Dystonia as an early and prominent feature in a patient with CYP2U1 gene mutation: expanding the phenotype of SPG56-a case report

Hereditary Spastic Paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Among them, Spastic Paraplegia Type 56 (SPG56) is a rare autosomal recessive form caused by CYP2U1 mutations. While spasticity is the hallmark of SPG56, recent reports have shown expanding phenotypic variability, including dystonia. We report an 8-month-old Arab male who presented with generalized tonic seizures and abnormal head movements, later identified as dystonic in nature. MRI revealed cerebral atrophy and delayed myelination. Given the early symptom onset and unexplained neurodevelopmental presentation, exome-based next-generation sequencing was performed. This identified a homozygous missense variant in CYP2U1 (c.947 A > T; p.Asp316Val), classified as likely pathogenic. This variant has previously been associated with SPG56 but rarely with dystonia as a predominant feature. Over 6 months of follow-up, seizure frequency decreased markedly and dystonia improved substantially on sodium valproate and levetiracetam, although mild dystonic movements persisted and no lower-limb spasticity was observed. This case highlights the diagnostic value of exome-based genetic testing in unexplained early-onset neurodevelopmental disorders. It also underscores the phenotypic heterogeneity of SPG56 and suggests that dystonia may, in some cases, be an early and dominant manifestation of CYP2U1-related pathology. Reporting such rare presentations is essential to broaden our understanding of the clinical spectrum of CYP2U1 mutations.