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L-2 hydroxyglutaric Aciduria

Summary

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  • Rare neurometabolic disorder characterised by elevated levels of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid
  • Presents with developmental delay, epilepsy, and progressive neurological deterioration
  • MRI shows distinctive white matter abnormalities and subcortical cystic lesions1

Pathophysiology

  • Autosomal recessive disorder caused by mutations in the L2HGDH gene
  • Deficiency of L-2-hydroxyglutarate dehydrogenase enzyme leads to accumulation of L-2-hydroxyglutaric acid
  • Toxic accumulation results in:
    • Oxidative stress
    • Mitochondrial dysfunction
    • Impaired energy metabolism in the brain

Demographics

  • Rare disorder with an estimated prevalence of <1/1,000,000
  • No significant gender predilection
  • Typically presents in infancy or early childhood
  • Higher prevalence in populations with consanguineous marriages

Diagnosis

  • Clinical features:
    • Developmental delay
    • Seizures
    • Ataxia
    • Macrocephaly
    • Progressive cognitive decline
  • Laboratory findings:
    • Elevated L-2-hydroxyglutaric acid in urine, plasma, and CSF
    • Genetic testing for L2HGDH mutations
  • Neuroimaging findings (crucial for diagnosis)

Imaging

  • MRI is the modality of choice
  • Characteristic findings:
    • Subcortical white matter abnormalities (high T2, low T1 signal)
    • Sparing of deep white matter and corpus callosum
    • Bilateral symmetrical involvement of:
    • Cerebral hemispheres
    • Basal ganglia (especially putamen and caudate nucleus)
    • Dentate nuclei
    • Subcortical cystic lesions, particularly in frontal and temporal lobes
    • Cerebellar atrophy (late finding)
  • Differential diagnosis:
    • Canavan disease
    • Alexander disease
    • Megalencephalic leukoencephalopathy with subcortical cysts

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  • 20-year-old patient with learning difficulties.
  • MRI showed a diffuse supratentorial leukoencephalopathy and dentate nucleus hyperintensity without diffusion restriction, significant volume loss, or pathological enhancement.

Treatment

  • Supportive; riboflavin is trialled. The peripheral (subcortical) white matter, dentate and basal ganglia pattern is characteristic, and there is an increased risk of CNS tumours

Differential diagnosis

Differential Diagnosis Differentiating Feature
Canavan disease Elevated N-acetylaspartic acid in urine and CSF; macrocephaly more prominent
Alexander disease Predominant frontal white matter involvement; presence of Rosenthal fibres on histology
Megalencephalic leukoencephalopathy with subcortical cysts Presence of subcortical cysts; less severe clinical course
Glutaric aciduria type 1 Frontotemporal atrophy; basal ganglia lesions; elevated glutaric acid in urine
Mitochondrial disorders Lactate elevation; involvement of brainstem and basal ganglia
Sjögren-Larsson syndrome Ichthyosis; spastic diplegia; retinal changes
Van der Knaap disease Swollen white matter with cystic degeneration; milder clinical course
Aicardi-Goutières syndrome Calcifications in basal ganglia; elevated interferon-alpha in CSF
Metachromatic leukodystrophy Peripheral neuropathy; sulfatide accumulation in urine
Krabbe disease Peripheral neuropathy; elevated galactocerebrosidase levels

  1. Patay et al. Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. 2012. AJNR. American journal of neuroradiology - Open in new tab. ↩