Hereditary spastic paraplegia 23

Summary

Hereditary spastic paraplegia 23 (MONDO:0010046) is a disease caused by DSTYK (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DSTYK (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12
• 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:0001003	Multiple lentigines	Frequent (30-79%)
HP:0001045	Vitiligo	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002607	Bowel incontinence	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0012701	Bowel urgency	Frequent (30-79%)
HP:0000085	Horseshoe kidney	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002218	Silver-gray hair	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 23
Mondo ID	MONDO:0010046
MeSH	C536859
OMIM	270750
Orphanet	101003
DOID	DOID:0110774
SNOMED CT	726608002
UMLS	C0796019
MedGen	167094
GARD	0000336
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in DSTYK · DSTYK autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 23 · Lison syndrome · spastic paraparesis-vitiligo-premature graying-characteristic facies syndrome · spastic paraplegia 23 · spastic paraplegia and pigmentary abnormalities · spastic paraplegia vitiligo premature graying and characteristic facies · spastic paraplegia vitiligo premature greying and characteristic facies · spastic paraplegia with pigmentary abnormalities · SPG 23 · SPG23

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 23

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

12 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 conflicting classifications of pathogenicity, 2 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
417786	NM_015375.3(DSTYK):c.2467+930_*1895delinsTGTAGTCCTGCTCCTTGAGG	DSTYK	Pathogenic	no assertion criteria provided
1031910	NM_015375.3(DSTYK):c.1384C>T (p.Arg462Ter)	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60684	NM_015375.3(DSTYK):c.654+1G>A	DSTYK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334458	NM_015375.3(DSTYK):c.1169G>A (p.Arg390His)	DSTYK	Uncertain significance	criteria provided, single submitter
1706463	NM_015375.3(DSTYK):c.623T>C (p.Leu208Pro)	DSTYK	Uncertain significance	criteria provided, single submitter
1952039	NM_015375.3(DSTYK):c.1979G>A (p.Arg660Gln)	DSTYK	Uncertain significance	criteria provided, single submitter
2371404	NM_015375.3(DSTYK):c.95G>A (p.Gly32Asp)	DSTYK	Uncertain significance	criteria provided, multiple submitters, no conflicts
3578158	NM_015375.3(DSTYK):c.1317G>C (p.Glu439Asp)	DSTYK	Uncertain significance	criteria provided, single submitter
3578160	NM_015375.3(DSTYK):c.55G>A (p.Gly19Ser)	DSTYK	Uncertain significance	criteria provided, single submitter
807907	NM_015375.3(DSTYK):c.609T>G (p.His203Gln)	DSTYK	Uncertain significance	criteria provided, multiple submitters, no conflicts
260657	NM_015375.3(DSTYK):c.1921T>C (p.Cys641Arg)	DSTYK	Benign	criteria provided, multiple submitters, no conflicts
260658	NM_015375.3(DSTYK):c.2028C>T (p.Phe676=)	DSTYK	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
DSTYK	Strong	Autosomal recessive	hereditary spastic paraplegia 23	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSTYK	Orphanet:101003	Autosomal recessive spastic paraplegia type 23
DSTYK	Orphanet:93100	Renal agenesis, unilateral

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSTYK	HGNC:29043	ENSG00000133059	Q6XUX3	Dual serine/threonine and tyrosine protein kinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSTYK	Dual serine/threonine and tyrosine protein kinase	Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSTYK	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	1
medial globus pallidus	1
superior vestibular nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSTYK	287	ubiquitous	marker	lateral nuclear group of thalamus, medial globus pallidus, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSTYK	1,487

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSTYK	Q6XUX3	81.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of kinase activity	1	3370.4×	0.001	DSTYK
positive regulation of fibroblast growth factor receptor signaling pathway	1	1532.0×	0.002	DSTYK
cellular response to fibroblast growth factor stimulus	1	543.6×	0.003	DSTYK
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.015	DSTYK
negative regulation of apoptotic process	1	34.8×	0.029	DSTYK

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
DSTYK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSTYK	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	DSTYK
NERATINIB	4	DSTYK
DABRAFENIB	4	DSTYK
BOSUTINIB	4	DSTYK
SUNITINIB	4	DSTYK
CRIZOTINIB	4	DSTYK
MIDOSTAURIN	4	DSTYK
ALVOCIDIB	3	DSTYK
LESTAURTINIB	3	DSTYK
FORETINIB	2	DSTYK
SU-014813	2	DSTYK
DEFOSBARASERTIB	2	DSTYK
RG-547	2	DSTYK
KW-2449	1	DSTYK
AST-487	1	DSTYK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DSTYK	90	Binding:90

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

15 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)
FEDRATINIB	4	DSTYK
NERATINIB	4	DSTYK
DABRAFENIB	4	DSTYK
BOSUTINIB	4	DSTYK
SUNITINIB	4	DSTYK
CRIZOTINIB	4	DSTYK
MIDOSTAURIN	4	DSTYK
ALVOCIDIB	3	DSTYK
LESTAURTINIB	3	DSTYK
FORETINIB	2	DSTYK
SU-014813	2	DSTYK
DEFOSBARASERTIB	2	DSTYK
RG-547	2	DSTYK
KW-2449	1	DSTYK
AST-487	1	DSTYK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DSTYK
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.