Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients
- 1Department of Medical Genetics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- 2Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Abstract
Background: Inborn errors of metabolism (IEMs) are a rare and often underrecognized cause of spastic paraplegia in children and adults.Owing to their high energy demands and long axons, motor neurons and the corticospinal tracts are particularly vulnerable to metabolic defects. Consequently, several potentially treatable neurometabolic disorders can mimic both pure and complex hereditary spastic paraplegia (HSP). Although spasticity is a shared hallmark, these disorders differ in their genetic etiology, metabolic profiles, clinical manifestations, and treatment responses.
Methods: We investigated 10 Egyptian patients with spastic paraplegia as the core clinical feature using an integrated approach combining clinical assessment, biochemical profiling, and molecular diagnostics.
Results: We identified (3) pathogenic, (4) VUS, and (4) likely pathogenic variants in nine disease-causing genes (SLC25A15, MTHFR, ARG1,OPA3, MOCS2, ETHE1, PANK2, C19orf12, and MTR), including eight homozygous and two compound heterozygous genotypes, with seven novel variants. Patients’ ages ranged from 1.9 to 17 years, with a median symptom onset of 1.8 years and median diagnosis age of 9.25 years. Most of the patients (80%) were born to consanguineous parents. Gait disturbance/spasticity was the most common presenting feature (90%; 100% respectively). Abnormal Metabolic profile was reported in (5/10, 50%).
Conclusion: Our findings highlight the value of integrated metabolic and genomic investigations in unexplained spastic paraparesis. Early molecular diagnosis enables precise disease identification, targeted therapy, and improved outcomes.
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BibTeX
@article{khalifa2026inherited,
title = {{Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients}},
author = {Ola A. Khalifa and Tarek M. Youssef and Radwa G. Mahmoud},
journal = {Frontiers in Genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1963118},
url = {https://doi.org/10.3389/fgene.2026.1963118},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients
AU - Ola A. Khalifa
AU - Tarek M. Youssef
AU - Radwa G. Mahmoud
PY - 2026
DA - 2026/10/22
JO - Frontiers in Genetics
DO - 10.3389/fgene.2026.1963118
UR - https://doi.org/10.3389/fgene.2026.1963118
AB - Background: Inborn errors of metabolism (IEMs) are a rare and often underrecognized cause of spastic paraplegia in children and adults.Owing to their high energy demands and long axons, motor neurons and the corticospinal tracts are particularly vulnerable to metabolic defects. Consequently, several potentially treatable neurometabolic disorders can mimic both pure and complex hereditary spastic paraplegia (HSP). Although spasticity is a shared hallmark, these disorders differ in their genetic etiology, metabolic profiles, clinical manifestations, and treatment responses. Methods: We investigated 10 Egyptian patients with spastic paraplegia as the core clinical feature using an integrated approach combining clinical assessment, biochemical profiling, and molecular diagnostics. Results: We identified (3) pathogenic, (4) VUS, and (4) likely pathogenic variants in nine disease-causing genes (SLC25A15, MTHFR, ARG1,OPA3, MOCS2, ETHE1, PANK2, C19orf12, and MTR), including eight homozygous and two compound heterozygous genotypes, with seven novel variants. Patients’ ages ranged from 1.9 to 17 years, with a median symptom onset of 1.8 years and median diagnosis age of 9.25 years. Most of the patients (80%) were born to consanguineous parents. Gait disturbance/spasticity was the most common presenting feature (90%; 100% respectively). Abnormal Metabolic profile was reported in (5/10, 50%). Conclusion: Our findings highlight the value of integrated metabolic and genomic investigations in unexplained spastic paraparesis. Early molecular diagnosis enables precise disease identification, targeted therapy, and improved outcomes.
SN - 1664-8021
ER -