Autophagy reportsSep 12, 2026

A new VPS16 gene change blocks cell recycling and causes early-onset DYT-VPS16 movement disorder

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 14, 2026

Abstract

A child with infantile-onset generalized dystonia was found to have a de novo VPS16 missense variant, p. Ala466Thr.

Heterozygous loss-of-function variants in VPS16 are linked to autosomal dominant DYT-VPS16 dystonia.
Fibroblasts from the patient display enlarged, stalled autolysosomes, indicating a disruption in the degradation process.
There is an elevation of SQSTM1/p62 levels and a higher MAP1LC3B/LC3B-II:LC3B-I ratio, suggesting a blockage in autophagic activity.
Neuroimaging revealed a previously unrecognized caudate-predominant pattern associated with this condition.
Striatal neurons may be particularly vulnerable to dysfunction in the .

Simplified

terminates in the degradation of cargo delivered by fusion of the autophagosome with the lysosome, a step tethered by the homotypic fusion and vacuole protein sorting (HOPS) complex. Heterozygous loss-of-function variants in VPS16, which encodes a core HOPS subunit, cause autosomal dominant DYT-VPS16 dystonia. The pathogenicity of missense alleles has remained uncertain due to a lack of mechanistic data from patient-derived cells. We summarize our recent report of the youngest individual with DYT-VPS16 described to date. This child presented with infantile-onset generalized dystonia caused by a de novo VPS16 missense variant, p. Ala466Thr. Patient-derived fibroblasts accumulate enlarged, stalled autolysosomes and show concurrent elevation of SQSTM1/p62 and the MAP1LC3B/LC3B-II:LC3B-I ratio, consistent with a block in autophagic flux. We discuss the consequences for variant interpretation, describe a previously unrecognized caudate-predominant neuroimaging correlate, and speculate on why striatal neurons are selectively vulnerable to HOPS dysfunction. Abbreviations: HOPS: homotypic fusion and vacuole protein sorting; LOF: loss-of-function; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; SQSTM1: sequestosome 1.

Key numbers

9 months

Earliest DYT-VPS16 Onset

Age at which the patient first exhibited symptoms.

significantly elevated

Elevated SQSTM1/p62 Level

Indicates impaired autophagic flux in patient-derived fibroblasts.

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A new VPS16 gene change blocks cell recycling and causes early-onset DYT-VPS16 movement disorder

Abstract

Key numbers

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