Spastic Paraplegia 5A via the CYP7B1 Gene

Spastic paraplegia 5A (SPG5A) is a type of hereditary spastic paraplegia (HSP) with a wide phenotypic spectrum (Lo Giudice et al. 2014). Some SPG5A patients have “pure” spastic paraplegia, i.e., the symptoms are primarily limited to lower limb weakness and spasticity. While in other patients, the clinical feature is complicated by distal muscle atrophy, axonal neuropathy, cerebellar ataxia, and white matter abnormalities on brain MRI (Biancheri et al. 2009; Criscuolo et al. 2009; Arnoldi et al. 2012). The age at onset of SPG5A ranges from 4-47 years (Wilkinson et al. 2003; Goizet et al. 2009).

SPG5A is inherited in an autosomal recessive (AR) manner. This disorder makes up approximately 5%-10% of AR HSP (Arnoldi et al. 2012; Denora et al. 2013; Lo Giudice et al. 2014). SPG5A is caused by pathogenic variants in the CYP7B1 gene. Pathogenic variants in this gene include missense, nonsense, splicing and frame shift variants (Human Gene Mutation Database).

CYP7B1 encodes cytochrome P450 oxysterol 7-alpha-hydroxylase (CYP7B1), an enzyme that regulates the cholesterol catabolic pathway to convert cholesterol to bile acids (Tsaousidou et al. 2008). The abnormal cholesterol metabolism in the brain is believed to be involved in the pathogenicity of SPG5A (Mignarri et al. 2014).

SPG3A is allelic with another autosomal recessive disorder, congenital bile acid synthesis defect 3. To date, two homozygous pathogenic variants have been identified to cause severe cholestasis (Setchell et al. 1998; Ueki et al. 2008).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. All the reported pathogenic variants in CYP7B1 can be detected by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CYP7B1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.