Genotypic and phenotypic spectrum of hereditary spastic paraplegia 56: insights from novel CYP2U1 variants and a literature review

Hereditary spastic paraplegia type 56 (HSP56) is a rare, autosomal recessive neurodegenerative disorder caused by pathogenic variants in the CYP2U1 gene which encodes a cytochrome P450 enzyme that is critical for fatty acid metabolism and mitochondrial function. Herein, we explore the diagnosis and management of three patients with novel variants in CYP2U1 and review the literature on phenotype-genotype correlations in CYP2U1-related disorders. Through whole-genome sequencing and targeted validation by Sanger sequencing, we identified novel causative CYP2U1 variants in three female patients from two families who presented with early-onset spastic paraplegia. Twin sisters of Middle Eastern descent were found to carry a novel, homozygous in-frame deletion, c. 367₃75del (p. Gly123Tyr125del), that was predicted to disrupt CYP2U1 protein structure and enzymatic stability. A third patient of South Asian descent carried a homozygous missense variant in CYP2U1, c. 1355 A > T (p. Asp452Val), also not previously reported in public databases. This patient also had axonal sensory motor polyneuropathy. Clinically, all the patients presented with progressive lower-limb spasticity and delayed motor milestones. Cognitive impairment and brain magnetic resonance imaging (MRI) findings of hypomyelination were observed in both twins, but not in the third patient. Comprehensive metabolic panels for all three patients showed no evidence of folate deficiency. A literature review revealed no genotype–phenotype correlation for CYP2U1, as both truncating and missense variants can present with clinical findings of variable severity and age of onset. These findings document the CYP2U1 genotypic and phenotypic spectrum and reinforce the need for early recognition and metabolic monitoring for patients with HSP56. Further studies are warranted to evaluate whether interventions targeting nutrition or mitochondrial function can improve outcomes in CYP2U1-related neurodegeneration.