Krabbe disease

A 7-months-old male child came with complaints of neuroregression and tightening of body while crying since 4 months. The mother also complained of reduced oral feeds with not recognising her. He had never achieved head holding.

MRI brain showed confluent T2/FLAIR hyperintensity in bilateral periventricular white matter, corona radiata, centrum semiovale and posterior limb of internal capsules on both sides. Both thalami appeared small and showed T2 hypointense signal. Thickening of prechiasmatic optic nerves as well as of optic chiasma was observed.

Corpus callosum appeared thin. Both dentate nuclei showed central hilar hyperintensity with mild surrounding T2 hyperintensity, leading to sandwich sign.

On MRS, there was elevation of choline, decrease in NAA and small lipid peak is seen.

Overall imaging findings were consistent with Krabbe’s disease.

Background

Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of galactocerebroside beta-galactosidase.

It is mapped to chromosome 14q (GALC gene). This results in accumulation of sphingosine within the lysosomes of oligodendrocytes and Schwann cells, which results in activation of macrophages and progressive demyelination of central nervous system with variable involvement of peripheral nerves.

Based on the age of onset, they can be further subgrouped into early infantile (<6 months of age), late infantile (7 months- 3 years), juvenile (3-8 years) and adult [1,2].

Clinical Perspective

Adequate birth history, present clinical history and examination is necessary to arrive at a diagnosis.  In an early stage, patient presents with irritability , hypertonicity and regression of psychomotor development. Later stages may present with opisthotonus, hypertonic flexion of limbs, exaggerated DTR and clonic seizures.

Imaging Perspective

There are 4 patterns of white matter involvement that are identified on MRI which are identified based on onset of symptoms.

Pattern 1: T2 hyperintense signal changes in confluent deep and periventricular white matter, Posterior limb of internal capsule (PLIC), Corticospinal tract (CST) in brainstem and deep cerebellar nuclei and hilum of dentate nuclei- this gives it a sandwich appearance. (Central hilar T2 hyperintensity surrounded by T2 hypointensity surrounded by T2 hyperintensity)(Infantile)

Pattern 2: T2 hyperintense signal in confluent posterior periventricular region and deep white matter changes with splenial involvement. (Juvenile and adult)

Pattern 3: Isolated CST involvement with mild CC and cerebral atrophy. (Juvenile and adult)

Pattern 4: Non-confluent deep white matter signal changes in frontal and posterior distribution without CST/cerebellar involvement. (Juvenile and adult)

Thalamic and basal ganglia atrophy is noted predominantly with hypointense signal in thalamus.

Optic nerve thickening was seen in infantile group of patients.

No significant diffusion restriction is seen.

MRS shows decrease in NAA and increase in choline [3].  

Outcome

Palliative and supportive care are the only treatment. Hematopoietic Stem Cell Transplant  may be considered in patients diagnosed early or asymptomatic patient.

Take-Home Message/Teaching Points

Bilateral T2/FLAIR hyperintensity in corticospinal tracts with associated optic nerve thickening and sandwich sign in dentate nucleus is highly sensitive for diagnosis of Krabbe disease.  Early diagnosis is important as early diagnosis will result in adequate management of disease. 

Clinical and radiological correlation is necessary for diagnosis. Gold standard for diagnosis is deficiency of galactocerebroside beta-galactosidase.