Skip to main content

Conference Program

Subpage Hero

Loading

Genome sequencing reveals a novel, homozygous in-frame deletion, c.367_375del, in CYP2U1 in twin sisters with early onset spastic paraplegia

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Hereditary spastic paraplegia (HSP) type 56 is an autosomal recessive disorder associated with pathogenic variants in CYP2U1. The 32 patients previously reported exhibit a variable phenotype including early-onset, progressive spastic paraplegia of the upper and lower limbs, ataxia, dystonia, developmental delays, and intellectual disability, with white matter abnormalities and hypomyelination. Progression in adulthood results in pigmentary degenerative maculopathy. Loss of function variants account for nearly half of reported variants, but missense variants have also been described. Here, we present twins with early-onset HSP and regression caused by a novel homozygous in-frame deletion of CYP2U1

Case Presentation
Twin A and her dizygotic twin sister (B) were the product of a pregnancy with preimplantation genetic diagnosis for an HLA match. The family history was positive for consanguinity. Twin A presented at 2 years with impaired mobility, lower limb spasticity, dystonia, and global developmental delays. She could pull to stand and crawl but never walked. Her language remained limited to single words at 3 years. Examination showed lower limb hypertonia with ankle plantarflexion, patellar and ankle clonus, and dystonia. Brain MRI showed diminished corpus callosum and patchy deep white matter signal abnormality. Twin B presented at 2.5 years with similar findings of lower limb hypertonia, lower extremity clonus, and ankle plantarflexion. She achieved independent walking but lost this ability across 6-8 months. Speech became stagnant at approximately 10 words. Discomfort with hypertonia improved in both twins after starting baclofen and carbidopa-levodopa. Red blood cell and serum folate were above the normal range in both children.

Diagnostic Workup
After consent and clinical chart review, short-read genome sequencing (GS) was performed as part of the CincyKidsSeq study for Twin A using NovaSeq Plus Illumina sequencing to an average depth of 30x. Alignment against reference build 38 and variant calling were performed with Illumina DRAGEN pipeline. Variants were prioritized for review using GEM (Fabric Genomics) and classified for clinical significance based on ACMG guidelines. GS indicated homozygosity for an in-frame deletion of CYP2U1, c.367_375del p.(Gly123_Tyr125del), resulting in the loss of 3 amino acids.  Targeted Sanger sequencing identified biological parents as heterozygous carriers, and Twin B was confirmed to be homozygous.

Treatment and Management
The CYP2U1 gene encodes a member of the cytochrome P450 family and pathogenic variants impaired mitochondrial function and vitamin B hydrolysis in a murine model of Cyp2u1 deficiency. CYP2U1 HSP has previously been associated with reduced folate and treated with folinic acid in one sibling pair, with resultant stabilization of the disorder. However, neither twin had reduced folate levels in blood and folinic acid was not started.

Outcome and Follow-Up
Management plans have been initiated with Neurology, Genetics, Pediatric Rehabilitation, Developmental Pediatrics, and Ophthalmology. Botox injections have been recommended for lower limb hypertonia.

Discussion
The twins have early-onset HSP caused by a novel in-frame deletion in CYP2U1, underscoring the pathogenic potential of in-frame deletions in CYP2U1, a mechanism not previously well-characterized. The observation of increased folic acid in these siblings is interesting as CYP2U1 HSP has previously been associated with reduced folate in one previously reported affected sibling pair. Further data is needed on the relationship between folic acid levels and pathogenicity for CYP2U1 variants in consideration of potentially helpful therapies.

Conclusion
This report expands the phenotypic and molecular spectrum of HSP 56 by documenting the clinical presentation of dizygotic twins with a novel homozygous in-frame deletion in CYP2U1. The observed clinical features align with the known spectrum of CYP2U1 HSP. This case highlights the importance of detailed genetic analysis in clarifying genotype-phenotype correlations and advancing our understanding and management of HSP 56.

Agenda

Sponsors