ABHD16A and Hereditary Spastic Paraplegia

This summary describes the compelling association between ABHD16A (HGNC:13921) and hereditary spastic paraplegia (MONDO_0019064). Evidence arises from independent reports including a case study from a Chilean family (PMID:34866177), a multi‐patient study with 11 affected individuals from six unrelated families (PMID:34587489), and another study involving two consanguineous Sudanese families with four patients (PMID:34489854).

Genetic evidence consistently supports an autosomal recessive inheritance pattern. In the case report, a homozygous nonsense variant was identified in two affected siblings, and subsequent studies have revealed biallelic deleterious variants segregating in affected families. Cumulatively, approximately 17 probands from independent cohorts have been documented (PMID:34866177; PMID:34587489; PMID:34489854), with additional affected relatives further supporting the segregation of variants within families.

The variant spectrum includes both missense and nonsense changes. Notably, the variant c.835C>T (p.Gln279Ter) was reported in the initial study and is representative of the deleterious events found in ABHD16A. This variant meets the required HGVS nomenclature criteria and exemplifies the loss‐of‐function alleles contributing to the phenotype.

Functional studies have demonstrated a reduction or absence of ABHD16A protein in patient fibroblasts, as evidenced by immunoblot analysis (PMID:34587489). These findings support a loss‐of‐function mechanism in which the deficit in ABHD16A activity leads to lipid metabolic disturbances, aligning with the clinical features observed in affected individuals.

There is minimal conflicting evidence regarding this gene–disease association. Although one study mentioned complex hereditary spastic paraplegia (MONDO_0015150), the bulk of the data robustly support an association with hereditary spastic paraplegia (MONDO_0019064).

In conclusion, the integration of genetic and functional evidence indicates a strong association between ABHD16A variants and hereditary spastic paraplegia. This association bears significant clinical utility in diagnostic decision-making, guiding targeted genetic testing for patients with spasticity, developmental delay, and related neurological abnormalities.

Key Take‑home Sentence: ABHD16A loss‐of‐function variants represent a robust molecular marker for hereditary spastic paraplegia, thus informing both clinical management and future research.

References

• Clinical Genetics • 2022 • A homozygous ABHD16A variant causes a complex hereditary spastic paraplegia with developmental delay, absent speech, and characteristic face PMID:34866177
• American Journal of Human Genetics • 2021 • ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies PMID:34587489
• Frontiers in Neurology • 2021 • Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia PMID:34489854

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