Metabolic disorders mimic hereditary spastic paraplegia in Egyptian children

A cross-sectional study of 10 Egyptian patients with progressive spastic paraplegia found that their symptoms were linked to nine different inherited metabolic genes rather than to a single form of hereditary spastic paraplegia (HSP). Researchers at Ain Shams University combined clinical assessment, biochemical testing, targeted metabolic gene sequencing and whole-exome sequencing. All 10 participants received a molecular diagnosis, including eight with homozygous variants and two with compound heterozygous variants. The findings show how neurometabolic disorders can resemble HSP in children and adolescents, while also illustrating why symptoms alone or routine metabolic screening may not be enough to identify the underlying cause.

The cohort included patients evaluated between November 2025 and April 2026 at the Metabolic Clinic in the Department of Medical Genetics at Ain Shams University. Participants ranged from 1.9 to 17 years old, and all presented with progressive spastic paraplegia, with lower-limb spasticity as the predominant feature. Median symptom onset was 1.8 years, whereas the median age at diagnosis was 9.25 years, indicating a substantial interval between the appearance of neurological symptoms and molecular confirmation. Eight of the 10 patients were born to consanguineous parents. Gait disturbance occurred in nine patients, spasticity in all 10, and psychomotor regression or cognitive impairment in four each.

The researchers identified variants in nine disease-associated genes: SLC25A15, MTHFR, ARG1, OPA3, MOCS2, ETHE1, PANK2, C19orf12 and MTR. Under American College of Medical Genetics and Genomics criteria, three variants were classified as pathogenic, four as likely pathogenic and four as variants of uncertain significance. Seven of the 11 variants were reported as novel. Eight patients carried homozygous variants, while two had compound heterozygous variants. Genetic diagnoses were established by whole-exome sequencing in eight cases and by the CentoMetabolic targeted panel in two. The study was small and descriptive, and the authors noted that the clinical significance of the four variants of uncertain significance still requires additional functional or segregation evidence.

One 17-year-old boy had a homozygous likely pathogenic SLC25A15 frameshift variant associated with hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, or HHH syndrome. He had developed normally but experienced protein aversion and recurrent vomiting at 15 months, followed by progressive falls, toe-walking and a shuffling gait from age 10. His examination showed microcephaly, lower-limb wasting, spasticity, hyperreflexia and extensor plantar responses. Routine metabolic tests, urine organic acids, venous blood gas and neuroimaging were unremarkable. Protein restriction, sodium benzoate, L-arginine hydrochloride and baclofen were associated with clinical stability and mild improvement in spasticity.

Two siblings, a 7-year-old girl and a 15-year-old boy, were diagnosed with arginase-1 deficiency caused by the same homozygous likely pathogenic ARG1 variant, c.947G>A, p.(Arg316Gln). Both had progressive gait disturbance, spasticity, protein aversion and cognitive decline. Their plasma arginine concentrations were markedly elevated at 682 and 590 micromoles per litre, respectively, despite normal ammonia levels. Rigorous dietary protein restriction reduced arginine concentrations in the girl to 131 micromoles per litre, with reported improvement in cognition, speech and development. The boy also received dietary restriction and baclofen, and the diagnosis of the second sibling was facilitated after evaluation of the first.

Several cases showed that normal initial metabolic results did not exclude a metabolic disorder. A 12-year-old girl with a homozygous MTHFR variant of uncertain significance had severe hyperhomocysteinemia of 288 micromoles per litre, low methionine of 3.5 micromoles per litre and normal methylmalonic acid. Magnetic resonance imaging showed cerebral atrophy and demyelinating changes. Betaine therapy reduced total homocysteine to 114 micromoles per litre, with biochemical improvement and clinical stabilization. A 4-year-old boy with ethylmalonic encephalopathy had normal ammonia, lactate and extended metabolic screening but showed high-anion-gap metabolic acidosis and a deep right temporal cyst. Whole-exome sequencing found compound heterozygous ETHE1 variants, and treatment with L-carnitine, riboflavin, coenzyme Q10, sodium bicarbonate and metronidazole was followed by gradual developmental improvement.

