Spastic quadriplegic cerebral palsy

Summary

Spastic quadriplegic cerebral palsy (MONDO:0016215) is a disease with 5 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 2
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic quadriplegic cerebral palsy
Mondo ID	MONDO:0016215
OMIM	603513, 612900
Orphanet	210141
DOID	DOID:10970
ICD-10-CM	G80.0
ICD-11	1155284708
NCIT	C116904
SNOMED CT	192965001
UMLS	C0426970
MedGen	98433
GARD	0017109
Is cancer (heuristic)	no

Also known as: inherited congenital spastic quadriplegia · quadriplegic infantile cerebral palsy · spastic quadriplegia · spastic quadriplegic cerebral palsy · spastic tetraplegia cerebral palsy · tetraplegic infantile cerebral palsy

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

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › cerebral palsy › spastic cerebral palsy › spastic quadriplegic cerebral palsy

Related subtypes (4): spastic diplegia, spastic hemiplegia, spastic monoplegia, spastic triplegia

Subtypes (3): cerebral palsy, spastic quadriplegic, 2, cerebral palsy, spastic quadriplegic, 3, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
183353	NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)	ISCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982795	NM_004135.4(IDH3G):c.694T>C (p.Phe232Leu)	IDH3G	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 4 · 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
ADD3	Strong	Autosomal recessive	cerebral palsy, spastic quadriplegic, 3	4
GAD1	Supportive	Autosomal recessive	spastic quadriplegic cerebral palsy	7
KANK1	Supportive	Autosomal recessive	spastic quadriplegic cerebral palsy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KANK1	Orphanet:210141	Inherited congenital spastic tetraplegia
ADD3	Orphanet:210141	Inherited congenital spastic tetraplegia
GAD1	Orphanet:210141	Inherited congenital spastic tetraplegia
ISCA2	Orphanet:457406	Multiple mitochondrial dysfunctions syndrome type 4

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KANK1	HGNC:19309	ENSG00000107104	Q14678	KN motif and ankyrin repeat domain-containing protein 1	gencc
ADD3	HGNC:245	ENSG00000148700	Q9UEY8	Gamma-adducin	gencc
GAD1	HGNC:4092	ENSG00000128683	Q99259	Glutamate decarboxylase 1	gencc
ISCA2	HGNC:19857	ENSG00000165898	Q86U28	Iron-sulfur cluster assembly 2 homolog, mitochondrial	clinvar
IDH3G	HGNC:5386	ENSG00000067829	P51553	Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KANK1	KN motif and ankyrin repeat domain-containing protein 1	Adapter protein that links structural and signaling protein complexes positioned to guide microtubule and actin cytoskeleton dynamics during cell morphogenesis.
ADD3	Gamma-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.
GAD1	Glutamate decarboxylase 1	Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5’-phosphate as cofactor.
ISCA2	Iron-sulfur cluster assembly 2 homolog, mitochondrial	Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.
IDH3G	Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial	Regulatory subunit which plays a role in the allosteric regulation of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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
Enzyme (other)	2	4.8×	0.176
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KANK1	Scaffold/PPI	no		Ankyrin_rpt, KN_motif, Ankyrin_rpt-contain_sf
ADD3	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf
GAD1	Enzyme (other)	yes	4.1.1.15	PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
ISCA2	Other/Unknown	no		ATAP_core_dom, ATAP, FeS_cluster_insertion_CS
IDH3G	Enzyme (other)	yes	1.1.1.41	Isocitrate_DH_NAD, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
cartilage tissue	1
descending thoracic aorta	1
dorsal motor nucleus of vagus nerve	1
oocyte	1
secondary oocyte	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
cardiac muscle of right atrium	1
deltoid	1
left ventricle myocardium	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KANK1	291	ubiquitous	marker	blood vessel layer, cartilage tissue, descending thoracic aorta
ADD3	303	ubiquitous	marker	secondary oocyte, oocyte, dorsal motor nucleus of vagus nerve
GAD1	199	broad	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
ISCA2	257	ubiquitous	marker	left ventricle myocardium, deltoid, cardiac muscle of right atrium
IDH3G	299	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GAD1	4,362
IDH3G	2,794
KANK1	1,931
ADD3	1,882
ISCA2	1,444

