1 - Pediatrics Resident, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - Centro de Estudos do Bebé e da Criança, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3 - Neuropediatric Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
4 - Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, Instituto Nacional de Saúde Dr Ricardo Jorge, Porto, Portugal
5 - Genetic Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
6 - Reference Center of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Poster no 16º Simposio Internacional da Sociedade Portuguesa de Doenças Metabólicas, Virtual, 11-13 novembro de 2020
Background: Isolated methylmalonic acidemia is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 or mut–), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. The knowledge of the underlying enzymatic defect and genotype (MUT, MMAA, MMAB, MMADHC or MCEE) is of great importance since residual enzyme activity and vitamin-B12 responsiveness influences the clinical course and can be associated with a better long term outcome. The cblD-MMA is among the rarest of the disorders of intracellular cobalamin metabolism, with only seven cases reported so far.
Case Report: We report the case of a 5-year-old girl, 2nd child of consanguineous healthy parents from Bangladesh, born in Portugal after an uneventful gestation, delivery and neonatal period. The metabolic newborn screening was negative. She had poor weight gain, feeding difficulties with protein aversion and moderate motor and language delay. At four years of age she was admitted for vomiting, fever, prostration, ataxia, and dehydration, severe metabolic acidosis (pH 7,101, pCO2 16 mmHg, HCO3- 5,1 mmol/L) with increased anion gap 35,7 mmol/L, hyperlactacidemia and hypermonemia. After correction with intravenous fluids, there was complete clinical and metabolic recovery. Laboratory investigation in crisis showed massive amounts of urinary methylmalonic acid (3,745 micromol/mmol creatinine), elevated propionylcarnitine (C3), normal plasma total homocysteine and B12 vitamin. Microarray shown a region of loss of heterozigosity 2q22.1q31.1 (141,348,339-170,445,880) which included MMADHC gene. NGS analysis revelead a c.228dup variant in homozygosity in MMADHC gene, confirming the diagnosis of cblD–MMA. Meanwhile, response to hydroxicobalamin was confirmed by the test according to Fowler, and hydroxicobalamin intramuscular weekly was started with good clinical and metabolic evolution.
Comments: We report a rare case cblD-MMA presenting with an intermediate phenotype with feeding difficulties, failure to thrive, developmental delay and an episode of severe metabolic acidosis. As these children are at risk for a catastrophic decompensation it is of extremely importance to make a correct and timely diagnosis. This case was not detected in newborn screening probably because it was a milder phenotype and because the C3 cut-off at that time was higher than that currently in use.