Practical Management of Combined Methylmalonicaciduria and Homocystinuria

Abstract

Combined methylmalonicaciduria and homocystinuria is a disorder of intracellular cobalamin metabolism that remains a challenge to the physician unfamiliar with the diagnosis. We have followed six patients with combined methylmalonicaciduria and homocystinuria (four males, two females, age 4.2-24 years) for a median of 6.5 years (range 4-9 years). Age at diagnosis was between 18 days and 14 months in early-onset cases (n = 4) and 15 and 19 years in late-onset cases. Predominant clinical features include microcephaly, hydrocephalus, seizures, and white-matter changes on magnetic resonance imaging in early-onset cases. The white-matter changes may be secondary to impaired methylation owing to a lack of readily available methyl groups. Spastic quadriparesis and diplegia are long-term sequelae in late-onset cases. Management consists of hydroxycobalamin intramuscular injections, oral folate, betaine, and carnitine supplementation. Dietary protein restriction may be necessary when metabolic control remains difficult. The implementation of an emergency regimen should alleviate episodes of metabolic decompensation and reduce the rate of hospital admissions.

Creatine metabolism in combined methylmalonic aciduria and homocystinuria

“…Deficient remethylation of homocysteine in individuals with cblC and the reduced availability of labile methyl groups with its likely impact on creatine synthesis led us to study creatine and homocysteine metabolism in five patients with cblC. 4,6 Plasma GAA concentrations were significantly increased in all subjects with cblC to levels typically found in patients with GAMT deficiency, 3 whereas creatine concentrations remained in the low-reference to reference range. No diurnal fluctuation of plasma GAA and creatine concentrations was observed, and no effect could be attributed to dietary intake.…”

“…4,6 Anthropometric and relevant clinical data are listed in Table 1. CblC was confirmed by complementation analysis in fibroblast cultures of all patients (Dr D. Rosenblatt, McGill University).…”

“…5 This defect leads to impaired remethylation of homocysteine, resulting in low methionine and high homocysteine concentrations, and to neurological symptoms that include developmental delay, muscular hypotonia, seizures, and nystagmus. 4,5 We hypothesized that the lack of methyl groups for the methylation reaction mediated by GAMT might be responsible for a clinical presentation in cblC similar to that of GAMT-deficient patients. This hypothesis prompted us to study a group of patients with cblC to evaluate the integrity of their creatine synthesis by measuring different metabolites of the creatine biosynthesis pathway.…”

Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

“…These developmental complications include intrauterine growth retardation (IUGR) (Frattini et al 2010; Robb et al 1984; Bartholomew et al 1988; Smith and Bodamer 2002; Nogueira et al 2008) mild dysmorphic features (long facies, flat philtrum and large low-set ears), (Cerone et al 1999), microcephaly (Francis et al 2004; Smith et al 2006; Rosenblatt et al 1997; Andersson et al 1999), congenital heart disease (Profitlich et al 2009b; Andersson et al 1999) and fetal dilated cardiomyopathy De Bie et al (2009).…”

Hydroxocobalamin dose escalation improves metabolic control in cblC

“…The mainstay of therapy for cblC consists of intramuscular (IM) hydroxocobalamin (OHCbl) injections (Ogier de Baulny et al 1998; Rosenblatt et al 1997; Smith and Bodamer 2002). Clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, accompanied by an increase in methionine, is typically observed after OHCbl therapy is initiated (Bartholomew et al 1988).…”