CYP2U1 – CYP2U1-Related Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a clinically heterogeneous neurodegenerative disorder distinguished by progressive lower-limb spasticity and weakness. Biallelic variants in CYP2U1 underlie SPG56, a rare autosomal recessive subtype of Hereditary spastic paraplegia (PMID:23176821;PMID:26914923). Patients typically present with early-onset spastic paraplegia, but complex features including pigmentary maculopathy, intellectual disability, cerebellar ataxia, dystonia, and delayed myelination have been reported. Short stature and basal ganglia calcifications further broaden the phenotype, indicating multisystem involvement. Visual impairments, such as pigmentary degenerative maculopathy, underscore the need for ophthalmologic evaluation. Recognition of this spectrum is critical to guiding genetic testing and differential diagnosis.

To date, at least 17 individuals from nine unrelated families have been described with autosomal recessive CYP2U1 variants (PMID:26914923;PMID:32006740). Homozygous nonsense variants (e.g., c.1168C>T (p.Arg390Ter)) and compound heterozygous combinations (e.g., c.913C>T (p.His305Tyr)) have been identified via exome or genome sequencing. Segregation analyses in three consanguineous families confirmed co-segregation of pathogenic alleles with disease in multiple affected relatives (PMID:26914923;PMID:31281085;PMID:32006740). Loss-of-function alleles, including frameshift and nonsense mutations, predominate, consistent with a recessive loss-of-function mechanism. A recurrent c.1168C>T (p.Arg390Ter) allele suggests potential population-specific founder effects.

The CYP2U1 variant spectrum encompasses at least 20 distinct alleles: 12 protein-truncating variants, six missense substitutions, and two splice-site changes (PMID:23176821;PMID:29034544). Representative frameshift variants include c.651del (p.Phe218fs) and c.543_544del (p.His182fs), while functionally disruptive missense changes such as c.784T>G (p.Cys262Gly) and c.1462C>T (p.Arg488Trp) have been validated. The predominance of truncating alleles aligns with a loss-of-function disease mechanism. No deep-intronic or large structural variants have been described to date.

Clinically, SPG56 manifests with progressive spastic paraplegia (HP:0007020) frequently accompanied by intellectual disability (HP:0001249), cerebellar ataxia (HP:0001251), and visual impairment (HP:0000505) (PMID:28725025;PMID:27292318). Uncommon findings include pigmentary degenerative maculopathy, basal ganglia calcification (HP:0002135), and delayed myelination (HP:0012448). Dystonia (HP:0001332) and short stature (HP:0004322) further exemplify the phenotypic heterogeneity. Neuroimaging often reveals thinning of the corpus callosum and periventricular white-matter hyperintensities. Overlap with pseudoxanthoma elasticum phenotypes underscores shared pathogenic pathways (PMID:33107650).

Mechanistically, CYP2U1 encodes a brain-expressed cytochrome P450 implicated in fatty acid ω-hydroxylation (PMID:28083596). In vitro assays demonstrate that missense variants (e.g., p.Cys262Gly, p.Arg488Trp) impair heme binding and enzymatic activity, leading to protein destabilization (PMID:29034544). Cellular models reveal mitochondrial architectural alterations, reduced bioenergetic capacity, and increased oxidative stress upon CYP2U1 loss, recapitulating neuronal dysfunction observed in HSP (PMID:23176821). These data support a loss-of-function mechanism underpinning neurodegeneration.

Collectively, the abundance of unrelated cases, robust segregation, and concordant functional data fulfill ClinGen “Strong” criteria for the CYP2U1–Hereditary Spastic Paraplegia association. Further animal models and rescue studies will refine pathogenic insights. Inclusion of CYP2U1 in diagnostic HSP panels—particularly for patients with ocular or cognitive features—will enhance clinical detection. Key take-home: CYP2U1 testing is clinically useful for early and accurate diagnosis of complex HSP56 phenotypes.

References

• American journal of human genetics • 2012 • Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. PMID:23176821
• Journal of neurology • 2016 • Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/CYP2U1 family. PMID:26914923
• European journal of paediatric neurology : EJPN • 2016 • CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia. PMID:27292318
• Journal of human genetics • 2017 • An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination. PMID:28725025
• Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia • 2019 • Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families. PMID:31281085
• Journal of the neurological sciences • 2020 • Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia. PMID:32006740
• Human mutation • 2018 • CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56. PMID:29034544
• Journal of internal medicine • 2021 • Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56. PMID:33107650
• Cellular and molecular life sciences • 2017 • Cytochrome P450 2U1, a very peculiar member of the human P450s family. PMID:28083596
• BMC neurology • 2025 • Diagnostic journey and genetic analysis of a novel homozygous CYP2U1 mutation causing autosomal recessive spastic paraplegia type 56 (SPG56) in a consanguineous family. PMID:40375209

Evidence Based Scoring (AI generated)