A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

Neuromyelitis Optica (NMO) in Children: A Rare Case Report

Background: Neuromyelitis optica (NMO) is a rare autoimmune disease that covers 20-30% of diseases related to autoimmune disorders and about 1% of demyelination diseases. NMO symptoms are vary between individuals, there are generally 2 main symptoms, transverse myelitis and optic neuritis. This article reported a child with NMO disease based on The Consensus of the International Panel for NMO Diagnosis (IPND) 2015.Case Presentation: An 8-year old boy with spastic tetraparesis, bilateral nervus opticus dysfunction, urinary retention, and allodynia et causa suspected NMO. Patient received therapy using high-dose intravenous methylprednisolone and showing a clinical improvement.Conclusion: This patient was diagnosed NMO based on IPND 2015 with an unknown AQP4-Ab status accompanied by supporting clinical symptoms. The management of NMO with high-dose intravenous methylprednisolone in this patient provides a meaningful response to the clinical improvement of the disease.

Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report

Leigh syndrome (LS) usually presents as an early onset mitochondrial encephalopathy characterized by bilateral symmetric lesions in the basal ganglia and cerebral stem. More than 75 genes have been associated with this condition, including genes involved in the biogenesis of mitochondrial complex I (CI). In this study, we used a next-generation sequencing (NGS) panel to identify two novel biallelic variants in the NADH:ubiquinone oxidoreductase subunit A13 (NDUFA13) gene in a patient with isolated CI deficiency in skeletal muscle. Our patient, who represents the second family report with mutations in the CI NDUFA13 subunit, presented with LS lesions in brain magnetic resonance imaging, mild hypertrophic cardiomyopathy, and progressive spastic tetraparesis. This phenotype manifestation is different from that previously described in the first NDUFA13 family, which was predominantly characterized by neurosensorial symptoms. Both in silico pathogenicity predictions and oxidative phosphorylation (OXPHOS) functional findings in patient’s skin fibroblasts (delayed cell growth, isolated CI enzyme defect, decreased basal and maximal oxygen consumption and as well as ATP production, together with markedly diminished levels of the NDUFA13 protein, CI, and respirasomes) suggest that these novel variants in the NDUFA13 gene are the underlying cause of the CI defect, expanding the genetic heterogeneity of LS.

Adrenoleukodystrophy presenting as glue sniffing

Adrenoleukodystrophy classically presents in childhood with bronze skin, spastic tetraparesis, dysphagia, behavioural abnormalities and adrenal insufficiency. However, atypical presentations are known. Here we report an adolescent with adrenoleukodystrophy who first sought medical attention for glue sniffing.

Novel FARS2 mutations in patients with non-fatal early onset encephalopathy with or without epilepsy

Mitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Mutations in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations.Mutations in the FARS2 gene encoding the mitochondrial phenylalanyl-tRNA synthetase are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.

THE OUTCOME OF CEREBRAL PATHOLOGY BY THE END OF THE FIRST YEAR OF LIFE IN NEWBORN BABIES WITH CYTOMEGALOVIRUS INFECTION

Objective: to study costimulatory molecules (CD28, CD40) on lymphocytes of the peripheral blood in newborn babies with CMVI and to determine prognostic indices of the cerebral pathology outcome by the end of the first year of life.We examined 114 children at the age of three months, who had CMVI during neonatal period. In 37 children neurological symptoms remained by the end of the first year of life. At 37 children the neurologic symptomatology by the end of the first year of life remained: delay of psychomotor development (44.8%), deafness (5.9%), epilepsy (11.9%), spastic tetraparesis (32.2%) blindness (13.4%). At 77 children was absent neurologic symptomatology by the end of the first year of life.A control group was comprised of 15 healthy newborns. The content of lymphocytes, expressing CD28, CD40, CD3+, CD4+, CD28+, CD20+, was determined using laser flow cytofluorometer “Beckman COULTER” Epics XL II (USA) by means of monoclonal antibodies to the clusters of differentiation CD3+, CD20+, CD4+, CD28+, CD40+ of IMMUNOTECH Company (France).The analysis of multidimentional nonlinear dependencies was performed using PolyAnalist 3.5. Pro package. The formula of the forecast of preservation of neurologic symptomatology is calculated.((CD3-CD28+ * 0.074) + CD4+ * (-0.182) + (CD3+CD28- * 0.035) + CD40 * (-0.2862) + CD3 * 0.1062) + + (CD28 * 0.1952)) - 0.4588.If the result of the calculation according to the formula is > 0.39, than a child will have brain damages by the end of the first year of life. Sensitivity - 71.43%, specificity - 88.89%. The likelihood ratio of the positive result is 13.5.The determination of CD3+T-lymphocytes, lymphocytes, expressing CD28 in the total population, T-lymphocytes without the costimulatory marker CD28 (CD3+CD28-) and also B-lymphocytes, expressing CD40 on their surface, is significant for the prognosis of neurological symptomatology preservation by the end of the first year of life.