Novel biallelic compound heterozygous mutations in FDXR cause optic atrophy in a young female patient: a case report.
Ontology highlight
ABSTRACT:
SUBMITTER: Song SJ
PROVIDER: S-EPMC8569559 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.
| S-EPMC5886230 | biostudies-literature
Project description:Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290. This case report details a family with Biallelic Optic Atrophy 1 (OPA1). The proband is a child with a severe phenotype and two variants in the OPA1 gene. He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia, and was found to have two likely pathogenic variants in his OPA1 gene: c.2287del (p.Ser763Valfs*15) maternally inherited and c.1311A>G (p.lIle437Met) paternally inherited. The first variant is predicted to be pathogenic and likely to cause DOA. In contrast, the second is considered asymptomatic by itself but has been reported in patients with DOA phenotype and is presumed to act as a phenotypic modifier. On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes. A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease.
| S-EPMC9223020 | biostudies-literature
Project description:Mutations in the optic atrophy 1 gene (OPA1) are associated with autosomal dominant optic atrophy and 20% of patients demonstrate extra-ocular manifestations. In addition to these autosomal dominant cases, only a few syndromic cases have been reported thus far with compound heterozygous OPA1 mutations, suggestive of either recessive or semi?dominant patterns of inheritance. The majority of these patients were diagnosed with Behr syndrome, characterized by optic atrophy, ataxia and peripheral neuropathy. The present study describes a 10-year-old boy with Behr syndrome presenting with early?onset severe optic atrophy, sensorimotor neuropathy, ataxia and congenital cataracts. He had optic atrophy and was declared legally blind at six years old. Electrophysiological, radiological, and histopathological findings were compatible with axonal sensorimotor polyneuropathy. At birth, he presented with a congenital cataract, which has not been previously described in patients with OPA1 mutations. Whole exome sequencing indicated a pair of novel compound heterozygous mutations: p.L620fs*13 (c.1857?1858delinsT) and p.R905Q (c.G2714A). Neither mutation was observed in controls (n=300), and thus, they were predicted to be pathogenic by multiple in silico analyses. The mutation sites were highly conserved throughout different vertebrate species. The patients parents did not have any ophthalmic or neurologic symptoms and the results of electrophysiological studies were normal, suggestive of an autosomal recessive pattern of inheritance. The present study identified novel compound heterozygous OPA1 mutations in a patient with recessive optic atrophy, sensorimotor neuropathy and congenital cataracts, indicating an expansion of the clinical spectrum of pathologies associated with OPA1 mutations. Thus, OPA1 gene screening is advisable in the workup of patients with recessive optic atrophy, particularly with Behr syndrome and cataracts.
| S-EPMC4918608 | biostudies-literature
Project description:BackgroundAcephalic spermatozoa syndrome (ASS) is an extremely rare form of severe teratozoospermia, where in most of the sperm either appear to lack heads or have disconnected or poorly connected heads and tails.Case summaryWe reported the case of a male patient with secondary infertility whose sperm showed typical ASS upon morphological analysis. Whole-exome sequencing was performed on the patient's peripheral blood, which revealed two heterozygous variants of the PMFBP1 gene: PMFBP1c.414+1G>T (p.?) and PMFBP1c.393del (p.C132Afs*3).ConclusionIt is speculated that the compound homozygous mutation of PMFBP1 may be the cause of ASS. We conducted a literature review in order to provide the basis for genetic counseling and clinical diagnosis of patients with ASS.
| S-EPMC9791525 | biostudies-literature
Project description:Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function.
| S-EPMC9947397 | biostudies-literature
Project description:Aicardi-Goutières Syndrome (AGS) is a rare disorder characterized by neurological and immunological signs. In this study we have described a child with a phenotype consistent with AGS carrying a novel compound heterozygous mutation in RNASEH2B gene. Next Generation Sequencing revealed two heterozygous variants in RNASEH2B gene. We also highlighted a reduction of RNase H2B transcript and protein levels in all the family members. Lower protein levels of RNase H2A have been observed in all the members of the family as well, whereas a deep depletion of RNase H2C has only been identified in the affected child. The structural analysis showed that both mutations remove many intramolecular contacts, possibly introducing conformational rearrangements with a decrease of the stability of RNase H2B and strongly destabilizing the RNase H2 complex. Taken together, these results highlight the importance of an integrated diagnostic approach which takes into consideration clinical, genetic, and molecular analyses.
| S-EPMC8107470 | biostudies-literature
Project description:BackgroundGalloway-Mowat syndrome (GAMOS) is a rare genetic disease characterized by early-onset nephrotic syndrome and microcephaly with central nervous system abnormalities. Pathogenic variants in genes encoding kinase, endopeptidase, and other proteins of small size (KEOPS) complex subunits cause GAMOS. The subunit TPRKB (TP53RK binding protein) has been reported in only two patients with GAMOS with homozygous missense variants.Clinical reportHerein, we described a three-year-old male with GAMOS. He exhibited developmental delay, developmental regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. Brain magnetic resonance imaging revealed progressive brain atrophy, delayed myelination, T2-hypointense signals in the thalamus, and multiple intracranial abnormal signals on diffusion-weighted imaging. He presented with relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. Exome sequencing identified compound heterozygous missense and frameshift variants in TPRKB: c.224dup, p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe).ConclusionsOur study supports that pathogenic TPRKB variants cause KEOPS complex-related GAMOS.
| S-EPMC11018998 | biostudies-literature
Project description:ObjectiveDefects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.MethodsExome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.ResultsWe compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.ConclusionDetailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
| S-EPMC7261753 | biostudies-literature
Project description:Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.
| S-EPMC3928641 | biostudies-literature
Project description:Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported. Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased. Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.
| S-EPMC8527088 | biostudies-literature