Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte

Abstract

Introduction: Combined methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is an inherited disorder of vitamin B(12) metabolism caused by mutations in MMACHC. CblC typically presents in the neonatal period with neurological deterioration, failure to thrive, cytopenias, and multisystem pathology including renal and hepatic dysfunction. Rarely, affected individuals present in adulthood with gait ataxia and cognitive decline. Treatment with hydroxocobalamin may ameliorate the clinical features of early-onset disease and prevent clinical late-onset disease. Propionic acidemia (PA), methylmalonic acidemia (MMA), and various disorders of cobalamin metabolism are characterized by elevated propionylcarnitine (C3) on newborn screening (NBS). Distinctions can be made between these disorders with secondary analyte testing. Elevated methionine is already routinely used as a NBS marker for cystathionine beta-synthase deficiency. We propose that low methionine may be useful as a secondary analyte for specific detection of cbl disorders among a larger pool of infants with elevated C3 on NBS.

Methods: Retrospective analysis of dried blood spot (DBS) data in patients with molecularly confirmed cblC disease.

Results: Nine out of ten patients with confirmed cblC born in New York between 2005 and 2008 had methionine below 13.4mumol/L on NBS. Elevated C3, elevated C3:C2 ratio, and low methionine were incorporated into a simple screening algorithm that can be used to improve the specificity of newborn screening programs and provide a specific and novel method of distinguishing cblC from other disorders of propionate metabolism prior to recall for confirmatory testing.

Conclusions: It is anticipated that this algorithm will aid in early and specific detection of cobalamin C, D, and F diseases, with no additional expense to NBS laboratories screening for organic acidemias and classical homocystinuria.

Figure 1

Extracellular and intracellular cobalamin metabolism. Cobalamin is absorbed in the terminal ileum facilitated by gastric intrinsic factor (IF). Cobalamin enters the cell bound to transcobalamin (TC) by means of lysosome-mediated endocytosis. It is then hypothesized that the MMACHC protein accepts the cofactor from the lysosomal compartment, and catalyzes the reductive elimination of cyanocobalamin (CN-Cbl) [2]. The steps in the cytosol after lysosomal release are unclear but are defined by the complementation groups cblC and cblD [3]. In addition, the exact forms of cobalamin at this stage remain unclear and are indicated by Cblx. In the cytoplasm, cobalamin is reductively methylated by methionine synthase reductase (cblE) to methylcobalamin (MeCbl), the cofactor for methionine synthase (cblG). After its transport into the mitochondrion, cobalamin is converted to adenosylcobalamin (AdoCbl), the cofactor for methylmalonyl–CoA mutase (mut), by cobalamin adenosyltransferase (cblB). The broken line indicates the location of the hypothesized defect in cblC disease.

Figure 2

Algorithms employed for referral and evaluation of elevated C3 levels following New York State MS/MS newborn screening, (a) prior to September 2008, and (b) after September 2008. *Positive screen: C3 >5 μmol/L and C3:C2 ratio >0.2 when sample repeated at recall