Teaching Case

A 9-year-old girl reported to us for epilepsy imaging. The birth history was uneventful. History of developmental delays such as delay in unsupported walking, speech delay and febrile seizures were there. Over the years, the child developed slowly progressive neurological dysfunction and cerebellar ataxia with slow intellectual decline.

Brain magnetic resonance imaging (MRI) showed:

• Multifocal, partly confluent, sub-cortical T2 hyperintensities in bilateral cerebral hemispheres, with the lesions involving the subcortical U-fibres (Figures 1a and 1b). White matter abnormalities exhibited a very characteristic centripetal and slightly anteroposterior gradient.
• Bilateral basal ganglia (caudate, putamen and globus pallidi) were swollen and oedematous with T2/FLAIR hyperintensity (Figure 2).
• Cerebellar white matter was spared, but symmetrical T2/FLAIR hyperintensities in dentate nuclei were evident (Figures 3a and 3b).
• Central periventricular white matter, central corticospinal tracts and corpus callosum were spared (Figure 4).

Background

Cerebral organic acidurias (COA) are rare neurometabolic diseases characterised predominantly by central nervous dysfunction. L-2-hydroxyglutaric aciduria is a rare, infantile-onset, autosomal recessive organic aciduria caused by L-2-hydroxyglutarate dehydrogenase enzyme deficiency, which is involved in the oxidation of L-2-hydroxyglutarate (L-2-HG) to alpha 2-ketoglutarate. Increased L-2-HG in tissues induces free radical formation and increases glutamate uptake in synaptosomes and synaptic vesicles. It is toxic to the brain, causes leukoencephalopathy, and is also an oncometabolite [1].

Clinical Perspective

L-2-HGA patients present with cerebellar ataxia, extrapyramidal and pyramidal symptoms and slowly progressive neurodegeneration with seizures and macrocephaly [2].

Imaging Perspective

Brain MRI shows a symmetric T2 and FLAIR high signal intensity and T1 low signal intensity of the subcortical white matter (U-fibres), globus pallidus, and dentate nucleus. White matter involvement presents a centripetal pattern, starting in the U-fibres and extending to the deeper white matter with a confluent pattern as the disease progresses [3].

Even in advanced cases, the corpus callosum, internal capsule, and periventricular white matter are spared. There is no involvement of the brainstem and cerebellar white matter. There is no contrast enhancement and no restricted diffusion. Advanced cases show cerebral and cerebellar vermis atrophy [3].

The definite diagnosis is made by urinary organic acid screening with gas chromatography-mass spectrometry and liquid chromatography, i.e., tandem mass spectrometry [3].

Outcome

There have been reports of significant clinical response with riboflavin; an early diagnosis thus extends an opportunity to modify the clinical course [4].

Take Home Message / Teaching Points

• Unlike other organic acidurias, L-2-HGA commonly has a chronic progressive clinical course, which often leads to delayed diagnosis.
• Awareness of the characteristic imaging pattern in L-2-HGA helps in early diagnosis and targeted metabolic and genetic workup [4].

Written informed patient consent for publication has been obtained.