Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.

A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration.

We report the clinical and molecular characterization of a novel biallelic mutation in the CSF1R gene leading to an autosomal recessive form of childhood onset leukoencephalopathy in a consanguineous family. The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months. Her elder brother presented with encephalopathy at 4 years of age, with a subsequent loss of all achieved milestones over 8 months. Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles. Clinical exome trio analysis showed homozygosity for a p.T833M mutation in CSF1R in the girl. Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age. Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele.

Clinical profile of patients with rolandic epilepsy at a clinic in rural Maharashtra.

PURPOSE: To describe the seizure pattern, treatment strategies and outcome in a series of children with Rolandic seizures or childhood epilepsy with centrotemporal spikes. MATERIALS AND METHODS: Patients were defined as Rolandic epilepsy if on electroencephalographic studies high voltage spike and waves were seen in centrotemporal areas, could be followed by slow waves, often activated on sleep and could shift from one side to other or be secondarily generalized. Typical (TRS) or benign were those with normal intellect. Atypical rolandic seizures (ARS) were those associated with neuroregression of language and cognitive milestones. Patients were treated with antiepileptic drugs if more than one episode occurred or the first episode was generalized status epilepticus. RESULTS: Thirty-three patients were included over the period of eight years (2012-2020). There was male preponderance (21 males versus 12 females). Four patients (12.12%) later evolved into Landau Kleffner syndrome (ARS group). The mean age of onset of epilepsy in the TRS group (29 patients) was 7.2 (+/-2.2) with the youngest patient being 4 years and the eldest being 12 years. In the ARS group the mean age of onset was 5 yrs. (+/-1.41). In the TRS group, 23 (79.31%) patients were managed on monotherapy AED. Seventeen patients (58.62%) responded (remission) to carbamazepine monotherapy alone. Six patients (20.68%) could afford oxcarbazepine monotherapy and went in remission with this therapy. In the ARS group all patients required three drugs (valproate, clobazam and levetiracetam). By the end of the study period, 23/33 (75.75%) patients remained seizure free. CONCLUSIONS: Most patients with rolandic seizures have excellent prognosis being seizure free around puberty. The neurological outcome in most patients was normal.

Novel Consensus Splice Site Pathogenic Variation in THOC2 Gene Leads to Recurrent Arthrogryposis Multiplex Congenita Phenotype: A Case Report.

The THOC2 gene encodes THO complex subunit 2, a subunit of the Transcription-Export (TREX) complex which binds specifically to splice messenger ribonucleic acid (mRNAs) to facilitate mRNA export. Mutations in the THOC2 gene have been described to lead to X-linked mental retardation syndrome type 12/35 (XLMR-12/35) (MIM#300957). Here, we describe for the first time a recurrent arthrogryposis multiplex congenita phenotype (AMC) in two male fetuses in a family. Exome sequencing identified a novel pathogenic variation chrX: 122761817_122761820delTGAC (genome assembly GRCh37 format) or c.2482-1_2484delGTCA (as per Genbank transcript ID NM_001081550) in theTHOC2 gene. This variant affects the consensus acceptor splice site between intron 22 and exon 23. This is the most severe phenotype described in THOC2 gene-related disease till date. This case report expands the clinical phenotype of THOC2 gene related defects.

Clinical Characteristics, Molecular Profile, and Outcomes in Indian Patients with Glutaric Aciduria Type 1.

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date.

Prenatal Diagnosis for Primary Immunodeficiency Disorders-An Overview of the Indian Scenario.

Prenatal Diagnosis (PND) forms an important part of primary preventive management for families having a child affected with primary immunodeficiency. Although individually sparse, collectively this group of genetic disorders represents a significant burden of disease. This paper discusses the prenatal services available for affected families at various centers across the country and the challenges and ethical considerations associated with genetic counseling. Mutation detection in the index case and analysis of chorionic villous sampling or amniocentesis remain the preferred procedures for PND and phenotypic analysis of cordocentesis sample is reserved for families with well-characterized index case seeking PND in the latter part of the second trimester of pregnancy. A total of 112 families were provided PND services in the last decade and the presence of an affected fetus was confirmed in 32 families. Post-test genetic counseling enabled the affected families to make an informed decision about the current pregnancy.