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Isabel Brito1, João Franco1, Raquel Maia2, Paula Kjöllerström2, Diana Antunes3, Ana Cristina Ferreira4

1 - Pediatric Service, Hospital Garcia d’Orta, Almada, Portugal
2 - Hematology Unit, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3 - Genetics Service, Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
4 - Reference Center of Inherited Metabolic Diseases, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal

- Poster em 16º Simposio Internacional da Sociedade Portuguesa de Doenças Metabólicas Virtual, 11-13 novembro de 2020

Background: Cobalamin G (CblG) defect is a rare inborn error of intracellular cobalamin metabolism caused by deficiency of methionine synthase (MIM 250940), leading to an impairment in homocysteine to methionine remethylation. Patients usually present in infancy with failure to thrive, feeding problems, developmental delay, muscular hypotonia, cognitive impairment and macrocytic anemia with megaloblastic features.
Case report: We report the case of a 15 month-old-girl, first child of a healthy unrelated couple, with uneventful full-term pregnancy, delivery and neonatal period and exclusively breastfed until 5 months, who presented at 6 months of age with poor weight gain, global developmental delay and hypotonia. Laboratory investigation showed severe arregenerative macrocytic anemia (Hb 5,2 g/dL, MCV 102 fL), moderate neutropenia (610 x10^6) and elevated LDH. Vitamin B12 and folic acid deficiency were excluded. Bone marrow biopsy excluded dyserythropoiesis. Further investigation showed markedly elevated homocysteine (130 µmol/l), low plasma methionine and normal urinary methylmalonic acid, suggesting a CblE/CblG disorder of intracellular cobalamin metabolism. Treatment was started with hydroxocobalamin, betaine, folic acid and L-carnitine There was an excellent hematological and biochemical response and significant improvement on neurocognitive development. Genetic testing (Next-Generation Sequencing panel for genes associated vitamin B12 deficiency) revealed two variants in heterozygosity in the MTR gene: a pathogenic frameshift c.2101del variant and an uncertain clinical significance (missense) c.1228G>A variant supporting CblG deficiency. Parental studies are ongoing
Comments: Cobalamin metabolism defects are a very rare cause of megaloblastic anemia and a high level of suspicion is needed, especially after excluding the main causes, as vitamin B12 and folic acid deficiency. In the presented case the classic triad of hyperhomocysteinemia with normal levels of methylmalonic acid and low levels of methionine strongly suggested the diagnosis, leading to prompt treatment. In previously reported cases early treatment corrects cytological abnormalities, improves biochemical parameters but has limited effect on neurocognitive impairment and ophthalmologic and CNS changes tend to progress despite it. In the presented case a developmental improvement was noted in the beginning, but long term follow-up is required.