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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.


Spleen resection—Patient 1.The spleen's sinusoids are filled with groups of macrophages (A, hematoxylin–eosin, original magnification × 8). At higher magnification (B, hematoxylin-eosin, original magnification × 30 and C, PAS staining, original magnification × 20), the macrophages have a greyish fibrillary cytoplasm, weakly positive for PAS.
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f0005: Spleen resection—Patient 1.The spleen's sinusoids are filled with groups of macrophages (A, hematoxylin–eosin, original magnification × 8). At higher magnification (B, hematoxylin-eosin, original magnification × 30 and C, PAS staining, original magnification × 20), the macrophages have a greyish fibrillary cytoplasm, weakly positive for PAS.

Mentions: During the year following the liver transplantation, splenomegaly became more obvious and accompanied by severe anemia and thrombocytopenia. Bone marrow examination, performed twice, was normal. At 3 years of age, partial splenectomy was performed and histological analysis revealed the presence of foamy cells considered as consistent with Gaucher's cells (Fig. 1). Gaucher disease was confirmed by low glucocerebrosidase activity and presence of the homozygous c.1448 T > C (p.Leu483Pro) mutation in the GBA gene, usually associated with type 3 Gaucher disease. Enzyme replacement therapy (ERT) was started by imiglucerase at the dose of 60 U/kg, followed by normalization of hematological parameters. Clinical follow-up showed failure to thrive, developmental delay and mild cerebellar ataxia. Unaided walk was achieved at the age of 3 years. Fine motor control was impaired by clumsiness. She also presented with nystagmus, strabismus, paucity of facial movement and progressive external ophthalmoplegia. Nevertheless, she made progress, and at age 10 years, she was able to attend normal school with support.


Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease
Spleen resection—Patient 1.The spleen's sinusoids are filled with groups of macrophages (A, hematoxylin–eosin, original magnification × 8). At higher magnification (B, hematoxylin-eosin, original magnification × 30 and C, PAS staining, original magnification × 20), the macrophages have a greyish fibrillary cytoplasm, weakly positive for PAS.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: Spleen resection—Patient 1.The spleen's sinusoids are filled with groups of macrophages (A, hematoxylin–eosin, original magnification × 8). At higher magnification (B, hematoxylin-eosin, original magnification × 30 and C, PAS staining, original magnification × 20), the macrophages have a greyish fibrillary cytoplasm, weakly positive for PAS.
Mentions: During the year following the liver transplantation, splenomegaly became more obvious and accompanied by severe anemia and thrombocytopenia. Bone marrow examination, performed twice, was normal. At 3 years of age, partial splenectomy was performed and histological analysis revealed the presence of foamy cells considered as consistent with Gaucher's cells (Fig. 1). Gaucher disease was confirmed by low glucocerebrosidase activity and presence of the homozygous c.1448 T > C (p.Leu483Pro) mutation in the GBA gene, usually associated with type 3 Gaucher disease. Enzyme replacement therapy (ERT) was started by imiglucerase at the dose of 60 U/kg, followed by normalization of hematological parameters. Clinical follow-up showed failure to thrive, developmental delay and mild cerebellar ataxia. Unaided walk was achieved at the age of 3 years. Fine motor control was impaired by clumsiness. She also presented with nystagmus, strabismus, paucity of facial movement and progressive external ophthalmoplegia. Nevertheless, she made progress, and at age 10 years, she was able to attend normal school with support.

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.