scholarly journals CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis

2017 ◽  
Vol 3 (2) ◽  
pp. e144 ◽  
Author(s):  
Holger Hengel ◽  
Alex Magee ◽  
Muhammad Mahanjah ◽  
Jean-Michel Vallat ◽  
Robert Ouvrier ◽  
...  
Keyword(s):  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Nerve Biopsy ◽  
Compound Heterozygous ◽  
Arthrogryposis Multiplex Congenita ◽  
Whole Exome ◽  
Paranodal Junctions ◽  
Distinct Features ◽  
Deep Phenotyping

Objective:To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the CNTNAP1 gene.Methods:In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the CNTNAP1 gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further CNTNAP1 mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.Results:We identified 3 novel CNTNAP1 mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.Conclusions:CNTNAP1 mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature. CNTNAP1-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.

scholarly journals Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis

2018 ◽  
Vol 33 (10) ◽  
pp. 642-650 ◽  
Author(s):  
Alexander Conant ◽  
Julian Curiel ◽  
Amy Pizzino ◽  
Parisa Sabetrasekh ◽  
Jennifer Murphy ◽  
...  
Keyword(s):  
Quadriceps Muscle ◽  
Magnetic Resonance Images ◽  
Compound Heterozygous ◽  
Arthrogryposis Multiplex Congenita ◽  
Axonal Pathology ◽  
Whole Exome ◽  
Paranodal Junctions ◽  
Biallelic Mutations ◽  
Congenital Hypomyelinating Neuropathy ◽  
Muscle Biopsies

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

scholarly journals Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

2020 ◽  
Author(s):  
Aldesia Provenzano ◽  
Andrea La Barbera ◽  
Mirko Scagnet ◽  
Angelica Pagliazzi ◽  
Giovanna Traficante ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Chromatin Remodeling ◽  
Brain Mri ◽  
Cranial Bone ◽  
Genetic Syndromes ◽  
Whole Exome ◽  
Cerebellar Tonsillar Herniation ◽  
Brain Magnetic Resonance Image

AbstractType 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals Neurodevelopmental Disorder With Microcephaly, Hypotonia, And Variable Brain Anomalies In A Consanguineous Iranian Family Is Associated With A Novel Homozygous Start Loss Variant In The PRUNE1 Gene

2021 ◽  
Author(s):  
Mehdi Agha Gholizadeh ◽  
Mina Mohammadi-Sarband ◽  
Fatemeh Fardanesh ◽  
Masoud Garshasbi
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Neurodevelopmental Disorder ◽  
Cerebellar Atrophy ◽  
Compound Heterozygous ◽  
Protein Structure Analysis ◽  
Whole Exome ◽  
Iranian Family ◽  
Loss Variant

Abstract Background: Homozygous or compound heterozygous PRUNE1 mutations cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations (NMIHBA) (OMIM #617481). The PRUNE1 gene encodes a member of the phosphoesterase (DHH) protein superfamily that is involved in the regulation of cell migration. To date, most of the described mutations in the PRUNE1 gene are clustered in DHH domain. Methods: We subjected 4 members (two affected and two healthy) of a consanguineous Iranian family in the study. The proband underwent whole-exome sequencing and a novel identified variant was confirmed by Sanger sequencing. Co-segregation of the detected variant with the disease in family was confirmed.Results: By whole-exome sequencing, we identified the first start loss variant, NM_021222.3:c.3G>A; p.(Met1?), in the PRUNE1 in two patients of a consanguineous Iranian family with spastic quadriplegic cerebral palsy (CP), hypotonia, developmental regression, and cerebellar atrophy. Sanger sequencing confirmed the segregation of the variant with the disease in the family. Protein structure analysis also revealed that the variant probably leads to the deletion of DHH (Asp-His-His) domain, the active site of the protein, and loss of PRUNE1 function. Conclusion: We identified a novel start loss variant, NM_021222.3:c.3G>A; p.(Met1?) in the PRUNE1 gene in two affected members as a possible cause of NMIHBA in an Iranian family. We believe that the study adds a new pathogenic variant in spectrum of mutations in the PRUNE1 gene as a cause of PRUNE1-related syndrome.

