Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Abstract

Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato‐cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06–189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1–312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5–132): all alive at 19, 18 and 3 years post‐LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early‐onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency

“… 16 Secondary hepatic failure, frequently precipitated by valproate administration, was responsible for the deaths of 4 of the 9 children with N forms, echoing reports in the literature. 15 , 17 - 19 These deaths should be regarded as the consequence of (1) unawareness of mitochondrial dysfunction as the cause of partial epilepsy, (2) misleading MRI patterns mimicking focal cortical lesions, (3) ignorance by prescribers of the toxicity of valproate in oxidative phosphorylation defects, and (4) delayed molecular genetic diagnoses. Nonetheless, 5 of 9 patients receiving valproate did not develop hepatic dysfunction.…”

“…This study also demonstrates the extent of central, peripheral, and autonomous nervous system involvement in these patients. Peripheral neuropathy with the absence of deep tendon reflexes 3 , 7 , 19 , 20 and cranial nerve and cervical root enhancement have occasionally been reported in POLG deficiency. 21 , 22 Our study gives additional support to the view that POLG-deficient patients may present with chronic inflammatory demyelinating polyradiculoneuropathy and provide postgadolinium MRI evidence of diffuse cranial nerve root (III, V, VII, VIII) and cauda equina enhancement in 6 patients.…”