48uep6bbphidcol2|ID

48uep6bbphidvals|2956

48uep6bbph|2000F98CTab_Articles|Fulltext

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are autosomal recessive disorders characterized by a tissue-specific reduction in mtDNA copy number leading to organ failure.^1,2 MDS are classified as myopathic, encephalomyopathic, or hepato-cerebral forms. The hepato-cerebral form (mtDNA depletion in liver and brain) is associated with mutations in the DNA polymerase gamma (POLG), Twinkle helicase (PEO1), deoxyguanosine kinase (DGUOK) and MPV17 genes.^1,2 MPV17 encodes a mitochondrial inner membrane protein of unknown function in mtDNA maintenance. The human MPV17 gene is located on chromosome 2p21-23, comprising eight exons and encoding 176 amino acids. It is expressed in the human pancreas, kidney, muscle, liver, lung, placenta, brain, and heart.² We describe the liver histopathology in a case of mitochondrial DNA depletion syndrome 6 with a homozygous mutation in the MPV17 gene. 

The present case concerns a 2.5-month-old girl child, third born to third-degree consanguinity (or 1st cousins). She presented with jaundice and dark coloured urine over one month, with normal appearance of stools. Her birth weight was 2500 gm, and weight at presentation 4 kg. Clinical examination revealed mild hepatosplenomegaly without any dysmorphism. An ophthalmologic evaluation revealed normal fundus. 

She was invetigated further, with liver function test revealing total bilirubin 7.3 mg/dL (Reference 0.2-1.2 mg/dL) with direct bilirubin 4.7 mg/dL (Ref 0.0-0.4 mg/dL), aspartate aminotransferase233 IU/L (Ref 0-45 IU/L), alanine aminotransferase 66 IU/L (Ref 0-45 IU/L), alkaline phosphatase 343 IU/L (Ref 150-420 IU/L), gamma-glutamyl transferase104 IU/L (Ref 0-49 IU/L), albumin 4.6 gm/dL (Ref 3.4-5gm/dL), and INR of 1.12 (Ref 1).Her serum alpha fetoprotein (AFP) level was high 1,93,600 U/L (Ref 45-601 U/L). Ultrasound abdomen revealed mild hepatosplenomegaly with tiny gall bladder calculi. Urine succinyl acetone assay was normal, and TORCH IgM panel was negative. Initial inborn error of metabolism screen was negative. 

She underwent a liver biopsy, and light microscopy revealed mild lobular disarray. The portal tracts showed expansion with mild inflammatory cells comprising of lymphomononuclear cells and hematopoietic elements. Interlobular bile ducts were present in all of the portal tracts. The lobular parenchyma showed patchy giant cell transformation and hepato-canalicular bilirubinostasis with cholestatic resetting (Figure 1A). Patchy cellular ballooning with rarefied cytoplasm was identified (Figure 1B). Cytoplasmic eosinophilia, steatosis, and occasional lobular inflammation were also present. Sinusoids showed periodic acid Shiffs after diastase (PASD) positive pigment laden Kupffer cells. There was portal/periportal fibrosis with focal bridging septa formation (Figure 1C and 1D). 

There was stainable iron in few periportal hepatocytes and macrophages. Stainable granules of copper/copper-associated proteins were identified in few periportal hepatocytes. No storage cells or periportal PASD positive globules are noted. We advised further etiological work-up. Her clinical exome sequencing revealed homozygous missense variation in exon 3 of the MPV17 gene (chr2:27535899; G>A; Depth: 91x) that resulted in the amino acid substitution of tryptophan for arginine at codon 50 (p.Arg50Trp; ENST00000380044). She was diagnosed as mitochondrial DNA depletion syndrome 6 (hepato-cerebral type). She remained on follow-up and died at ten months of age.   

The MPV17 gene maps to chromosome 2p23.3 and contains eight exons. The MPV17 protein on the inner mitochondrial membrane is predicted to contain 4 trans-membrane (TM) segments.² It has been suggested to play a role in controlling mtDNA maintenance and oxidative phosphorylation activity in mammals and yeast. Initially, mutations in the MPV17 gene were identified in patients who presented in the first year of life with liver failure, hypoglycemia, failure-to-thrive and neurological symptoms.¹ The pathological examination of the liver in mitochondrial DNA depletion syndrome is rarely described. Hazard et al³ describes liver biopsy and post-mortem liver examination findings of patients with confirmed mtDNA depletion syndrome. All specimens predominantly showed morphologic features of chronic liver injury. Pathologic features consisted of varying degrees of fibrosis, bilirubinostasis, steatosis, and hemosiderosis. Cytoplasmic eosinophilia was also demonstrated. In cases described by Wong et al⁴,  hepatocyte cytoplasm in all instances was severely expanded and contained coarse, evenly dispersed eosinophilic granules, numerous small lipid vacuoles, or both. Canalicular and hepatocellular bile stasis or focal hepatocyte necrosis were also demonstrated. Liver inflammation was minimal, and the architecture was characterized by delicate periportal and pericellular fibrosis coexisting with areas of intralobular collapse. A case with neonatal giant hepatitis has also been described.⁵ To conclude, in cases of giant cell hepatitis with significant fibrosis, if initial tests are unrevealing, work-up for mitochondrial disorders should be considered.