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

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.

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UNC13B variants associated with partial epilepsy with favourable outcome

Brain ◽

10.1093/brain/awab164 ◽

2021 ◽

Author(s):

Jie Wang ◽

Jing-Da Qiao ◽

Xiao-Rong Liu ◽

De-Tian Liu ◽

Yan-Hui Chen ◽

...

Keyword(s):

Neuronal Excitability ◽

Brain Mri ◽

Missense Variant ◽

Febrile Seizures ◽

Favourable Outcome ◽

Partial Epilepsy ◽

Favorable Outcome ◽

Compound Heterozygous ◽

Developmental Abnormalities ◽

Seizure Rate

Abstract The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13–2 (Munc13-2), that is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

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PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Neuropediatrics ◽

10.1055/s-0038-1661396 ◽

2018 ◽

Vol 49 (05) ◽

pp. 330-338 ◽

Cited By ~ 4

Author(s):

Anna Schossig ◽

Tobias Haack ◽

Reka Kovács-Nagy ◽

Matthias Braunisch ◽

Christine Makowski ◽

...

Keyword(s):

Developmental Delay ◽

Early Onset ◽

Brain Mri ◽

Missense Variant ◽

Global Developmental Delay ◽

Multiplex Family ◽

Consistent Finding ◽

Whole Exome ◽

Severe Developmental Disabilities ◽

Stem Lesions

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

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Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations

Neurology Genetics ◽

10.1212/nxg.0000000000000521 ◽

2020 ◽

Vol 6 (6) ◽

pp. e521

Author(s):

Vanessa Zanette ◽

Aurelio Reyes ◽

Mark Johnson ◽

Daniel do Valle ◽

Alan J. Robinson ◽

...

Keyword(s):

Metabolic Acidosis ◽

Phenotypic Variability ◽

Brain Mri ◽

Rna Polymerase Iii ◽

Resonance Spectroscopy ◽

Compound Heterozygous ◽

Expression Levels ◽

Abnormal Movements ◽

Generalized Dystonia ◽

Pol Iii

ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [1H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.ResultsThe patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.ConclusionsMutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.

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CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis

Neurology Genetics ◽

10.1212/nxg.0000000000000144 ◽

2017 ◽

Vol 3 (2) ◽

pp. e144 ◽

Cited By ~ 15

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.

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A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽

10.1186/s12883-021-02380-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Natalie C. Lippa ◽

Subit Barua ◽

Vimla Aggarwal ◽

Elaine Pereira ◽

Jennifer M. Bain

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Phenotypic Variability ◽

Missense Variant ◽

Global Developmental Delay ◽

Related Disorder ◽

Patient Reported

Abstract Background Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43–55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. Case presentation Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. Conclusions This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

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Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽

10.3390/genes12101508 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1508

Author(s):

Isabelle Jéru ◽

Amira Nabil ◽

Gehad El-Makkawy ◽

Olivier Lascols ◽

Corinne Vigouroux ◽

...

Keyword(s):

Phenotypic Variability ◽

Genetic Disorders ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Compound Heterozygous ◽

Partial Lipodystrophy ◽

Mandibular Hypoplasia ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

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

10.1101/2019.12.18.867333 ◽

2019 ◽

Cited By ~ 2

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.

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A Case of Combined Oxidative Phosphorylation Deficiency 35 Associated with a Novel Missense Variant of the TRIT1 Gene

Molecular Syndromology ◽

10.1159/000518373 ◽

2021 ◽

pp. 1-7

Author(s):

Miraç Yıldırım ◽

Ömer Bektaş ◽

Ebru Tunçez ◽

Nurşah Yeniay Süt ◽

Yavuz Sayar ◽

...

Keyword(s):

Aortic Valve ◽

Oxidative Phosphorylation ◽

Bicuspid Aortic Valve ◽

Clinical Manifestations ◽

Missense Variant ◽

Global Developmental Delay ◽

Comparative Genomic ◽

Normal Male ◽

Compound Heterozygous ◽

Ketotic Hypoglycemia

Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder associated with homozygous or compound heterozygous mutations in the tRNA isopentenyltransferase (TRIT1) gene in chromosome 1p34.2. To date, only 10 types of allelic variants in the TRIT1 gene have been previously reported in 9 patients with COXPD35. Herein, we describe a case with a novel homozygous missense variant in TRIT1. A 6-year, 6-month-old boy presented with global developmental delay, microcephaly, intractable seizures, and failure to thrive. The other main clinical manifestations were intellectual disability, spastic tetraparesis, truncal hypotonia, malnutrition, polyuria and polydipsia, ketotic hypoglycemia, dysmorphic facial features, strabismus, bicuspid aortic valve, and nephrolithiasis. The detailed biochemical, radiological, and metabolic evaluations were unremarkable. Chromosomal analysis confirmed a normal male 46,XY karyotype and the array comparative genomic hybridization analysis revealed no abnormalities. We identified a novel homozygous missense variant of c.246G>C (p.Met82Ile) in the TRIT1 gene, and the variant was confirmed by Sanger sequencing. The present case is the first report describing strabismus, ketotic hypoglycemia, nephrolithiasis, and bicuspid aortic valve in TRIT1-related COXPD35. This study expands the genotype-phenotype spectrum of TRIT1-related COXPD35.

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YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations

Brain ◽

10.1093/brain/awaa235 ◽

2020 ◽

Vol 143 (10) ◽

pp. 2911-2928

Author(s):

Jorge Diaz ◽

Xavier Gérard ◽

Michel-Boris Emerit ◽

Julie Areias ◽

David Geny ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Golgi Apparatus ◽

Cell Membrane ◽

Primary Cilium ◽

Primary Cilia ◽

Brain Mri ◽

Cerebellar Atrophy ◽

Global Developmental Delay ◽

Specific Cell ◽

Neurodevelopmental Delay

Abstract Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

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