Hereditary spastic paraplegia

Gene: CYP27A1

Green List (high evidence)

CYP27A1 (cytochrome P450 family 27 subfamily A member 1)
EnsemblGeneIds (GRCh38): ENSG00000135929
EnsemblGeneIds (GRCh37): ENSG00000135929
OMIM: 606530, Gene2Phenotype
CYP27A1 is in 28 panels

3 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Amber to Green after clinical advice from Helen Brittain, who agrees that it seems appropriate to include in terms of phenotypic overlap. Sufficient unrelatd cases (>3) to support diagnostic rating.
Created: 14 Jan 2019, 9:35 a.m.
Comment on list classification: Updated rating from Red to Amber awaiting further clinical review. CYP27A1 was added to panel and rated Amber by Chris Buxton (Bristol NHS). Multiple cases from literature of spastic paresis presenting with Cerebrotendinous xanthomatosis (CTX), which is caused by variants in CYP27A1.
Created: 8 Jan 2019, 1:26 p.m.
PMID:29321515 (Sekijima et al, 2018) conducted a Japanese survey on Cerebrotendinous xanthomatosis (CTX). The most common initial symptom was tendon xanthoma, followed next by spastic paraplegia, cognitive dysfunction, cataract, ataxia, and epilepsy.
Created: 8 Jan 2019, 1:21 p.m.
PMID:27455001 (Zhang et al 2017) report a 27 year old male with mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. The patient was found to have a compound het variant in CYP27A1. The article is in Chinese, preventing further reading.
Created: 8 Jan 2019, 1:21 p.m.
PMID:28623566 (Chen et al 2017) investigated clinical symptoms of Chinese CTX patients. Three novel variants of p.Arg513Cys, c.1477-2A>C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in the study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4.
Created: 8 Jan 2019, 1:21 p.m.
PMID:26874936 (Rasafio et al 2016) report 2 Italian siblings from a consanguineous family with Cerebrotendinous xanthomatosis and different phenotypes but the same G-to-A transition causing splicing alteration. The 41 year old male presented with mutacism, spastic tetraparesis, bilateral pes cavus, sialorrhea, progressive dysphagia and head dystonia. Genetic testing of other family members revealed the same variant in a sister who had mild spastic paraparesis amongst her symptoms, and a status of asymptomatic carriers of heterozygous mutation in two sisters.
Created: 8 Jan 2019, 1:21 p.m.
Nicholls (2015, 25862734) describe a 27-year-old man with a 3-year history of spontaneous clonus, leg stiffness and falls (mimicing HSP) and a longer history of urinary disturbance and chronic diarrhoea. The patient was homozygous for a previously reported mutation in exon 6 of the CYP27A1 gene, c.1183C>T, R395W.
Created: 8 Jan 2019, 1:08 p.m.

Sarah Leigh (Genomics England Curator)

Comment on list classification: This gene is awaiting curator evaluation and rating.
Created: 19 Dec 2018, 2:11 p.m.

Chris Buxton (North Bristol NHS Trust)

I don't know

Nicholls (2015, 25862734)
Cerebrotendinous xanthomatosis AR disorder of bile acid metabolism can mimic more common conditions such as hereditary spastic paraparesis, or MS particularly if the phenotype is spinal xanthomatosis where the disease causes a spastic paraplegia
Associated with rased cholestanol. paper describes homozygous, previously reported CYP27A1 variant, c.1183C>T, p.Arg395Trp (R395W)
Diagnostic on Sheffield HSP panel
Sources: Literature
Created: 27 Nov 2018, 4:28 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
progressive lower extremity spasticity,often disproportionate to any degree of weakness

Publications

History Filter Activity

14 Jan 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cyp27a1 has been classified as Green List (High Evidence).

8 Jan 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: CYP27A1 were set to 25862734; 26874936; 28623566; 27455001; 29321515

8 Jan 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: CYP27A1 were changed from progressive lower extremity spasticity,often disproportionate to any degree of weakness to Cerebrotendinous xanthomatosis, 213700; progressive lower extremity spasticity,often disproportionate to any degree of weakness

8 Jan 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cyp27a1 has been classified as Amber List (Moderate Evidence).

8 Jan 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: CYP27A1 were set to 25862734

19 Dec 2018, Gel status: 1

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cyp27a1 has been classified as Red List (Low Evidence).

27 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Chris Buxton (North Bristol NHS Trust)

gene: CYP27A1 was added gene: CYP27A1 was added to Hereditary spastic paraplegia. Sources: Literature Mode of inheritance for gene: CYP27A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP27A1 were set to 25862734 Phenotypes for gene: CYP27A1 were set to progressive lower extremity spasticity,often disproportionate to any degree of weakness Penetrance for gene: CYP27A1 were set to unknown Review for gene: CYP27A1 was set to AMBER