Novel GALC Deletion and Paradoxical Optic Nerve Hypertrophy in Severe Infantile Krabbe Disease

Case

A 9-month-old girl, born to non-consanguineous parents, presented with developmental regression beginning at 3 months of age, with progressive irritability, seizures, feeding difficulty, and spasticity. She had an unremarkable perinatal period with a birth weight of 3.5 kg. Her early development was normal, and she had attained partial neck control, turning to the side, hand movements, and a social smile by 3 months of age. Subsequently, she gradually developed irritability, feeding problems, generalized seizures, and progressive stiffness of limbs. By 6 months, she had no voluntary movements or visual fixation. On examination, she had severe microcephaly (38.5 cm, −5.7 z), was severely underweight (4.7 kg, −3.8 z) and stunted (56 cm, −4.6 z), generalized spasticity, hypotonia in distal lower limbs, areflexia, and bilateral optic atrophy. Magnetic resonance imaging (MRI) revealed prechiasmatic optic nerve hypertrophy with diffuse cerebral and cerebellar atrophy with leukodystrophy ([Fig. 1A–F]). Nerve conduction study showed demyelinating polyneuropathy in the lower limbs. Whole exome sequencing identified a novel, homozygous, likely pathogenic, multinucleotide exonic deletion (NM_000153.4) [g.(87968491_87976357)_(87976489_87982204]del, [c.(621 + 1_622–1)_(752 + 1_753–1); ENST00000261304.7] in the GALC gene on chromosome 14, which results in the complete deletion of exon 7 starting within intron 6 and extending to intron 7, and causing a frameshift effect, confirming the diagnosis of Krabbe disease (KD). Segregation analysis could not be done due to financial constraints. The child succumbed to illness 2 months later following aspiration during feeding at home.

Fig. 1 Axial T2-weighted magnetic resonance images (A–F) showing bilateral symmetrical changes involving cerebral white matter, posterior limb of internal capsule and cerebellar white matter. Altered signal intensity is also seen along corticospinal tract and entire corpus callosum, and prominent thickening of the prechiasmatic optic nerves in axial T2 (C) and oblique sagittal reformatted image of three-dimensional FLAIR image (D). We also note the diffuse cerebral and cerebellar atrophy.

KD is the prototypic, infantile-onset leukodystrophy with a relentless progression and early death. The typical clinical and radiological findings, as above, enable a bedside diagnosis.[1] Optic nerve hypertrophy occurs secondary to the accumulation of the multinucleated globoid cells, perineural edema, and reactive astrocytosis preceding axonal loss, explaining the paradox of enlargement rather than the atrophy typically expected in leukodystrophies.[2] [3] This atypical enlargement may occasionally be seen in other cranial nerves, peripheral nerves, bilateral brachial plexus, and cauda equine nerve roots.[4] [5] This phenotype-linked but mutation-non-specific finding assists early diagnosis. Large GALC deletions, including multiexon losses, are strongly associated with severe early-infantile forms.[6] However, no single pathogenic GALC variant has been shown to have a direct mechanistic association with optic nerve hypertrophy. Our case broadens the genotype–phenotype correlation for KD and highlights the unique paradox of prechiasmatic optic nerve enlargement/hypertrophy in contrast to the cerebral atrophy typically seen in severe KD.

Contributors' Statement

Y.S.: Conceptualization, data curation, formal analysis, funding acquisition, writing–original draft, writing–review and editing. A.R.: Data curation, formal analysis, investigation, writing–review and editing. S.V.: Data curation, formal analysis, validation, writing–review and editing. A.G.S.: Conceptualization, data curation, formal analysis, funding acquisition, supervision, validation, writing–original draft, writing–review and editing.

Publication History

Received: 01 December 2025

Accepted: 23 January 2026

Article published online:
04 February 2026

• References

• 1 Hussain SA, Zimmerman HH, Abdul-Rahman OA, Hussaini SM, Parker CC, Khan M. Optic nerve enlargement in Krabbe disease: A pathophysiologic and clinical perspective. J Child Neurol 2011; 26 (05) 642-644
• 2 Patel B, Gimi B, Vachha B, Agadi S, Koral K. Optic nerve and chiasm enlargement in a case of infantile Krabbe disease: Quantitative comparison with 26 age-matched controls. Pediatr Radiol 2008; 38 (06) 697-699
• 3 Sharawat IK, Saini AG, Vyas S, Sankhyan N. Cystic changes and optic nerve hypertrophy in early infantile neuroregression. Indian J Pediatr 2019; 86 (09) 863-864
• 4 Beslow LA, Schwartz ES, Bönnemann CG. Thickening and enhancement of multiple cranial nerves in conjunction with cystic white matter lesions in early infantile Krabbe disease. Pediatr Radiol 2008; 38 (06) 694-696
• 5 Hiyama T, Masumoto T, Hara T. et al. Enlargement of the brachial plexus on magnetic resonance imaging: A novel finding in adult-onset Krabbe disease. BJR Case Rep 2016; 2 (03) 20150213
• 6 Irahara-Miyana K, Enokizono T, Ozono K, Sakai N. Exonic deletions in GALC are frequent in Japanese globoid-cell leukodystrophy patients. Hum Genome Var 2018; 5 (01) 28