Heterozygous variants in <scp><i>AP4S1</i></scp> are not associated with a neurological phenotype

Biallelic loss-of-function variants in AP4S1 cause childhood-onset hereditary spastic paraplegia. A recent report suggested that heterozygous AP4S1 variants lead to a syndrome of lower limb spasticity and dysregulation of sphincter function. We critically evaluate this claim against clinical observations in 28 heterozygous carriers of the same AP4S1 variant (NM_007077.3: c.289C>T, p.Arg97Ter). In these 14 males and 14 females (mean age: 37.6 ± 4.9 years [SD], range: 30-50 years), we ascertain no increased prevalence of neurological manifestations. Alternative causes should be considered when evaluating patients with heterozygous AP4S1 variants and neurological symptoms, as misattribution of pathogenicity can impact clinical care and genetic counseling.

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Publication Details

Journal
Annals of Clinical and Translational Neurology
Published
2025-01-27
DOI
https://doi.org/10.1002/acn3.52302
Primary Topic
Hereditary Neurological Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

Heterozygous variants in AP4S1 are not associated with a neurological phenotype

Kathryn Yang, Amy Tam, Darius Ebrahimi‐Fakhari, Julian E. Alecu et al.
Annals of Clinical and Translational Neurology
Hereditary Neurological Disorders
article

Heterozygous variants in AP4S1 are not associated with a neurological phenotype

Kathryn Yang, Amy Tam, Darius Ebrahimi‐Fakhari, Julian E. Alecu, Vicente Quiroz, Luca Schierbaum, Junkang Rong, Umar Zubair, Habibah A.P. Agianda, Nicole Battaglia
article en

Abstract

Biallelic loss-of-function variants in AP4S1 cause childhood-onset hereditary spastic paraplegia. A recent report suggested that heterozygous AP4S1 variants lead to a syndrome of lower limb spasticity and dysregulation of sphincter function. We critically evaluate this claim against clinical observations in 28 heterozygous carriers of the same AP4S1 variant (NM_007077.3: c.289C>T, p.Arg97Ter). In these 14 males and 14 females (mean age: 37.6 ± 4.9 years [SD], range: 30-50 years), we ascertain no increased prevalence of neurological manifestations. Alternative causes should be considered when evaluating patients with heterozygous AP4S1 variants and neurological symptoms, as misattribution of pathogenicity can impact clinical care and genetic counseling.

Annals of Clinical and Translational NeurologyVol. 12(4)
Boston Children's Hospital (US), Harvard University (US)
International Parkinson and Movement Disorder Society, Spastic Paraplegia Foundation, Deutsche Forschungsgemeinschaft, National Institute of Neurological Disorders and Stroke
Good health and well-being
Openalex Percentile: Top 99%
Hereditary Neurological Disorders
DOIOpen Access PDFOpenAlex
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Heterozygous variants in <scp><i>AP4S1</i></scp> are not associated with a neurological phenotype — Kathryn Yang, Amy Tam, et al. · Annals of Clinical and Translational Neurology (2025) | TGRS Research Map | TGRS