title: Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia--a new metabolic disorder.
abstract: We report a new constellation of clinical features consisting of hypermanganesaemia, liver cirrhosis, an extrapyramidal motor disorder and polycythaemia in a 12 year-old girl born to consanguineous parents. Blood manganese levels were >3000 nmol/L (normal range <320 nmol/L) and MRI revealed signal abnormalities of the basal ganglia consistent with manganese deposition. An older brother with the same phenotype died at 18 years, suggesting a potentially lethal, autosomal recessive disease. This disorder is probably caused by a defect of manganese metabolism with the accumulation of manganese in the liver and the basal ganglia similar to the copper accumulation in Wilson disease. In order to assess the genetic basis of this syndrome we investigated two candidate genes: ATP2C2 and ATP2A3 encoding the manganese-transporting calcium-ATPases, SPCA2 and SERCA3, respectively. Genotyping of the patient and the family for microsatellite markers surrounding ATP2C2 and ATP2A3 excluded these genes. The patient was found to be heterozygous for both gene loci. Despite the unknown pathophysiology, we were able to develop a successful treatment regime. Chelation therapy with disodium calcium edetate combined with iron supplementation is the treatment of choice, lowering blood manganese levels significantly and improving clinical symptoms.
authors.affiliation: University College London Institute of Child Health with Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Howard
authors.initials: H
authors.lastname: Parsons
authors.forename: Marian
authors.initials: M
authors.lastname: Malone
authors.forename: Darren
authors.initials: D
authors.lastname: Fowler
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D000293:Adolescent; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D002614:Chelating Agents / Q000627:therapeutic use; D002648:Child; D004252:DNA Mutational Analysis; D019587:Dietary Supplements; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007501:Iron / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese / Q000097:blood*; D008659:Metabolic Diseases / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D002614:Chelating Agents; D008345:Manganese; D007501:Iron; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506949:ATP2A3 protein, human; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases