[en] A one 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 the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabism, 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 in MPV17. 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, strabism and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17 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. 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.
Disciplines :
Pediatrics
Author, co-author :
HARVENGT, Julie ; Centre Hospitalier Universitaire de Liège - CHU > Pédiatrie
wanty, catherine; Université Catholique de Louvain - UCL > Pediatric department > Liver Unit
De Paepe, Boel
Sempoux, Christine
Revencu, Nicole
Smet, Joel; Universiteit Gent - Ugent
VanCoster, Rudy; Universiteit Gent - Ugent
Lissens, Willy; Vrije Universiteit Brussel - VUB
Seneca, Sara; Vrije Universiteit Brussel - VUB
WEEKERS, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de néphrologie
Sokal, Etienne; Université Catholique de Louvain - UCL
D. Chretien et al. Pitfalls and tips in measuring and interpreting mitochondrial enzyme activities J. Inherit. Metab. Dis. 26 2003 189 198 (Pubitemid 36889742)
J. Martin-Garcia et al. Skeletal muscle mitochondrial defects in nonspecific neurologic disorders Pediatr. Neurol. 21 1999 538 542
A.W. El-Hattab, and F. Scaglia Mitochondrial DNA Depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options Neurotherapeutics 10 2013 186 198
R.H. Lachmann et al. Massive hepatic fibrosis in Gaucher's disease: clinicopathological and radiological features QJM 93 4 2000 237 244 (Pubitemid 30198961)
Y. Perel et al. Gaucher's disease and fatal hepatic fibrosis despite prolonged enzyme replacement therapy Pediatrics 109 2002 1170 1173 (Pubitemid 34587448)
A. Tylki-Szymańska, A. Vellodi, A. El-Beshlawy, J.A. Cole, and E. Kolodny Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry J. Inherit. Metab. Dis. 33 4 2010 Aug 339 346
I.A. Trounce, Y.L. Kim, A.S. Jun, and D.C. Wallace Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts and transmitochondrial cell lines Methods Enzymol. 264 1996 484 509
B. De Paepe, J.L. De Beecker, and R. Van Coster Histochemical methods for the diagnosis of mitochondrial diseases Curr. Protoc. Hum. Genet. 63 2009 19.2.1 19.2.19 (Chapter 19: unit 19:2)
R.-K. Bai, and L.-J. Wong Simultaneous detection and quantification of mitochondrial DNA deletion(s), depletion, and over-replication in patients with mitochondrial disease J. Mol. Diagn. 7 5 2005 613 622 (PubMed: 16258160) (Pubitemid 41601513)
Smet J. De Paepe, and J.G. Leroy et al. Diagnostic value of immunostaining in cultured skin fibroblasts from patients with oxidative phosphorylation defects Pediatr. Res. 59 no.1 2006 2 6
J. Uusimaa, J. Evans, C. Smith, A. Butterworth, K. Craig, N. Ashley, C. Liao, J. Carver, A. Diot, L. Macleod, I. Hargreaves, A. Al-Hussaini, E. Faqeih, A. Asery, M. Al Balwi, W. Eyaid, A. Al-Sunaid, D. Kelly, I. van Mourik, S. Ball, J. Jarvis, A. Mulay, N. Hadzic, M. Samyn, A. Baker, S. Rahman, H. Stewart, A.A. Morris, A. Seller, C. Fratter, R.W. Taylor, and J. Poulton Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene Eur. J. Hum. Genet. 2013 10.1038/ejhg.2013.112 (Epub ahead of print)
L.J. Wong, N. Brunetti-Pierri, Q. Zhang, N. Yazigi, K.E. Bove, B.B. Dahms, M.A. Puchowicz, I. Gonzalez-Gomez, E.S. Schmitt, C.K. Truong, C.L. Hoppel, P.C. Chou, J. Wang, E.E. Baldwin, D. Adams, N. Leslie, R.G. Boles, D.S. Kerr, and W.J. Craigen Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy Hepatology 46 2007 1218 1227 (Pubitemid 350144786)
A.W. El-Hattab, F. Scaglia, W.J. Craigen, and L.J. Wong MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome. 2012 May 17 R.A. Pagon, M.P. Adam, T.D. Bird, GeneReviews™ 2012 University of Washington, Seattle Seattle (WA) (1993-2013. Available from: http://www.ncbi.nlm.nih.gov/books/ NBK92947/)
R.M. Ayto, D.A. Hughes, P. Jeevaratnam, K. Rolles, A.K. Burroughs, P.K. Mistry, A.B. Mehta, and G.M. Pastores Long-term outcomes of liver transplantation in type 1 Gaucher disease Am. J. Transplant. 10 2010 1934 1939
T.E. Starzl, A.J. Demetris, M. Trucco, C. Ricordi, S. Ildstad, P.I. Terasaki, N. Murase, R.S. Kendall, M. Kocova, and W.A. Rudert Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease N. Engl. J. Med. 328 1993 745 749 (Pubitemid 23082036)
A.W. El-Hattab, F.Y. Li, E. Schmitt, S. Zhang, W.J. Craigen, and L.J. Wong MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations Mol. Genet. Metab. 99 2010 300 308
E.L. Blakely, A. Butterworth, R.D. Hadden, I. Bodi, L. He, R. McFarland, and R.W. Taylor MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle Neuromuscul. Disord. 22 2012 587 591
B.A. Mendelsohn, N. Mehta, B. Hameed, M. Pekmezci, S. Packman, and J. Ralph Adult-Onset Fatal Neurohepatopathy in a Woman Caused by MPV17 Mutation JIMD Rep. 2013 10.1007/8904-2013-267 (Epub ahead of print] PMID:24190800)
V. Koprivica, D.L. Stone, J.K. Park, M. Callahan, A. Frisch, I.J. Cohen, N. Tayebi, and E. Sidransky Analysis and classification of 304 mutant alleles in patients with Type 1 and Type 3 Gaucher disease Am. J. Hum. Genet. 66 2000 1777 1786 (Pubitemid 30480085)
K.S. Hrusk, M.E. LaMarca, and E. Sidransky Gaucher disease: molecular biology and genotype-phenotype correlations A.H. Futerman, A. Zimran, Gaucher disease 2006 Taylor & Francis Boca Raton, FL 13 48
C.M. Harris, D.S. Taylor, and A. Vellodi Ocular motor abnormalities in Gaucher disease Neuropediatrics 30 1999 289 293 (Pubitemid 30088319)
D.P. Dimmock, Q. Zhang, C. Dionisi-Vici, R. Carrozzo, J. Shieh, L.Y. Tang, C. Truong, E. Schmitt, M. Sifry-Platt, S. Lucioli, F.M. Santorelli, C.H. Ficicioglu, M. Rodriguez, K. Wierenga, G.M. Enns, N. Longo, M.H. Lipson, H. Vallance, W.J. Craigen, F. Scaglia, and L.J. Wong Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase Hum. Mutat. 29 2008 330 331
A. Vellodi, A. Tylki-Szymanska, E.H. Davies, E. Kolodny, B. Bembi, T. Collin-Histed, E. Mengel, A. Erikson, R. Schiffmann, and European Working Group on Gaucher Disease Management of neuronopathic Gaucher disease: revised recommendations J. Inherit. Metab. Dis. 32 2009 660 664
