6 research outputs found
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder
PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype, but with limited neuroradiological data and insufficient evidence for causality of the variants. METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays, and a zebrafish model. RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity
SĂndrome de Prader Willi : etiologĂa molecular y su importancia para el asesoramiento genĂ©tico, pronĂłstico y tratamiento
El sĂndrome de Prader WiIIi (SPW) es una patologĂa multisistĂ©mica compleja, caracterizado por severa hipotonĂa, hipogonadismo, retardo mental, problemas de conducta y desarrollo gradual de obesidad mĂłrbida. Se produce como consecuencia de Ia pĂ©rdida de expresiĂłn de genes paternos del cromosoma 15q11-13. Diferentes mecanismos moleculares pueden causar esta patologĂa: gran deleciĂłn 15q11q13 (75% de los casos), disomĂa uniparental materna del cromosoma 15 (matDUP15) (23%) y defectos de impronta (Dl) (2%). La tĂ©cnica de FISH y el análisis de microsatĂ©lites son requeridos para establecer Ia etiologĂa molecular, Io cual resulta esencial para un apropiado asesoramiento genĂ©tico y cuidado de los pacientes.Prader Willi Syndrome (PWS) is a complex disorder characterized by severe hypotonia, hyppogonadism, mental retardation, behavioral problems and gradual development of morbid obesity. lt is caused by the loss of expression of paternally transcribed genes in chromosome 15q11-13. Different molecular mechanisms have been recognized to lead PWS: deletion 15q11-q13 (75% of cases), maternal uniparental disomy (matUPD15) (23%) and imprinting defects (ID) (2%). FISH and microsatellite analyses are required to establish the molecular etiology, which is essential for an appropriate genetic counseling and care management.Fil: Aráoz, Hilda VerĂłnica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Genotype–phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina
Background/Purpose: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. Methods: 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. Results: A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. Conclusion: This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters.Fil: Medrano, SofĂa. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Monges, Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Gravina, Luis Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: AlĂas, Laura. Hospital de la Santa Creu i Sant Pau; España. CIBERER; EspañaFil: Mozzoni, Julieta. Hospital de la Santa Creu i Sant Pau; EspañaFil: Aráoz, Hilda VerĂłnica. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Bernal, Sara. Hospital de la Santa Creu i Sant Pau; España. CIBERER; EspañaFil: Moresco, AngĂ©lica. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Chertkoff, Lilien Patricia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Tizzano, Eduardo. Hospital Valle Hebron; España. CIBERER; Españ
Clinical and molecular characterization of mitochondrial DNA disorders in a group of Argentinian pediatric patients
Objective: To describe the clinical and molecular features of a group of Argentinian pediatric patients with mitochondrial DNA (mtDNA) disorders, and to evaluate the results of the implementation of a classical approach for the molecular diagnosis of mitochondrial diseases. Methods: Clinical data from 27 patients with confirmed mtDNA pathogenic variants were obtained from a database of 89 patients with suspected mitochondrial disease, registered from 2014 to 2020. Clinical data, biochemical analysis, neuroimaging findings, muscle biopsy and molecular studies were analyzed. Results: Patients were 18 females and 9 males, with ages at onset ranging from 1 week to 14 years (median = 4 years). The clinical phenotypes were: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 11), Leigh syndrome (n = 5), Kearns-Sayre syndrome (n = 3), Chronic Progressive External Ophthalmoplegia (n = 2), Leber hereditary optic neuropathy (n = 2), myoclonic epilepsy associated with ragged-red fibers (n = 1) and reversible infantile myopathy with cytochrome-C oxidase deficiency (n = 3). Most of the patients harbored pathogenic single nucleotide variants, mainly involving mt-tRNA genes, such as MT-TL1, MT-TE and MT-TK. Other point variants were found in complex I subunits, like MT-ND6, MT-ND4, MT-ND5; or in MT-ATP6. The m.13513G > A variant in MT-ND5 and the m.9185 T > C variant in MT-ATP6 were apparently de novo. The rest of the patients presented large scale-rearrangements, either the ?common? deletion or a larger deletion. Conclusions: This study highlights the clinical and genetic heterogeneity of pediatric mtDNA disorders. All the cases presented with classical phenotypes, being MELAS the most frequent. Applying classical molecular methods, it was possible to achieve a genetic diagnosis in 30% of the cases, suggesting that this is an effective first approach, especially for those centers from low-middle income countries, leaving NGS studies for those patients with inconclusive results.Fil: Loos, Mariana Amina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Gomez, Gimena. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Mayorga, LĂa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Caraballo, Roberto Horacio. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Eiroa, Hernán Diego. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Obregon, MarĂa Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Rugilo, Carlos. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Taratuto, Ana LĂa. No especifĂca;Fil: Saccoliti, MarĂa. No especifĂca;Fil: Alonso, Cristina NoemĂ. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; ArgentinaFil: Aráoz, Hilda VerĂłnica. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂa "Juan P. Garrahan"; Argentin