Hereditary spastic paraplegia 56

Summary

Hereditary spastic paraplegia 56 (MONDO:0014015) is a disease caused by CYP2U1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CYP2U1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 48
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002453	Abnormal globus pallidus morphology	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 56
Mondo ID	MONDO:0014015
OMIM	615030
Orphanet	320411
DOID	DOID:0110808
UMLS	C3539507
MedGen	761343
GARD	0017480
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 56 · CYP2U1 hereditary spastic paraplegia · hereditary spastic paraplegia caused by mutation in CYP2U1 · hereditary spastic paraplegia type 56 · spastic paraplegia 56, autosomal recessive · SPG56

Data availability: 48 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › hereditary spastic paraplegia 56

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

48 retrieved; paginated sample, class counts are floors:

15 pathogenic, 10 uncertain significance, 8 likely pathogenic, 7 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068252	NM_183075.3(CYP2U1):c.343G>A (p.Gly115Ser)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686868	NM_183075.3(CYP2U1):c.1391C>G (p.Pro464Arg)	CYP2U1	Pathogenic	no assertion criteria provided
1686869	NM_183075.3(CYP2U1):c.41del (p.Pro14fs)	CYP2U1	Pathogenic	no assertion criteria provided
1686870	NM_183075.3(CYP2U1):c.808dup (p.Val270fs)	CYP2U1	Pathogenic	no assertion criteria provided
1951827	NM_183075.3(CYP2U1):c.543_544del (p.His182fs)	CYP2U1	Pathogenic	criteria provided, multiple submitters, no conflicts
3255488	NM_183075.3(CYP2U1):c.913C>T (p.His305Tyr)	CYP2U1	Pathogenic	no assertion criteria provided
3381975	NM_183075.3(CYP2U1):c.1084_1088del (p.Leu362fs)	CYP2U1	Pathogenic	criteria provided, single submitter
374541	NM_183075.3(CYP2U1):c.1396C>T (p.Arg466Ter)	CYP2U1	Pathogenic	criteria provided, multiple submitters, no conflicts
3768835	NM_183075.3(CYP2U1):c.1001del (p.Asn334fs)	CYP2U1	Pathogenic	criteria provided, single submitter
3778669	NM_183075.3(CYP2U1):c.1307T>C (p.Ile436Thr)	CYP2U1	Pathogenic	no assertion criteria provided
39500	NM_183075.3(CYP2U1):c.947A>T (p.Asp316Val)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39501	NM_183075.3(CYP2U1):c.1139A>G (p.Glu380Gly)	CYP2U1	Pathogenic	no assertion criteria provided
39502	NM_183075.3(CYP2U1):c.61_73del (p.Leu21fs)	CYP2U1	Pathogenic	no assertion criteria provided
39503	NM_183075.3(CYP2U1):c.784T>C (p.Cys262Arg)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39504	NM_183075.3(CYP2U1):c.1462C>T (p.Arg488Trp)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429249	NM_183075.3(CYP2U1):c.1210_1211del (p.Glu404fs)	CYP2U1	Pathogenic	criteria provided, multiple submitters, no conflicts
433183	NM_183075.3(CYP2U1):c.943C>T (p.Gln315Ter)	CYP2U1	Pathogenic	criteria provided, single submitter
562229	NM_183075.3(CYP2U1):c.1168C>T (p.Arg390Ter)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620256	NM_183075.3(CYP2U1):c.895A>T (p.Lys299Ter)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
655971	NM_183075.3(CYP2U1):c.471del (p.Ile158fs)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989059	NM_183075.3(CYP2U1):c.1A>C (p.Met1Leu)	CYP2U1	Pathogenic	criteria provided, single submitter
989061	NM_183075.3(CYP2U1):c.1469G>A (p.Cys490Tyr)	CYP2U1	Pathogenic	criteria provided, single submitter
1709880	NM_183075.3(CYP2U1):c.640G>T (p.Gly214Ter)	CYP2U1	Likely pathogenic	criteria provided, single submitter
2500180	NM_183075.3(CYP2U1):c.533G>C (p.Arg178Thr)	CYP2U1	Likely pathogenic	criteria provided, single submitter
3392515	NM_183075.3(CYP2U1):c.898_899insCA (p.Lys300fs)	CYP2U1	Likely pathogenic	criteria provided, single submitter
4073418	NM_183075.3(CYP2U1):c.491-2A>G	CYP2U1	Likely pathogenic	no assertion criteria provided
4278101	NM_183075.3(CYP2U1):c.260del (p.Leu87fs)	CYP2U1	Likely pathogenic	criteria provided, single submitter
433182	NM_183075.3(CYP2U1):c.452C>T (p.Pro151Leu)	CYP2U1	Likely pathogenic	criteria provided, single submitter
804444	NM_183075.3(CYP2U1):c.739_742del (p.Glu247fs)	CYP2U1	Likely pathogenic	criteria provided, single submitter
974827	NM_183075.3(CYP2U1):c.311_336dup (p.Val113delinsArgCysSerTrpLeuThrTer)	CYP2U1-AS1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYP2U1	Definitive	Autosomal recessive	hereditary spastic paraplegia 56	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP2U1	Orphanet:320411	Autosomal recessive spastic paraplegia type 56

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	gencc,clinvar
CYP2U1-AS1	HGNC:54817	ENSG00000245293		CYP2U1 and SGMS2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
CYP2U1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelial cell of pancreas	1
germinal epithelium of ovary	1
thymus	1
C1 segment of cervical spinal cord	1
corpus callosum	1
substantia nigra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP2U1	241	ubiquitous	marker	thymus, germinal epithelium of ovary, epithelial cell of pancreas
CYP2U1-AS1	133	broad	marker	C1 segment of cervical spinal cord, corpus callosum, substantia nigra

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP2U1	1,748
CYP2U1-AS1	0

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP2U1	Q7Z449	88.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP2U1 causes SPG56	1	11420.0×	3e-04	CYP2U1
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	1268.9×	0.001	CYP2U1
Miscellaneous substrates	1	951.7×	0.001	CYP2U1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytochrome metabolic process	1	3370.4×	0.001	CYP2U1
obsolete organic acid metabolic process	1	2407.4×	0.001	CYP2U1
omega-hydroxylase P450 pathway	1	1532.0×	0.001	CYP2U1
steroid metabolic process	1	337.0×	0.004	CYP2U1
xenobiotic metabolic process	1	149.1×	0.007	CYP2U1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYP2U1	PAZOPANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP2U1	1	4
CYP2U1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP2U1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYP2U1	183	ADMET:181, Binding:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CYP2U1	183

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PAZOPANIB	4	CYP2U1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP2U1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CYP2U1-AS1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CYP2U1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.