Clarifying missense variants of uncertain significance in CLN6 Batten disease through the use of skin biopsy – a case report

Objective: To elucidate the role of skin biopsy in establishing a diagnosis of CLN6 Batten disease, an autosomal recessive neurodegenerative lysosomal storage disorder, in the setting of uncertain genetic findings.

Methods: A retrospective review was performed of a 5 year 9 month old female presenting with symptoms suggestive of late-infantile Batten disease.

Results: The proband presented for neurological evaluation after behavioral dysregulation noted at 1 year 10 months, ataxia at around 2 years of age, and generalized myoclonic epilepsy at 4 years of age. She had speech delay and intermittent dysfluency. Examination was notable for hypotonia, myoclonus and lower extremity clonus. Brain magnetic resonance imaging at 5 years 5 months revealed non-specific reduced cerebral and cerebellar volumes and patchy bilateral T2 hyperintensities of periventricular and deep white matter. Fundoscopic exam revealed bilateral mild macular pigment changes. A next-generation sequencing epilepsy panel and subsequent parental testing revealed biallelic variants in CLN6 – a maternally inherited known pathogenic exon 1 deletion and a paternally inherited missense variant of uncertain significance, c.679G>A, p.(Glu227Lys). Exome sequencing did not reveal any additional clinically relevant findings. Skin biopsy was then performed and electron microscopy demonstrated cytoplasmic granular osmiophilic densities and lipofuscin, suggestive of Batten disease.

Conclusions: Skin biopsy remains a relevant tool in the evaluation of Batten disease, and should be considered to help adjudicate variants of uncertain significance especially when treatment would be possible.