Dos mutaciones novedosas en el gen de glicina descarboxilasa en un niño con hiperglicinemia no cetósica clásica: a propósito de un caso / Two novel mutations in the glycine decarboxylase gene in a boy with classic nonketotic hyperglycinemia: case report

La hiperglicinemia no cetósica es una encefalopatía por glicina autosómica recesiva y hereditaria sumamente rara, causada por una deficiencia en el sistema enzimatico de división de la glicina mitocondrial, que provoca síntomas clínicos graves. La hiperglicinemia no cetósica se caracteriza por fenotipos diversos y complejos, por ejemplo, hipotonía, convulsiones, deterioro cognitivo, retrasos del desarrollo y espasmos mioclónicos que podrían causar apnea e incluso la muerte. En este artículo, presentamos el caso de un niño de 1 año con convulsiones mioclónicas, hipotonía y coma, con aumento de la concentración de glicina en el plasma y el líquido cefalorraquídeo y con un índice de glicina en líquido cefalorraquídeo/plasma de 0,24. Existen dos mutaciones heterocigotas novedosas que confirman el diagnóstico de hiperglicinemia no cetósica. Una es una mutación de aminoácido, c.2516A>G (p.Y839C), y la otra es una mutación en los sitios de corte y empalme, c.2457+2T>A, en el gen GLDC.

Nonketotic hyperglycinemia is an extremely rare autosomal recessively inherited glycine encephalopathy caused by a deficiency in the mitochondrial glycine cleavage system, which leads to severe clinical symptoms. Nonketotic hyperglycinemia is characterized by complex and diverse phenotypes, such as hypotonia, seizures, cognitive impairment, developmental delays and myoclonic jerks that may lead to apnea and even death. Here we report a 1-year-old boy with myoclonic seizures, hypotonia and coma; he had elevated plasma and cerebrospinal fluid glycine levels, and cerebrospinal fluid/plasma glycine ratio was 0.24. Two novel heterozygous mutations confirm the diagnosis of nonketotic hyperglycinemia. One is a missense mutation c.2516A>G (p.Y839C) and the other one is a splicing mutation c.2457+2T>A in the GLDC gene.

Novel mutations in PRG4 gene in two Indian families with camptodactyly-arthropathy- coxa vara- pericarditis (CACP) syndrome.

Background & objectives: Camptodactyly – arthropathy- coxa vara- pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (proteoglycan 4) gene. Hallmarks of the syndrome include congenital or early-onset camptodactyly and arthropathy with synovial hyperplasia, progressive coxa vara deformity and non-inflammatory pericardial effusions. Till date only around 25 pathogenic mutations have been reported in this gene and none have been reported from India. We report here the mutations in the PRG4 gene in three patients of CACP from two unrelated families from India. Methods: Molecular genetic studies were done for the three patients with the CACP syndrome, from two unrelated Indian families, through sequence analysis of all coding exons and the exon-intron boundaries of the PRG4 gene. Results: Two novel frame-shift deletion mutations leading to premature protein termination were found. One patient was identified to be homozygous for a 2 base pair deletion in exon 6 (c.2645_2646delGA) and the two affected siblings from the other family were found to be homozygous for a 4 base pair deletion in exon 6 (c.2883_2886delAAGA). Conclusions: This is perhaps the first report of PRG4 mutations from India. Further mutation studies in Indian CACP cases will help to determine the mutation spectrum of the PRG4 gene in the Indian population and also help to further elucidate the molecular pathology and the genotype-phenotype correlation of this rare disease.

Identification of Novel Compound Heterozygous Mutations in the ACADS Gene of an Asymptomatic Korean Newborn with Short Chain Acyl-CoA Dehydrogenase Deficiency by Tandem Mass Spectrometry

Short-chain acyl-CoA dehydrogenase deficiency (SCADD; OMIM # 201470) is an autosomal recessive inborn error of mitochondrial fatty acid beta-oxidation, presenting with a variety of clinical signs and symptoms. Developmental delay, hypertonia or hypotonia, ketotic hypoglycemia, and epilepsy are most frequently reported. In general, patients diagnosed through newborn screening have shown normal growth and development in contrast to those diagnosed as a result of clinically initiated evaluations. Here, the case of an asymptomatic Korean newborn with SCADD identified by tandem mass spectrometry is reported. The patient showed an elevated concentration of butyrylcarnitine detected on newborn screening. Urinary excretion of ethylmalonic acid was elevated by urine organic acid analysis. To confirm the diagnosis of SCADD, a direct sequencing analysis of 10 coding exons and the exon-intron boundaries of the ACADS gene were performed. Genetic analysis of ACADS showed the following novel compound heterozygous missense mutations: c.277C>A (p.Leu93Ile) on exon3 and c.682G>A (p.Glu288Lys) on exon6. These results will provide further evidence of mutational heterogeneity for SCADD.

The Hirschsprung's-multiple endocrine neoplasia connection

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.