Intra-cohort edges

A	B	Sources
GAD1	KANK1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IDH3G	P51553	12
KANK1	Q14678	5
GAD1	Q99259	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ISCA2	Q86U28	77.98
ADD3	Q9UEY8	66.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Citric acid cycle (TCA cycle)	2	169.2×	0.001	ISCA2, IDH3G
GABA synthesis	1	1142.0×	0.011	GAD1
MECP2 regulates transcription of genes involved in GABA signaling	1	761.3×	0.011	GAD1
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	456.8×	0.013	KANK1
Signaling by PDGFR in disease	1	326.3×	0.015	KANK1
Mitochondrial iron-sulfur cluster biogenesis	1	163.1×	0.024	ISCA2
GABA synthesis, release, reuptake and degradation	1	126.9×	0.026	GAD1
Maturation of TCA enzymes and regulation of TCA cycle	1	114.2×	0.026	ISCA2
Miscellaneous transport and binding events	1	87.8×	0.030	ADD3
RHOF GTPase cycle	1	51.9×	0.046	ADD3
RHOD GTPase cycle	1	40.8×	0.053	ADD3
Mitochondrial protein import	1	33.6×	0.059	IDH3G
ESR-mediated signaling	1	25.7×	0.071	KANK1
Signaling by Nuclear Receptors	1	20.4×	0.082	KANK1
Aerobic respiration and respiratory electron transport	1	17.7×	0.088	ISCA2
Estrogen-dependent gene expression	1	15.1×	0.097	KANK1
RHO GTPase cycle	1	12.0×	0.107	ADD3
Signal Transduction	2	4.1×	0.107	KANK1, ADD3
Diseases of signal transduction by growth factor receptors and second messengers	1	11.4×	0.107	KANK1
Signaling by Rho GTPases	1	6.8×	0.161	ADD3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	6.7×	0.161	ADD3
Transport of small molecules	1	5.0×	0.200	ADD3
Disease	1	2.6×	0.342	KANK1
Metabolism	1	2.3×	0.362	ISCA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GABA shunt	1	1685.2×	0.009	GAD1
negative regulation of lamellipodium morphogenesis	1	1685.2×	0.009	KANK1
L-glutamate catabolic process	1	842.6×	0.009	GAD1
isocitrate metabolic process	1	674.1×	0.009	IDH3G
positive regulation of cytoskeleton organization	1	561.7×	0.009	ADD3
podocyte cell migration	1	481.5×	0.009	KANK1
negative regulation of ruffle assembly	1	481.5×	0.009	KANK1
GABA biosynthetic process	1	421.3×	0.009	GAD1
cortical microtubule organization	1	374.5×	0.009	KANK1
negative regulation of substrate adhesion-dependent cell spreading	1	224.7×	0.013	KANK1
locomotory exploration behavior	1	198.3×	0.013	GAD1
negative regulation of actin filament polymerization	1	187.2×	0.013	KANK1
regulation of establishment of cell polarity	1	187.2×	0.013	KANK1
barbed-end actin filament capping	1	160.5×	0.014	ADD3
negative regulation of Rho protein signal transduction	1	153.2×	0.014	KANK1
iron-sulfur cluster assembly	1	120.4×	0.016	ISCA2
positive regulation of vasoconstriction	1	120.4×	0.016	ADD3
positive regulation of wound healing	1	105.3×	0.016	KANK1
tricarboxylic acid cycle	1	102.1×	0.016	IDH3G
regulation of Rho protein signal transduction	1	102.1×	0.016	KANK1
positive regulation of Wnt signaling pathway	1	76.6×	0.019	KANK1
negative regulation of insulin receptor signaling pathway	1	74.9×	0.019	KANK1
social behavior	1	54.4×	0.025	GAD1
negative regulation of neuron projection development	1	47.5×	0.028	KANK1
protein maturation	1	32.7×	0.039	ISCA2
positive regulation of canonical Wnt signaling pathway	1	30.9×	0.039	KANK1
carbohydrate metabolic process	1	27.2×	0.043	IDH3G
negative regulation of cell migration	1	22.3×	0.050	KANK1
cell population proliferation	1	20.6×	0.053	KANK1
actin cytoskeleton organization	1	15.8×	0.065	KANK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KANK1	0	0
ADD3	0	0
GAD1	0	0
ISCA2	0	0
IDH3G	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GAD1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAD1	4.1.1.15	glutamate decarboxylase
IDH3G	1.1.1.41	isocitrate dehydrogenase (NAD+)

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	GAD1, IDH3G
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	KANK1, ADD3, ISCA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KANK1	0	—
ADD3	0	—
GAD1	1	—
ISCA2	0	—
IDH3G	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07433647	Not specified	RECRUITING	Evaluation of Brain MRI Changes in Cerebral Palsy Patients
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury