Molecular characterization of mucopolysaccharidosis type IVA patients in the Andean region of Colombia.

Colombia has a high prevalence of mucopolysaccharidosis (MPS) type IVA. Nevertheless, data regarding the mutation spectrum for MPS IVA in this population have not been completely characterized. Forty-seven families and 53 patients from seven different Colombian regions were tested for MPS IVA mutations. We compared the sequences with the N-acetylgalactosamine-6-sulfatase (GALNS) reference sequence NM_000512.4, and gene variants were reported. Bioinformatics analysis was performed using SWISS-MODEL. The mutant proteins were generated by homology from the wild-type GALNS 4FDJ template obtained from the PDB database, and visualization was performed using Swiss-PDBViewer and UCSF Chimera. The predictive analysis was run using different bioinformatic tools, and the deleterious annotation of genetic variants was performed using a neural network. We found that 79% and 21% of the cohort was homozygous and compound heterozygous, respectively. The most frequent mutation observed was p.Gly301Cys (78.3% of alleles), followed by p.Arg386Cys (10.4% of alleles). A novel mutation (p.Phe72Ile) was described and classified in silico as a pathogenic variant. This study reveals the mutation spectrum of MPS IVA in Colombia. The high prevalence of the p.Gly301Cys mutation suggests a founder effect of this variant in the Colombian population that causes diseases in the Andean region (via migration). These data can facilitate genetic counseling, prenatal diagnosis, and the design of therapeutic interventions.

[Sucecesfull bone marrow transplantation in a case of familial hemophagocytic lymphohistiocytosis type 3]. / Trasplante de médula ósea exitoso en un caso de linfohistiocitosis hemofagocítica familiar tipo 3.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated activation of the immune system which can be either primary (familial) or secondary. Familial hemophagocytic lymphohistiocytosis type 3 (FHL-3) is a severe immune disorder, caused by mutations in the UNC13D gene, which codes for a protein crucial to the cytotoxic function of lymphocytes. OBJECTIVE: To describe the diagnostic relevance of next-generation sequencing in the approach of a patient with suspected FHL and to demonstrate the effectiveness of bone marrow transplantation as the only curative measure. CLINICAL CASE: 4-year-old preschool male, previously healthy, who presented with mononucleosis syndrome and positive IgM for Epstein Barr virus, developing hepatosplenomegaly and progressive clinical de terioration. A lymphoproliferative syndrome was suspected, which was ruled out by bone marrow aspiration, finding evidence of active hemophagocytosis. The patient met the criteria for hemophago cytic syndrome (bone marrow aspiration, pancytopenia, elevated ferritin, and hypertriglyceridemia) and, given the lack of response to first-line management, including antiviral treatment, a possible primary etiology was considered. A molecular study was completed with NGS that was positive for FHL-3. Due to the progressive clinical deterioration, a bone marrow transplantation was performed, presenting successful results after the first year had elapsed. CONCLUSION: NGS is an indispensable tool in the diagnosis of FHL, mainly when the response to standard treatment is not adequate and facilitates the timely implementation of the necessary therapeutic measures.

Syndromic progressive neurodegenerative disease of infancy caused by novel variants in HIBCH: Report of two cases in Colombia.

3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the HIBCH gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the HIBCH gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.

Novel ATP7A gene mutation in a patient with Menkes disease.

BACKGROUND: Menkes disease is a congenital neurodegenerative disorder caused by ATP7A gene mutations. Clinical features include epilepsy, growth delay, reduced muscle strength, skin laxity, abnormal hair, and urologic abnormalities. CASE PRESENTATION: We describe an infant with developmental delay, neurologic degeneration, and kinky hair. Molecular test revealed a novel heterozygous mutation in exon 21 of the ATP7A gene. The genotype and phenotype of the patient were compared with those of the patients reported in the literature. CONCLUSION: We propose that this mutation caused a dysfunctional protein resulting in classical Menkes disease. This case adds to the spectrum of pathogenic variants of the ATP7A gene known to cause disease.

Nueva mutación del gen TSC2 en un paciente pediátrico con diagnóstico clínico de esclerosis tuberosa / Novel mutation in TSC2 gene in pediatric patient with clinical diagnosis of tuberous sclerosis

El complejo de esclerosis tuberosa es un desorden neurocutáneo autosómico dominante causado por mutaciones en los genes TSC1 o TSC2. El diagnóstico se basa en criterios clínicos o el criterio genético. La presentación clínica es altamente variable y las manifestaciones de la enfermedad pueden desarrollarse durante toda la vida. Se reporta el caso de un niño que cumple criterios clínicos para el diagnóstico de esclerosis tuberosa y cuyo estudio molecular identificó una variante nueva del gen TSC2. Se trata de una mutación sin sentido, esporádica, no reportada previamente (c.583_586dupATCG) localizada en el exón 6, que provoca un codón de parada temprano y altera la estructura de la proteína. Puede considerarse una variante patogénica por el tipo de mutación y permite ampliar el espectro de variantes del gen TSC2 como causa del complejo de esclerosis tuberosa.

