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Leigh Disease

Summary

  • Rare, progressive neurometabolic disorder characterised by bilateral symmetric lesions in the basal ganglia, thalami, and brainstem
  • Caused by mutations affecting mitochondrial energy production
  • Typically presents in infancy with developmental delay, seizures, and lactic acidosis

Pathophysiology

  • Genetic mutations affecting mitochondrial energy production, particularly in the respiratory chain complexes
  • Deficiency in pyruvate dehydrogenase complex or coenzyme Q10
  • Results in cellular energy failure, particularly affecting high-energy demand tissues like the brain
  • Neuronal loss and demyelination in affected areas

Demographics

  • Incidence: approximately 1 in 40,000 live births
  • Typically presents in infancy or early childhood
  • Can rarely present in adolescence or adulthood
  • No significant gender predilection
  • Higher prevalence in certain populations (e.g., Saguenay-Lac-Saint-Jean region of Quebec)

Diagnosis

  • Clinical presentation:
    • Developmental delay or regression
    • Seizures
    • Ataxia
    • Dystonia
    • Respiratory difficulties
  • Laboratory findings:
    • Elevated lactate in blood and/or cerebrospinal fluid
    • Pyruvate elevation
    • Abnormal respiratory chain enzyme activities
  • Genetic testing:
    • Mitochondrial DNA mutations
    • Nuclear DNA mutations affecting mitochondrial function
  • Muscle biopsy:
    • May show ragged red fibres or cytochrome c oxidase-negative fibres

Imaging

  • MRI:
    • Bilateral, symmetric T2 hyperintensities in:
    • Basal ganglia (particularly putamen)
    • Thalami
    • Brainstem (particularly midbrain and pons)
    • Cerebral and cerebellar white matter involvement may occur
    • Contrast enhancement is uncommon
  • CT:
    • May show hypodensities in affected areas
    • Less sensitive than MRI
  • MR Spectroscopy:
    • Elevated lactate peak at 1.3 ppm
    • Decreased N-acetylaspartate (NAA) peak
  • Diffusion-weighted imaging:
    • May show restricted diffusion in acute lesions

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  • A 25-year-old patient presented following a slightly worsening of longstanding spastic paresis and dysarthria.
  • MRI showed old damage in the basal ganglia without DWI hyperintensity.
  • Genomic testing revealed X-linked Leigh disease caused by a hemizygous mutation in the PDHA1 gene.

Treatment

  • No curative treatment available
  • Supportive care and symptom management:
    • Anticonvulsants for seizure control
    • Respiratory support as needed
    • Nutritional support
  • Mitochondrial cocktail:
    • Coenzyme Q10
    • Thiamine
    • Riboflavin
    • L-carnitine
    • Alpha-lipoic acid
  • Dichloroacetate:
    • May help reduce lactic acidosis
  • Ketogenic diet:
    • May be beneficial in some cases
  • Gene therapy:
    • Experimental approaches under investigation
  • Prognosis:
    • Generally poor, with most patients not surviving beyond early childhood
    • Some individuals with milder variants may have longer survival

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Stroke-like episodes and migraines are more common in MELAS; Leigh disease typically presents earlier in life
Pyruvate dehydrogenase deficiency Often presents with congenital lactic acidosis; Leigh disease typically has later onset
Biotinidase deficiency Skin rash and alopecia are common; not typically seen in Leigh disease
Neurodegeneration with brain iron accumulation Iron accumulation in basal ganglia on MRI; not typically seen in Leigh disease