Expansion of the genetic and phenotypic spectrum of hereditary spastic paraplegia caused by ABHD16A gene variants: an integrated analysis based on novel variants and literature review

TL;DR

This paper expands the known genetic and clinical features of a rare neurodevelopmental disorder linked to the ABHD16A gene, including a new case from a Chinese patient.

Contribution

The study reports the first Chinese case of ABHD16A-related disorder and identifies a novel metabolic abnormality associated with the condition.

Findings

Elevated long-chain acylcarnitines were observed in a patient with ABHD16A variants, a previously unreported metabolic abnormality.

Two novel compound heterozygous frameshift variants in ABHD16A were identified and classified as pathogenic.

A literature review of 17 additional cases refined the clinical features of ABHD16A-related disease.

Abstract

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder. Biallelic pathogenic variants in ABHD16A have recently been linked to a neurodevelopmental phenotype featuring early-onset spasticity and global developmental delay.

To further define the clinical and genetic spectrum of ABHD16A-associated disease through the characterization of a novel pediatric case and an updated literature review.

We evaluated a child presenting with global developmental delay and progressive spastic paraplegia. Whole-exome sequencing (WES) was performed, and candidate variants were validated by Sanger sequencing. Clinical features were documented prospectively, and a systematic review of published cases was conducted to assess phenotypic patterns and genotype–phenotype relationships.

Consistent with prior reports, the core features of ABHD16A-related disease include global developmental delay, intellectual disability, and spastic paraplegia, often with early onset. In our patient, tandem mass spectrometry revealed elevated long-chain acylcarnitines (C16, C18:1, C18:2)—a metabolic abnormality not previously described in this condition. WES identified two novel compound heterozygous frameshift variants in ABHD16A: c.119delA (p.His40Leufs49) and c.559_562del (p.Pro187Cysfs29), both confirmed by Sanger sequencing and classified as pathogenic (ACMG criteria: PVS1, PM2, PM3, PP1). Our literature review identified 17 additional individuals from 9 families, enabling a refined clinical delineation: most patients exhibited motor and speech delay, axial hypotonia evolving into spasticity, and variable degrees of cognitive impairment.

To our knowledge, this is the first reported case of ABHD16A-related neurodevelopmental disorder in a Chinese patient. We provide a detailed phenotypic characterization and an updated review of the published literature to support clinical recognition and genetic diagnosis of this emerging condition.

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