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Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

View Article: PubMed Central - PubMed

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 the GBA gene. 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 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, strabismus 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. 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.

No MeSH data available.


Immunohistochemical staining for complex IV MTCO1 in paraffin-embedded liver tissues.Immunostaining of complex IV in the liver of patient 1 (A, C) and patient 2 (B, D), visualized with permanent red (pink), nuclei were counterstained with hematoxylin (blue). Liver of patient 1 displays a mosaic staining pattern (left panels), while normal staining is observed in patient 2 (right panels). Scale bars = 200 μm (A–B) 50 μm (C–D).
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f0020: Immunohistochemical staining for complex IV MTCO1 in paraffin-embedded liver tissues.Immunostaining of complex IV in the liver of patient 1 (A, C) and patient 2 (B, D), visualized with permanent red (pink), nuclei were counterstained with hematoxylin (blue). Liver of patient 1 displays a mosaic staining pattern (left panels), while normal staining is observed in patient 2 (right panels). Scale bars = 200 μm (A–B) 50 μm (C–D).

Mentions: Immunostaining on liver biopsies revealed a mosaic pattern of deficient complex IV staining in patient 1 (Figs. 4A, C), consistent with the mtDNA depletion. By contrast, immunostaining in patient 2, unaffected by the mtDNA depletion syndrome, was normal (Figs. 4B, D).


Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease
Immunohistochemical staining for complex IV MTCO1 in paraffin-embedded liver tissues.Immunostaining of complex IV in the liver of patient 1 (A, C) and patient 2 (B, D), visualized with permanent red (pink), nuclei were counterstained with hematoxylin (blue). Liver of patient 1 displays a mosaic staining pattern (left panels), while normal staining is observed in patient 2 (right panels). Scale bars = 200 μm (A–B) 50 μm (C–D).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121303&req=5

f0020: Immunohistochemical staining for complex IV MTCO1 in paraffin-embedded liver tissues.Immunostaining of complex IV in the liver of patient 1 (A, C) and patient 2 (B, D), visualized with permanent red (pink), nuclei were counterstained with hematoxylin (blue). Liver of patient 1 displays a mosaic staining pattern (left panels), while normal staining is observed in patient 2 (right panels). Scale bars = 200 μm (A–B) 50 μm (C–D).
Mentions: Immunostaining on liver biopsies revealed a mosaic pattern of deficient complex IV staining in patient 1 (Figs. 4A, C), consistent with the mtDNA depletion. By contrast, immunostaining in patient 2, unaffected by the mtDNA depletion syndrome, was normal (Figs. 4B, D).

View Article: PubMed Central - PubMed

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 the GBA gene. 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 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, strabismus 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. 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.

No MeSH data available.