A new mutation in an infant with Krabbe disease accompanied by enlargement of the optic nerves

Excerpt

Krabbe disease is a lysosomal disorder resulting in the accumulation of galactocerebroside and psychosine in macrophages; the condition is associated with demyelination and dysmyelination of the cerebral white matter [1]. A 7-month-old male infant was admitted to our clinic because of hyperirritability that had developed when he was 3 months of age and persisted thereafter. A neurological examination indicated excessive irritability without any accompanying abnormal visual tracking or fixation. The patient had also exhibited poor head control since he was 3 months of age, as well as reduced appendicular and truncal tone. Magnetic resonance imaging (MRI) of the brain revealed bilateral enlargement of the proximal prechiasmatic optic nerves and slight hypertrophy of the chiasmatic optic nerves (Fig. 1). T2-weighted images revealed that the dentate nuclei were hyperintense, accompanied by abnormal T2 prolongation at the posterior limbs of the capsules and in the deep periventricular white matter. Single-voxel MR spectroscopy showed that the N-acetylaspartate level was reduced, and that of choline elevated, in the white matter of the centrum semiovale (Fig. 2). The β-galactosyl-cerebrosidase level was 6.5 nmol/17 h/mg protein (normal 18–115 nmol/17 h/mg protein). Next-generation sequencing of the GALC gene revealed a novel homozygous c.943delG mutation in the proband (our patient). This was predicted to cause a substitution of glutamate 315 by asparagine (p.E315Nfs*10), resulting in a truncated protein. To the best of our knowledge, this mutation has not been reported before. Given the nature of the change caused by the mutation, it is very likely to be disease causing. The Polyphen-2 and Mutation Taster applications predicted that the mutation was disease causing with high probabilities. The Integrative Genomics Viewer display showing the novel homozygous GALC mutation in the proband is shown in Fig. 3. Krabbe disease is caused by various mutations that generally cause galactosylceramide β-galactosidase deficiencies [2]. Optic nerve hypertrophy (in particular hypertrophy of the prechiasmatic and chiasmatic nerves) was previously observed in early-onset (infantile) Krabbe disease patients [3]. Such nerve enlargement has extensive diagnostic implications; the differential diagnoses include retinoblastoma, medulloepithelioma, postviral optic neuritis, juvenile xanthogranuloma, leukemia, histiocytic or granulomatous infiltration, nerve sheath meningioma, and optic nerve glioma with dural ectasia [1, 3]. During differential diagnosis, it is also necessary to consider neurofibromatosis (NF) type 1. Children with NF type 1 generally exhibit developmental delays and seizures, but lack the severe hyperirritability normally associated with Krabbe disease; the former children may also develop various types of skin lesions [3]. Thus, in children with enlarged optic nerves, it is important to consider Krabbe disease during differential diagnosis, particularly if abnormal intracranial findings are evident.

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