Other diagnoses extended beyond the urea-cycle and remethylation disorders. A 1.9-year-old girl with a homozygous pathogenic MOCS2 variant had molybdenum cofactor deficiency type B. She developed seizures, dystonia and coma during a febrile gastroenteritis at 10 months, followed by developmental regression, recurrent metabolic decompensation, growth failure, microcephaly and generalized hypertonia. Management included a protein-restricted diet, levetiracetam, trihexyphenidyl and biperiden; during follow-up, seizure control improved and she gradually acquired new developmental milestones. A 5-year-old boy with optic atrophy, developmental regression and spasticity carried a homozygous OPA3 variant of uncertain significance consistent with Costeff syndrome. His urinary organic acid analysis was normal, and he was lost to follow-up, limiting further clinical and biochemical assessment.

Two patients were diagnosed with disorders associated with abnormal brain iron accumulation. An 8.5-year-old boy with a homozygous PANK2 variant of uncertain significance had toe-walking and visual difficulty from 18 months, followed by night blindness, cone-rod dystrophy, progressive stiffness, dystonia, dysarthria and dysphagia. Magnetic resonance imaging showed bilateral globus pallidus abnormalities with the characteristic “eye-of-the-tiger” sign, and ophthalmological testing confirmed severe rod and cone dysfunction. He was receiving supportive physical and occupational therapy. A 13-year-old boy with a homozygous pathogenic C19orf12 frameshift variant had gait difficulty, falls, toe-walking, speech disturbance and progressive motor impairment. MRI showed basal ganglia involvement, while ophthalmological testing identified optic disc pallor, retinal nerve fiber layer thinning and rod dystrophy, supporting a diagnosis of mitochondrial membrane protein-associated neurodegeneration.

A 15.5-year-old boy with delayed speech, poor school performance, progressive hyperpigmentation, lower-limb hypertonia and hyperreflexia had elevated plasma homocysteine of 150 micromoles per litre but normal methylmalonic acid. Whole-exome sequencing identified compound heterozygous MTR variants, one pathogenic and the other likely pathogenic, confirming methionine synthase deficiency, also called cblG-type homocystinuria. He was treated with hydroxocobalamin, betaine anhydrous, L-carnitine and folic acid. After adherence to treatment, biochemical measures improved, his hyperpigmentation faded and his academic performance improved. Across the cohort, abnormal metabolic profiles were found in only five patients, reinforcing the study’s central observation that a normal metabolic screen does not rule out an inherited metabolic cause of spastic paraplegia.

The authors emphasize that combining biochemical profiling with genomic testing may reveal treatable diseases hidden behind an HSP-like presentation. The approach was especially important in this cohort, where 80 percent of patients had consanguineous parents and several diagnoses were reached only after years of neurological progression. The researchers identified cost and limited access to genomic testing in local hospitals as contributors to diagnostic delay. Their results do not establish that every child with spasticity has a metabolic disorder, nor do they demonstrate that sequencing improves long-term outcomes in a controlled comparison. Instead, the cohort provides descriptive evidence that inherited metabolic diseases can produce progressive spastic paraplegia and that molecular testing may identify disorders missed by clinical appearance or routine screening alone. The four variants of uncertain significance also mean that some genetic interpretations remain provisional, reinforcing the need for further investigation.

Subject of Research: Inherited metabolic diseases presenting as hereditary spastic paraplegia in an Egyptian pediatric and adolescent cohort

Article Title: Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients

Article References: Khalifa, O. A., Youssef, T. M., & Mahmoud, R. G. (2026). Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients. Frontiers in Genetics, 17, Article 1963118. https://doi.org/10.3389/fgene.2026.1963118

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1963118

Keywords: hereditary spastic paraplegia, inborn errors of metabolism, neurometabolic disorders, whole-exome sequencing, metabolic gene panels, childhood spasticity, consanguinity, rare diseases, Egypt, genetic diagnosis, Inherited, metabolic