Long-term outcome in treated combined methylmalonic acidemia and homocystinemia

Abstract

To describe the clinical and biochemical features and long-term outcome of a cohort of eight patients with methylmalonic acidemia and homocystinuria (cblC). Methods: Documentation of clinical features at birth and longitudinal follow-up of the biochemical and clinical response to treatment with daily oral carnitine and intramuscular hydroxocobalamin observed during continuous follow-up for an average of 5.7 years. Results: Our patients had an increased incidence of congenital malformations including microcephaly (<5%) at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cblC retinopathy, and two patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures. No patients had acute acidotic crises before or after treatment. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of therapy with carnitine, intramuscular (IM) hydroxocobalamin (OHcbl) and, in two cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly was resolved in one patient. All patients were developmentally delayed regardless of age of treatment onset, although two patients had relatively mild developmental delay. Conclusion: cblC patients may have an increased incidence of congenital malformations suggesting prenatal effects of abnormal cbl metabolism. Treatment with IM OHcbl and carnitine successfully corrects the biochemical abnormalities and improves growth. Developmental delay of variable severity is always present regardless of age at diagnosis or treatment onset.

Proteomics of vitamin B12 processing

“…Downregulation of UCHL1 in cblC fibroblasts was not restored to normal levels upon supplementation with HOCbl. Therefore, downregulation of UCHL1 could contribute to the neurocognitive manifestations of the cblC disorder and the poor improvement observed after treatment with HOCbl [ 91 ]. Three other proteins were downregulated in cblC fibroblasts grown in the presence of exogenous HOCbl: DJ-1 (Parkinson ' s disease protein 7), dihydropyrimidase-like 2 (DPYLS2), and annexin V A2 isoform I. DJ-1 belongs to a family of peptidases that act as a positive regulator of androgen receptor-dependent transcription.…”

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

“…In the "early onset" form of cblC, infants present with failure to thrive, developmental delay, visual impairment, and hematologic problems (Carrillo-Carrasco et al 2011;Rosenblatt et al 1997). Malformations including congenital microcephaly and congenital heart diseases are frequently present (Andersson et al 1999). While the phenotypic spectrum of cblC disease is broad and age of onset is variable, encompassing prenatal and adult presentations, a prenatal cardiac presentation of right ventricular dilated cardiomyopathy in the third trimester has been documented in one infant with cblC disease (De Bie et al 2009).…”

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

“…Progression to coma is not uncommon. If the patient does not succumb to the initial metabolic decompensation, failure to thrive, developmental retardation, renal failure and metabolic strokes follow [1,[3][4][5][6][7][8][9][10][11][12][13][14].…”