1 - Serviço de Genética Médica, Centro Hospitalar Universitário de Lisboa Central;
2 - Unidade de Doenças Metabólicas, HDE - Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal;
3 - Serviço de Medicina 3.2., HSAC - Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal;
4 - Serviço de Neuropediatria, HDE - Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal;
- Poster no 17th International Symposium da Sociedade Portuguesa de Doenças Metabólicas, Fátima, 5 a 10 de setembro de 2021
Resumo:
BACKGROUND: Intracellular metabolism of cobalamin is a multiple step pathway leading to the synthesis of its active forms adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), cofactors respectively for mithocondrial methylmalony-CoA mutase and cytoplasmatic methionine synthase. Deficiency in AdoCbl leads to accumulation of methylmalonic acid in body fluids while deficiency in MeCbl results in elevated levels in homocysteine. The MMADHC gene encodes a protein involved in one of the steps of intracellular cobalamin metabolism. Depending on the nature and location of mutations within the protein, 1 of 3 biochemical phenotypes can occur: 1- Isolated Methylmalonic aciduria (MMA), 2- Isolated Homocystinuria (HC), and 3- Combined Methylmalonic Aciduria and Homocystinuria (MMA/HC). Here we report 3 clinical cases referred to our clinic, representing the 3 distinct phenotypes associated to MMADHC gene.
CASE REPORT: CASE 1 (CBID-MMA): 5-year-old girl presenting with feeding difficulties, failure to thrive, developmental delay and an episode of severe metabolic acidosis with MMA. Genetic investigation revealed a region of loss of heterozigosity 2q22.1q31.1 which included MMADHC gene and simultaneously a c.228dup (p.Asn77Glufs*5) variant in homozygosity in MMADHC gene. CASE 2 (CBID-HC): 16-month-old boy presenting with microcephaly, eating difficulties, hypotonia, severe developmental delay and failure to thrive. Metabolic investigation revealed HU and genetic studies detected the homozygous pathogenic variant c.746A>G (p.Tyr249Cys) in MMADHC gene. CASE 3 (CBID-MMA/HC): 20-year-old girl presenting at the age of 4 years with developmental delay, frequent vomiting, axial hypotonia, absent language and unsteady gait, whose metabolic investigation revealed MMA and HC. Genetic studies revealed a homozygous c.748C>T mutation in MMADHC gene.
COMMENTS: The presented cases reflect a genotype-phenotype correlation, which means the location of pathogenic variants within MMADHC correlates with the type of enzyme deficiency. cbID-MMA typically results from pathogenic nonsense and frameshift variants found in exons 3 and 4, which encode the region of the protein necessary for AdoCbl synthesis. cbID-HC usually results from pathogenic missense variants found in exons 6 and 8, which encode the region of the protein necessary for MeCbl synthesis. cbID-MMA/ HC typically results from pathogenic variants which occur in exon 5, exon 8 and intron 7, encoding the middle of the protein.