title: Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type).
abstract: Cobalamin is an essential cofactor for two mammalian enzymes: methionine synthase and methylmalonyl-CoA mutase. Patients with the cobalamin C (CblC) defect have combined methylmalonic aciduria and homocystinuria. Recently, the gene responsible for the CblC type, MMACHC, was identified, which enables molecular diagnostics. In this study, we describe two siblings, a 16-year-old girl and her 11-year-old brother, of a consanguineous family who presented with a very distinct clinical manifestation. The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis. Her brother presented at the age of 10 months with developmental delay and behavioural abnormalities. Biochemical analysis showed severely increased homocysteine and methylmalonic acid levels in plasma of both siblings. In addition, plasma cysteine levels were decreased in the girl but not in her brother. The diagnosis of CblC defect was confirmed by genomic sequencing of the coding exons of the MMACHC gene. Two heterozygous mutations were identified in both siblings; the common c.271dupA p.Arg91LysfsX14 and a novel mutation, c.1A > G p.Met1?. Therapy consisting of folic acid, vitamin B6, l-carnitine and intramuscular vitamin B12 resulted in a clear improvement of biochemical parameters and, importantly, resulted in amelioration of the Marfanoid features in the girl. These data might suggest that low cysteine levels account for the Marfanoid features observed in the girl and indicate that the CblC type of combined methylmalonic aciduria and homocystinuria should be considered in the differential diagnosis of patients with Marfanoid features.
authors.affiliation: Department of Pediatrics, Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Heil
authors.forename: Marije
authors.initials: M
authors.lastname: Hogeveen
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: P J
authors.initials: PJ
authors.lastname: van Dijken
authors.forename: Gerard B
authors.initials: GB
authors.lastname: van de Berg
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
mesh_terms: D000293:Adolescent; D002331:Carnitine / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D003545:Cysteine / Q000097:blood; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005091:Exons; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D005820:Genetic Testing; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood*; D006712:Homocystinuria / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis*; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008764:Methylmalonic Acid / Q000097:blood*; D009154:Mutation; D010088:Oxidoreductases; D010375:Pedigree; D010641:Phenotype; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000627:therapeutic use; D025101:Vitamin B 6 / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; D014815:Vitamins; D006710:Homocysteine; D025101:Vitamin B 6; D008764:Methylmalonic Acid; D005492:Folic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases; D003545:Cysteine; D014805:Vitamin B 12; D002331:Carnitine