Imaging hallmarks of late-infantile onset Krabbe’s disease: Case-based insights - A case report

INTRODUCTION

Krabbe disease (globoid cell leukodystrophy) is a progressive neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC), resulting in extensive demyelination in the central and peripheral nervous systems.^[1] The infantile form, which is the most common and severe, typically presents within the 1^st year of life with irritability, spasticity, feeding difficulties, and developmental regression.^[2] Neuroimaging and electrophysiological studies play a pivotal role in early diagnosis, which is essential for considering disease-modifying interventions.^[3]

CASE REPORT

A 10-month-old female presented with poor feeding, global developmental delay, and central hypotonia. She did not have any vision complaints. Her birth history was unremarkable, with no neonatal intensive care unit admission or perinatal complications. Family history was insignificant. Initial clinical impression included neuromuscular disorder or congenital hypotonia. Sensory and motor nerve conduction studies demonstrated electrophysiological evidence of motor demyelinating polyneuropathy, consistent with peripheral nervous system involvement. Otoacoustic emission (OAE) screening showed a possible hearing impairment in the right ear, indicating possible cochlear dysfunction or early hearing loss.

Magnetic resonance imaging (MRI) brain revealed bilateral, symmetrical T2 hyperintensity and T1 hypointensity in the periventricular white matter of the cerebral hemispheres, cerebellar white matter, and hilum of the dentate nucleus [Figures 1 and 2]. The subcortical white matter and cortical gray matter appeared normal. The thalamus and optic nerves appeared unremarkable. These findings were suggestive of a leukoencephalopathy. The patient then underwent genetic analysis. Genome sequencing identified a likely pathogenic variant in the GALC gene [Figure 3], suggesting the diagnosis of Krabbe disease.

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Figure 1:

Magnetic resonance imaging of brain in a 10-month-old female with developmental delay. Axial T2-weighted image shows bilateral symmetrical T2 hyperintensity in periventricular white matter in bilateral cerebral hemispheres (black arrows) with sparing of subcortical white matter. Thalami and basal ganglia as well as cerebral cortex appear unremarkable.

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Figure 2:

Magnetic resonance imaging of brain in a 10-month-old female with developmental delay. Coronal T1 weighted image (a) and T2 weighted image (b) show bilateral symmetrical T1 hypointensity and T2 hyperintensity in white matter in cerebral hemispheres (white arrows) and cerebellar hemispheres (black arrows). Bilateral dentate hilum appear T2 hyperintense (blue arrows).

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Figure 3:

Genome analysis report of a 10-month-old female with developmental delay showing Krabbe’s disease. CNV: Copy number variant, OMIM: Online mendelian inheritance in man.

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DISCUSSION

Infantile Krabbe disease presents with rapid neurological deterioration due to both central and peripheral demyelination. Typical magnetic resonance imaging (MRI) findings in Krabbe’s disease can be variable in different phenotypes depending on age of onset-early infantile (EI): <6 months of age, late infantile (LI): 7 months–3 years, juvenile (J): 3–8 years, and adult (A): >9 years.^[4] Findings in EI and LI groups typically include confluent deep cerebral and cerebellar white matter signal changes along with posterior limb of internal capsule and brainstem corticospinal tract (CST) involvement as well as dentate hilum involvement, which is more characteristic of EI onset disease.^[3,4] The Tigroid pattern of involvement of cerebral white matter may or may not be seen. Juvenile and adult groups may show variable imaging patterns, such as confluent posterior deep white matter hyperintensity with or without CST and/or splenial involvement, isolated CST involvement. Rarely, patchy supratentorial white matter and dentate hilum hyperintensities without deep cerebellar white matter involvement may also be seen, usually in the juvenile or adult group.^[4] Involved supratentorial white matter, CST, and corpus callosum may show restricted diffusion. Other typical findings include thalamic volume loss with T2 hypointensity and optic nerve hypertrophy, commonly seen in EI onset (<6 months) disease.^[4] Rare findings such as cervical cord and lower brainstem enlargement, cranial nerve enhancement, and involvement of lateral spinothalamic tract on spine imaging may also be seen.^[4]

The combination of MRI findings – specifically symmetrical periventricular white matter hyperintensities and dentate hilum involvement and polyneuropathy on electrophysiological testing is highly suggestive.^[2,5] The demyelinating motor polyneuropathy observed in this patient aligns with the known peripheral nervous system involvement in Krabbe disease, attributed to psychosine accumulation and Schwann cell dysfunction.^[1] In addition, early auditory pathway involvement, as suggested by OAE screening, is reported in lysosomal storage disorders but is less frequently documented in Krabbe disease.^[6]

Differentials include other infantile leukodystrophies such as metachromatic leukodystrophy and Canavan disease, which can be distinguished based on imaging, enzyme activity, and genetic findings.^[6] Early diagnosis is crucial, as hematopoietic stem cell transplantation may slow disease progression if initiated pre-symptomatically.^[7]

CONCLUSION

This case illustrates the classic imaging and electrophysiological features of infantile-onset Krabbe disease. Integration of MRI, nerve conduction studies, OAE screening, and genomic analysis was key in reaching a timely diagnosis. Awareness of early peripheral and auditory involvement may broaden the clinical suspicion of Krabbe disease in infants with hypotonia and developmental delay.

TEACHING POINTS

1. We should raise a concern about leukodystrophy in pediatric MRI showing bilateral symmetrical periventricular altered signal intensities in the correct clinical setting.

2. Involvement of the thalamus in the form of T2 hypointensity is not necessarily seen in all cases of Krabbe’s disease.

3. There is an importance of genetic testing in confirming or supporting the radiological interpretation in cases of leukodystrophies.

MCQs

1. Which MRI finding is most characteristic of Krabbe’s disease?

   1. Subcortical U-fiber involvement

   2. Symmetrical T2 hyperintensities in periventricular white matter

   3. Diffuse cortical atrophy without white matter changes

   4. Basal ganglia calcifications

   Answer key: b

2. Which of the following is not a finding of infantile-onset Krabbe’s disease?

   1. Symmetrical deep cerebral white matter involvement

   2. Isolated involvement of the corticospinal tract

   3. Dentate hilum hyperintensity

   4. Thalamic hypointensity

   Answer key: b

3. Which of the following areas is not involved in any phenotype of Krabbe’s disease?

   1. Cerebellar white matter

   2. Optic nerve

   3. Posterior limb of internal capsule

   4. Cerebral cortex

   Answer key: d