Heterozygous variants in AP4S1 are not associated with a neurological phenotype
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 clinica...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2025-04-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.52302 |
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| author | Vicente Quiroz Umar Zubair Luca Schierbaum Amy Tam Nicole Battaglia Joshua Rong Habibah A. P. Agianda Julian E. Alecu Kathryn Yang Darius Ebrahimi‐Fakhari |
| author_facet | Vicente Quiroz Umar Zubair Luca Schierbaum Amy Tam Nicole Battaglia Joshua Rong Habibah A. P. Agianda Julian E. Alecu Kathryn Yang Darius Ebrahimi‐Fakhari |
| author_sort | Vicente Quiroz |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8e63b2e2b6a34f6ca4d6431e730ca474 |
| institution | OA Journals |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-8e63b2e2b6a34f6ca4d6431e730ca4742025-08-20T02:20:12ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-04-0112485185410.1002/acn3.52302Heterozygous variants in AP4S1 are not associated with a neurological phenotypeVicente Quiroz0Umar Zubair1Luca Schierbaum2Amy Tam3Nicole Battaglia4Joshua Rong5Habibah A. P. Agianda6Julian E. Alecu7Kathryn Yang8Darius Ebrahimi‐Fakhari9Movement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAMovement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts USAAbstract 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.https://doi.org/10.1002/acn3.52302 |
| spellingShingle | Vicente Quiroz Umar Zubair Luca Schierbaum Amy Tam Nicole Battaglia Joshua Rong Habibah A. P. Agianda Julian E. Alecu Kathryn Yang Darius Ebrahimi‐Fakhari Heterozygous variants in AP4S1 are not associated with a neurological phenotype Annals of Clinical and Translational Neurology |
| title | Heterozygous variants in AP4S1 are not associated with a neurological phenotype |
| title_full | Heterozygous variants in AP4S1 are not associated with a neurological phenotype |
| title_fullStr | Heterozygous variants in AP4S1 are not associated with a neurological phenotype |
| title_full_unstemmed | Heterozygous variants in AP4S1 are not associated with a neurological phenotype |
| title_short | Heterozygous variants in AP4S1 are not associated with a neurological phenotype |
| title_sort | heterozygous variants in ap4s1 are not associated with a neurological phenotype |
| url | https://doi.org/10.1002/acn3.52302 |
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