title: Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease.
abstract: A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in theGBAgene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation inMPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs inMPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.
authors.affiliation: Metabolic Unit, Department of Medical Genetics, CHU-CHC, Liège, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Harvengt
authors.affiliation: Liver Unit, Department of Pediatrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wanty
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors.forename: Boel
authors.initials: B
authors.lastname: De Paepe
authors.affiliation: Department of pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.affiliation: Department of Medical Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Nicole
authors.initials: N
authors.lastname: Revencu
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.affiliation: Department of Medical Genetics, University Hospital AZ-VUB, Brussels, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.affiliation: Department of Medical Genetics, University Hospital AZ-VUB, Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Seneca
authors.affiliation: Metabolic Unit, Department of Medical Genetics, CHU-CHC, Liège, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Weekers
authors.affiliation: Liver Unit, Department of Pediatrics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sokal
authors.affiliation: Metabolic Unit, Department of Medical Genetics, CHU-CHC, Liège, Belgium.
authors.forename: François-Guillaume
authors.initials: FG
authors.lastname: Debray
keywords: ERT, enzyme replacement therapy; Gaucher disease; Mitochondrial disease; Neurohepatic; mtDNA depletion; mtDNA, mitochondrial DNA