Mitochondrial Disorders (Overview)

🧬 Overview of Mitochondrial Disorders

Mitochondrial disorders result from mutations affecting mitochondrial DNA (mtDNA) replication or translation, leading to conditions such as mitochondrial depletion syndrome (MDS). These mutations impair components of the respiratory chain, including ribosomal RNAs and tRNAs encoded by mtDNA. Because mtDNA is maternally inherited, lacks protective histones, and is exposed to oxidative stress from OXPHOS, it is particularly vulnerable to damage.

Categories of Mitochondrial Hepatopathies

1. Respiratory Chain Disorders

• Caused by defects in mitochondrial oxidative phosphorylation (OXPHOS)

• Lead to impaired ATP production and increased reactive oxygen species (ROS)

• Common genes involved: POLG, DGUOK, MPV17, RRM2B, GFM1, BCS1L, SUCLG1, QIL1, SERAC1, TYMP

2. Mitochondrial DNA Depletion Syndromes (MDS)

• Characterized by reduced mtDNA copy number in affected tissues

• Subtypes:

  • Hepatocerebral MDS (e.g., DGUOK, MPV17)

  • Myopathic MDS

  • Encephalomyopathic MDS

• Often present with liver failure in infancy and multisystem involvement

3. Fatty Acid Oxidation Defects

• Affect mitochondrial beta-oxidation pathway

• Examples: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), Carnitine transporter deficiency

• Typically autosomal recessive and detectable via newborn screening

4. Mitochondrial Translation and Replication Disorders

• Involve nuclear genes that regulate mtDNA synthesis and protein translation

• Examples: TRMU, C10orf2 (TWINKLE), GFM1

5. Mitochondrial Structural Disorders

• Affect mitochondrial morphology and function

• Can lead to progressive liver fibrosis and multisystem disease

Clinical Relevance in Pediatrics

• Infants often present with acute liver failure, hypotonia, seizures, and lactic acidosis

• Older children may develop chronic liver disease with neurological or cardiac symptoms

• Histology may show micro/macrovesicular steatosis, cholestasis, and abnormal mitochondrial morphology on EM

Clinical Presentation

Mitochondrial Hepatopathies

• Can present at any age.

• Infants often show acute liver failure (ALF); older children may develop chronic liver disease.

• Multisystem involvement (CNS, cardiac, renal) often precedes liver symptoms, suggesting a mitochondrial etiology.

Mitochondrial Depletion Syndrome (MDS)

• Tissue-specific and classified into:

  • Hepatocerebral

  • Myopathic

  • Encephalomyopathic

• Affects enzymes in the TCA cycle and OXPHOS complexes.

  • Complex II (nDNA-encoded) remains unaffected.

  • Complexes I, III, IV may show reduced activity (<40%), meeting diagnostic criteria.

Infant Presentation

Symptoms

• Poor feeding, hypotonia, lethargy, seizures

• Mild liver dysfunction progressing to failure

• Onset typically within the first weeks to months of life

Common Causes

• Respiratory chain defects, often linked to MDS

Laboratory Findings

• ↑ Lactate (>2.5 mM), ↑ lactate/pyruvate ratio (>25)

• Ketotic hypoglycemia

• ↑ Prothrombin time

• Possible ↑ AST, ALT, bilirubin

Differential Diagnosis

• Deoxyguanosine kinase (DGUOK) deficiency mimics gestational alloimmune liver disease, with hyperferritinemia

Histology and Electron Microscopy

• Micro- and macrovesicular steatosis

• Minimal inflammation

• Canalicular cholestasis, bile duct thrombi, ductular proliferation

• Clumped hepatocytes, highly eosinophilic

• Progressive portal fibrosis

• Electron microscopy shows wide variation in mitochondrial size, number, and cristae morphology

Outcome

• Poor prognosis, with some patients experiencing recurrent ALF depending on genotype

• Neurological manifestations are common

• Due to multisystem involvement, this condition is considered a relative contraindication to liver transplantation