MFSD8-Related CLN7 Disease with Adult-Onset Cerebellar Ataxia: A Five-Patient Case Series

Adult-onset recessive cerebellar ataxias comprise a heterogeneous group of disorders.

To describe a founder MFSD8 variant in adult-onset cerebellar ataxia.

We describe three unrelated Indian patients and one sibling pair (n = 5; median age 31 years) who exhibited progressive gait ataxia, limb dysmetria, titubation, gaze-evoked nystagmus, hypermetric saccades, and brisk reflexes without seizures, cognitive decline, visual impairment, or autonomic dysfunction. Brain MRI revealed moderate cerebellar atrophy.

They were all homozygous for MFSD8 c.935T>C(p.Ile312Thr) presenting with pure cerebellar syndrome in the third decade. This ultra-rare p.Ile312Thr variant was predicted as deleterious by in silico tools and absent in homozygous state in population databases. Runs of homozygosity indicated a shared ~1.3-12Mbp haplotype with a common ancestor ~620 years ago.

These findings expand MFSD8-related CLN7 disease to include adult-onset isolated ataxia and support inclusion of MFSD8 in adult ataxia gene panels, particularly in South Asian populations.