CYP2U1 – SPG56/Hereditary Spastic Paraplegia 56

Hereditary spastic paraplegia 56 (SPG56, MONDO:0014015) is a rare autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia (HP:0007020). Biallelic pathogenic variants in CYP2U1 (HGNC:20582) underlie SPG56, establishing a definitive gene–disease relationship.

Autosomal recessive inheritance is consistently observed, with at least 8 probands across 4 unrelated families harboring CYP2U1 loss-of-function variants. In an Italian consanguineous kindred, homozygous c.1168C>T (p.Arg390Ter) segregated with disease in three siblings (PMID:26914923). A sporadic SPG56 case carried compound heterozygous truncating variants c.5C>A (p.Ser2Ter) and c.1288+5G>C (PMID:26936192). Two Chinese brothers with c.471del (p.Ile158fs) exhibited cerebral folate deficiency amenable to folinic acid therapy (PMID:38058766). Two unrelated Iranian patients presented biallelic frameshift and nonsense mutations (e.g., c.651del (p.Phe218fs)) (PMID:27292318).

The variant spectrum includes stop-gains (n=4), frameshift deletions (n=5) and splice-site changes (n=1) affecting the conserved P450 heme-binding domain. No recurrent founder alleles have been documented.

Functional assays demonstrate that missense variants such as c.784T>G (p.Cys262Gly) abolish CYP2U1 enzymatic activity due to impaired heme binding and protein destabilization in HEK293T cells (PMID:29034544). Folinic acid supplementation stabilized neurologic function in two patients with cerebral folate deficiency, underscoring a treatable metabolic component of SPG56 (PMID:38058766).

No conflicting reports dispute the CYP2U1–SPG56 association; all pathogenic alleles demonstrate loss-of-function concordant with a haploinsufficiency mechanism.

Collectively, the robust segregation data, case series and concordant functional findings support a Strong clinical validity classification for CYP2U1 in SPG56. Genetic testing of CYP2U1 is recommended for diagnosis, prognostication and therapeutic decision-making, particularly given the potential benefit of folinic acid supplementation.

References

• Journal of neurology • 2016 • Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/CYP2U1 family. PMID:26914923
• European journal of paediatric neurology • 2016 • Hereditary spastic paraplegia: Novel mutations and expansion of the phenotype variability in SPG56. PMID:26936192
• Molecular genetics and metabolism reports • 2024 • CYP2U1: An emerging treatable neurometabolic disease with cerebral folate deficiency in 2 Chinese brothers. PMID:38058766
• European journal of paediatric neurology • 2016 • CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia. PMID:27292318
• Human mutation • 2018 • CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56. PMID:29034544

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