Molecular Genetics and Metabolism 87 (2006) 102–106 www.elsevier.com/locate/ymgme
Brain abnormalities in a case of malonyl-CoA decarboxylase deWciency M.C.Y. de Wit a,¤, I.F.M. de Coo a, E. Verbeek b, R. Schot b, G.C. Schoonderwoerd b, M. Duran c, J.B.C. de Klerk b, J.G.M. Huijmans b, M.H. Lequin d, F.W. Verheijen b, G.M.S. Mancini b b
a Department of Child Neurology, Erasmus Medical Center, Rotterdam, The Netherlands Department of Metabolic Diseases and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands c Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, The Netherlands d Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
Received 21 July 2005; received in revised form 8 September 2005; accepted 9 September 2005 Available online 4 November 2005
Abstract Malonyl-CoA decarboxylase (MCD) deWciency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deWciency, whose brain MRI shows white matter abnormalities and additionally diVuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be conWrmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deWciency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening. 2005 Elsevier Inc. All rights reserved. Keywords: Malonyl-CoA decarboxylase deWciency; Neuronal migration; Malformation of cortical development; MLYCD
Introduction Malonyl-CoA decarboxylase (MCD) catalyzes the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide. MCD deWciency (OMIM 248360) causes autosomal recessive malonic aciduria. Symptoms are psychomotor retardation, spasticity/hypotonia, seizures, cardiomyopathy, and episodes of metabolic acidosis. Seventeen cases have been published but brain pathology is poorly described (Table 1). The role and localization of MCD in the cell is controversial. Cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation by inhibiting the mitochondrial outer membrane enzyme carnitine palmitoyltransferase I (CPT1). Heart and skeletal muscle contain a
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[email protected] (M.C.Y. de Wit).
1096-7192/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.09.009
CPT1-isoform that is substantially more sensitive to inhibition by malonyl-CoA than liver CPT1, where cytoplasmic malonyl-CoA serves as a precursor for fatty acid synthesis [1]. Both isoforms are encoded by diVerent genes, CPT1B and CPT1A. A third brain-speciWc CPT1 protein-isoform with high aYnity for malonyl-CoA has been described [2]. Symptoms of cardiomyopathy and metabolic acidosis triggered by stress can be explained by inhibition of mitochondrial -oxidation by continuous high levels of malonyl-CoA in cytoplasm [3]. The carboxy-terminal of the MCD-protein contains a peroxisomal targeting sequence suggesting a peroxisomal function, but there is also a potential mitochondrial targeting sequence at the N-terminus and mitochondrial localization has been shown in rats [1,4,5]. In 1999, a mutation in a 2.1-kb cDNA fragment was identiWed on chromosome 16q24.3 encoding the human MCD gene MLYCD (OMIM 606761) [1]. Wightman et al. [6] further elucidated a probable mitochondrial and peroxi-
M.C.Y. de Wit et al. / Molecular Genetics and Metabolism 87 (2006) 102–106
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Table 1 Summary of neurological symptoms and neuroimaging Wndings of all MCD patients in the literature Reference
S
Age at presentation
Metabol. acidosis
PMR
Epileptic seizures
Head circumference
Brain imaging
Brown et al. [16] Haan et al. [17] Matalon et al. [18] Macphee et al. [19] Macphee et al. [19] Krawinkel et al. [20]
M M M M F M
5 years 10 months 7 months 9 years 1 years 4 days
+ + + ND + +
Mild + + + + +
¡ + (during crisis) + + + ¡
Normal Normal ND ND ND ND
Yano et al. [21]
M
4 years
+
+
+
Buyukgebiz et al. [22] Ozand et al. [23]
F M
died 8 days old 9 months
+ +
N/a +
N/a +
Borderline microceph. ND P50, decreased to