scholarly journals VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

2019 ◽  
Author(s):  
R.E.N. van der Welle ◽  
R. Jobling ◽  
C. Burns ◽  
P. Sanza ◽  
C. ten Brink ◽  
...  
Keyword(s):  
Neuroprotective Effect ◽  
Protein Sorting ◽  
Brain Mri ◽  
Retinal Dystrophy ◽  
Cerebellar Atrophy ◽  
Recessive Mutation ◽  
Compound Heterozygous ◽  
Mri Findings ◽  
Mtorc1 Signaling ◽  
Vacuolar Protein

AbstractThe vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson’s disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41R662* and VPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285P or VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285P and VPS41R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

scholarly journals Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous CACNA2D2 Variants

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Kameryn M. Butler ◽  
Philip J. Holt ◽  
Sarah S. Milla ◽  
Cristina da Silva ◽  
John J. Alexander ◽  
...  
Keyword(s):  
Cerebellar Atrophy ◽  
Epileptic Encephalopathy ◽  
First Year ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Novel Variants ◽  
Voltage Dependent ◽  
Clinical Description ◽  
Compound Heterozygous Variants ◽  
First Year Of Life

CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.

scholarly journals NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum

2020 ◽  
pp. jmedgenet-2020-106846
Author(s):  
Virginia Kimonis ◽  
Rehab al Dubaisi ◽  
Andrew E Maclean ◽  
Kathy Hall ◽  
Lan Weiss ◽  
...  
Keyword(s):  
Complex I ◽  
Phenotypic Variability ◽  
Brain Mri ◽  
Mitochondrial Disorder ◽  
Cerebellar Atrophy ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Yeast Model

BackgroundThe nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).MethodsWhole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.ResultsThe previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.ConclusionWe report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.

scholarly journals Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun Chu ◽  
Yi He ◽  
Ziyuan Li ◽  
Zhongxin Jiang ◽  
Liang Wang ◽  
...  
Keyword(s):  
Compound Heterozygous ◽  
Ovarian Insufficiency ◽  
Mutant Proteins ◽  
Adverse Health Outcomes ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Variant Analysis ◽  
First Time

Premature ovarian insufficiency (POI) affects about 1% of women under 40 years and leads most often to definitive infertility with adverse health outcomes. Genetic factor has been reported to play an important role in POI. However, the genetic etiology remains unknown in the majority of the POI patients. Whole-exome sequencing and variant analysis were carried out in a POI pedigree. In vitro studies of the wild-type and mutant proteins were conducted in primary granulosa cells (GCs) and granulosa cell line. The result showed that the patients carried compound heterozygous nonsynonymous mutations (c.245C > T and c.181C > G) in LAT gene, which were identified to be transmitted from their parents. The two variants were assessed to affect residues that were conserved across different species examined, and were predicted to be deleterious by software predictions. Protein structure predicting result indicated that the two variants could alter their interactions with surrounding residues, which may change the internal structure of the LAT protein. Moreover, LAT protein expression in GCs was demonstrated for the first time, and further functional assays suggested that this mutation could reduce LAT expression and influence GC survival, which may contribute to the etiology of POI. In summary, we detect novel LAT pathogenic variants in a POI pedigree and report for the first time that LAT is present and functional in the GCs of the ovary. Our findings not only shed new light on the role of LAT in GCs, but also broaden the spectrum of genetic causes of POI.

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

2020 ◽  
Author(s):  
Deirdre O'Sullivan ◽  
Michael Moore ◽  
Susan Byrne ◽  
Andreas O. Reiff ◽  
Susanna Felsenstein
Keyword(s):  
Young Child ◽  
Genetic Basis ◽  
Transverse Myelitis ◽  
Acute Disseminated Encephalomyelitis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Childhood Onset

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.

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