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins. This mutation is considered as a pathogenic variant and allows to broaden the spectrum of variants of TSC2 gene as a cause of TSC.

[Novel mutation in TSC2 gene in pediatric patient with clinical diagnosis of tuberous sclerosis]. / Nueva mutación del gen TSC2 en un paciente pediátrico con diagnóstico clínico de esclerosis tuberosa.

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins. This mutation is considered as a pathogenic variant and allows to broaden the spectrum of variants of TSC2 gene as a cause of TSC.

El complejo de esclerosis tuberosa es un desorden neurocutáneo autosómico dominante causado por mutaciones en los genes TSC1 o TSC2. El diagnóstico se basa en criterios clínicos o el criterio genético. La presentación clínica es altamente variable y las manifestaciones de la enfermedad pueden desarrollarse durante toda la vida. Se reporta el caso de un niño que cumple criterios clínicos para el diagnóstico de esclerosis tuberosa y cuyo estudio molecular identificó una variante nueva del gen TSC2. Se trata de una mutación sin sentido, esporádica, no reportada previamente (c.583_586dupATCG) localizada en el exón 6, que provoca un codón de parada temprano y altera la estructura de la proteína. Puede considerarse una variante patogénica por el tipo de mutación y permite ampliar el espectro de variantes del gen TSC2 como causa del complejo de esclerosis tuberosa.

Embarazo ectópico abdominal avanzado: reporte de casos y revisión de la literatura / Advanced ectopic abdominal pregnancy: Case report and review of the literature

RESUMEN Objetivo: Reportar dos casos de embarazo ectópico abdominal avanzado, con buen resultado materno / perinatal, y revisar la literatura disponible con respecto al manejo de la placenta y el pronóstico de esta entidad. Materiales y métodos: Se describen dos casos de embarazo ectópico abdominal avanzado en los que se realizó extracción de la placenta, con feto viable y resultado perinatal favorable. Estos fueron atendidos en una institución de cuarto nivel de complejidad,ubicada en la ciudad de Cali, Colombia. Se realizó una revisión de la literatura registrada en las bases de datos Medline vía PubMed, con los términos de búsqueda: "embarazo abdominal", "embarazo esplénico", "embarazo hepático", "embarazo omental" y "embarazo peritoneal". La búsqueda se limitó a artículos publicados durante los últimos doce años en inglés y español. Resultados: Se recuperaron 228 referencias, de las cuales 42 artículos cumplieron con los criterios de inclusión que informan un total de 74 pacientes con embarazo ectópico abdominal. En cuanto al manejo de la placenta, la remoción de la misma se informó en 42 casos (58%). La mortalidad materna se presentó en 4 casos (4,1%), todos por hemorragia posparto. Un total de 60 pacientes (81%) presentaron complicaciones, la más frecuente fue hemorragia en 38 de ellas (51%). En cuanto al resultado perinatal, se encontró una mortalidad perinatal del 43%. Conclusión: El manejo de la placenta es el punto clave del que podría depender la frecuencia de complicaciones maternas. Se requieren estudios prospectivos que evalúen el manejo más seguro y efectivo de esta condición.

ABSTRACT Objective: Report two cases of advanced ectopic abdominal pregnancy with good maternal/perinatal outcomes, and to review the literature available regarding the management of the placenta and the prognosis for this condition. Materials and methods: Description of two cases of advanced ectopic abdominal pregnancies with viable fetuses and favourable perinatal outcomes, in which the placenta was removed. The cases were seen at a Level IV institution in the city of Cali, Colombia. Review of the literature registered in the Medline data base via Pubmed using the search terms "abdominal pregnancy", "splenic pregnancy", "hepatic pregnancy", "omental pregnancy" and "peritoneal pregnancy". The search was limited to articles published in English and Spanish during the past 12 years. Results: Overall, 228 references were retrieved, of which 42 articles reporting on a total of 74 patients with ectopic abdominal pregnancy met the inclusion criteria. Regarding the management of the placenta, it was removed in 42 cases (58%). There were 4 cases of maternal mortality (4,1%) all of them due to postpartum bleeding. Complications occurred in 60 patients (81%), bleeding being the most frequent in 38 of them (51%). As for perinatal outcome, perinatal mortality was 43.8%. Conclusion: Placental management is the the key determinant factor of the frequency of maternal complications. Prospective studies to assess the safest and most effective management of this condition are required.