Severe Neonatal Metabolic Decompensation in Methylmalonic Acidemia Caused by CblD Defect

Abstract

CblD disorder is an autosomal recessive, rare, heterogeneous disease with variable clinical presentations, depending on the nature and location of the MMADHC gene mutations. Mutations in MMADHC lead to three distinct phenotypes: cblD-MMA, cblD-HC, and cblD-MMA/HC. To date, 18 cblD patients have been reported. Six of them were affected by cblD-MMA, but only three had a known clinical history. One of these patients presented with a metabolic decompensation at 11 months; the second one, born prematurely, was diagnosed with cblD after being treated for intracranial hemorrhage, respiratory distress syndrome, necrotizing enterocolitis, and convulsions at birth; the third one was diagnosed at 5 years of age.Here we present a case of a cblD-MMA patient who had an acute neonatal onset with severe hyperammonemia requiring hemodiafiltration. To the best of our knowledge, this is the first cblD-MMA patient who presented acutely in the newborn period. He has developed well upon treatment with B 12

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…Cobalamin D deficiency can either result in combined methylmalonic aciduria and homocystinuria, in isolated homocystinuria (variant 1) or in isolated MMA (variant 2). This type of isolated MMA is very rare compared to MCM deficiency and cobalamin A and B deficiency, and results in a cobalamin responsive phenotype similar to mut − and cobalamin A deficiency . MCE deficiency is also very rare and its' natural history is very variable, with asymptomatic patients, patients presenting with acute metabolic decompensations and patients having also a sepiapterin reductase deficiency .…”

“…This type of isolated MMA is very rare compared to MCM deficiency and cobalamin A and B deficiency, and results in a cobalamin responsive phenotype similar to mut − and cobalamin A deficiency. 11 MCE deficiency is also very rare and its' natural history is very variable, with asymptomatic patients, patients presenting with acute metabolic decompensations and patients having also a sepiapterin reductase deficiency. 12 Despite the differences between the different forms of isolated MMA, many publications assemble research data on MCM, cobalamin A and cobalamin B deficiency, and discuss isolated MMA as one disease entity.…”

Clinical, Biochemical, and Molecular Presentation in a Patient with the cblD-Homocystinuria Inborn Error of Cobalamin Metabolism

“…Mutations predicted to result in a nonfunctional protein resulted in combined homocystinuria and methylmalonic aciduria (Coelho et al 2008). Subsequently identified MMADHC mutations have been consistent with this hypothesis (Miousse et al 2009;Parini et al 2013).…”

“…Mutations in the MMADHC (methylmalonic aciduria, cblD type, and homocystinuria) gene on chromosome 2q23.2 have been reported in all identified cblD patients (Coelho et al 2008;Miousse et al 2009;Parini et al 2013;Stucki et al 2011). The MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a mitochondrial targeting sequence (Coelho et al 2008).…”

“…No additional patients with the cblD disorder were reported until 2004 when Suormala et al (2004) described two patients with cblD-HC and one patient with cblD-MMA using complementation analysis. To date, eighteen cblD patients have been reported; including five patients with the classic form of the disorder, six with cblD-HC, and seven with cblD-MMA (Coelho et al 2008;Miousse et al 2009;Parini et al 2013;Stucki et al 2011). Mutations at the MMADHC gene have been shown to underlie the cblD disorder in all of these patients.…”