

Refractory Epilepsy ◽

Dominant Negative ◽

De Novo Mutation ◽

De Novo Mutations ◽

Mild Intellectual Disability ◽

Neurodevelopmental Disease ◽

Neurological Phenotype

AbstractMutations in the DHDDS gene (MIM: 617836), encoding a subunit of dehydrodolichyl diphosphate synthase complex, have been recently implicated in very rare neurodevelopmental diseases. In total, five individuals carrying two de novo mutations in DHDDS have been reported so far, but genotype–phenotype correlations remain elusive. We reported a boy with a de novo mutation in DHDDS (NM_205861.3: c.G632A; p.Arg211Gln) featuring a complex neurological phenotype, including mild intellectual disability, impaired speech, complex hyperkinetic movements, and refractory epilepsy. We defined the electroclinical and movement disorder phenotype associated with the monoallelic form of the DHDDS-related neurodevelopmental disease and possible underlying dominant-negative mechanisms.

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ARHGEF9 disease

Neurology Genetics ◽

10.1212/nxg.0000000000000148 ◽

2017 ◽

Vol 3 (3) ◽

pp. e148 ◽

Cited By ~ 18

Author(s):

Michael Alber ◽

Vera M. Kalscheuer ◽

Elysa Marco ◽

Elliott Sherr ◽

Gaetan Lesca ◽

...

Keyword(s):

Intellectual Disability ◽

Motor Development ◽

De Novo ◽

Intractable Epilepsy ◽

Facial Dysmorphism ◽

Ph Domain ◽

Loss Of Function ◽

Protein Loss ◽

Severe Intellectual Disability ◽

Detailed Medical History

Objective:We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.Methods:Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.Results:A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.Conclusions:ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

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A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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MED13L-related intellectual disability due to paternal germinal mosaicism

Molecular Case Studies ◽

10.1101/mcs.a006124 ◽

2021 ◽

pp. mcs.a006124

Author(s):

Beata Bessenyei ◽

Istvan Balogh ◽

Attila Mokanszki ◽

Aniko Ujfalusi ◽

Rolph Pfundt ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Mediator Complex ◽

Facial Dysmorphism ◽

Facial Features ◽

Speech Delay ◽

Motor Delay ◽

First Case ◽

Intragenic Deletion ◽

Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

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Mosaicism and incomplete penetrance of PCDH19 mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-105235 ◽

2018 ◽

Vol 56 (2) ◽

pp. 81-88 ◽

Cited By ~ 15

Author(s):

Aijie Liu ◽

Xiaoxu Yang ◽

Xiaoling Yang ◽

Qixi Wu ◽

Jing Zhang ◽

...

Keyword(s):

Male Patient ◽

Sanger Sequencing ◽

De Novo ◽

Digital Pcr ◽

The Other ◽

Incomplete Penetrance ◽

Female Patients ◽

Targeted Next Generation Sequencing ◽

Male Patients ◽

Patients With Epilepsy

BackgroundMutations in the PCDH19 gene have mainly been reported in female patients with epilepsy. To date, PCDH19 mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.ObjectiveWe aimed to investigate the occurrence of mosaic PCDH19 mutations in 42 families comprising at least one patient with PCDH19-related epilepsy.MethodsTwo male patients with mosaic PCDH19 variants were identified using targeted next-generation sequencing. Forty female patients with PCDH19 variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with PCDH19 variants.ResultsFive mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred PCDH19 variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.ConclusionOur study provides new insights into phenotype-genotype correlations in PCDH19 related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.

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