Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Summary

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (MONDO:0033613) is a disease caused by HPDL (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HPDL (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 243

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		32	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
Mondo ID	MONDO:0033613
MeSH	C567853
OMIM	603513, 619026
Orphanet	641353
UMLS	C5436628
MedGen	1736667
GARD	0010447
Is cancer (heuristic)	no

Also known as: cerebral palsy spastic quadriplegic · cerebral palsy, spastic quadriplegic, 1 · cerebral palsy, spastic quadriplegic, type 1 · CPSQ1 · infantile neurodegeneration-progressive spasticity-intellectual disability-white matter lesions syndrome · NEDSWMA

Data availability: 243 ClinVar variants · 5 GenCC gene-disease records.

Disease family

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 › neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Related subtypes (2): cerebral palsy, spastic quadriplegic, 2, cerebral palsy, spastic quadriplegic, 3

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

243 retrieved; paginated sample, class counts are floors:

98 likely benign, 88 uncertain significance, 14 conflicting classifications of pathogenicity, 14 benign, 11 pathogenic, 11 likely pathogenic, 5 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
565722	NM_000817.3(GAD1):c.865C>T (p.Gln289Ter)	GAD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1184996	NM_032756.4(HPDL):c.527T>C (p.Leu176Pro)	HPDL	Pathogenic	no assertion criteria provided
1202639	NM_032756.4(HPDL):c.256del (p.Ala86fs)	HPDL	Pathogenic/Likely pathogenic	no assertion criteria provided
1202640	NM_032756.4(HPDL):c.797T>C (p.Ile266Thr)	HPDL	Pathogenic/Likely pathogenic	no assertion criteria provided
1224493	NM_032756.4(HPDL):c.353dup (p.Tyr118Ter)	HPDL	Pathogenic	no assertion criteria provided
1224495	NM_032756.4(HPDL):c.954dup (p.Gly319fs)	HPDL	Pathogenic	no assertion criteria provided
1224496	NM_032756.4(HPDL):c.94C>T (p.Gln32Ter)	HPDL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1327472	NM_032756.4(HPDL):c.599del (p.Gly200fs)	HPDL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344855	NM_032756.4(HPDL):c.3G>C (p.Met1Ile)	HPDL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344861	NM_032756.4(HPDL):c.835C>T (p.Gln279Ter)	HPDL	Pathogenic	criteria provided, single submitter
4686579	HPDL, MET1ILE (VCV001344855.6)	HPDL	Pathogenic	no assertion criteria provided
4686580	HPDL, 1-BP DEL, 789G (VCV002221909.2)	HPDL	Pathogenic	no assertion criteria provided
979207	NM_032756.4(HPDL):c.342_343insTGCC (p.Ala115fs)	HPDL	Pathogenic	no assertion criteria provided
979208	NM_032756.4(HPDL):c.779G>A (p.Gly260Glu)	HPDL	Pathogenic	no assertion criteria provided
979211	NM_032756.4(HPDL):c.537G>C (p.Trp179Cys)	HPDL	Pathogenic	no assertion criteria provided
979212	NM_032756.4(HPDL):c.149G>A (p.Gly50Asp)	HPDL	Pathogenic	criteria provided, multiple submitters, no conflicts
2129735	NM_000817.3(GAD1):c.548-2A>C	GAD1	Likely pathogenic	criteria provided, single submitter
4725966	NM_000817.3(GAD1):c.1264-350_1289delinsGAGGTATCCAGCACATCCTGGCTG	GAD1	Likely pathogenic	criteria provided, single submitter
800908	NM_000817.3(GAD1):c.1402T>G (p.Trp468Gly)	GAD1	Likely pathogenic	no assertion criteria provided
1224494	NM_032756.4(HPDL):c.232G>A (p.Ala78Thr)	HPDL	Likely pathogenic	criteria provided, single submitter
1328237	NM_032756.4(HPDL):c.1013T>C (p.Leu338Pro)	HPDL	Likely pathogenic	no assertion criteria provided
1344852	NM_032756.4(HPDL):c.769_771delinsTC (p.Gln257fs)	HPDL	Likely pathogenic	criteria provided, single submitter
3256610	NM_032756.4(HPDL):c.1066G>C (p.Ala356Pro)	HPDL	Likely pathogenic	criteria provided, single submitter
979209	NM_032756.4(HPDL):c.1024C>T (p.Gln342Ter)	HPDL	Likely pathogenic	criteria provided, single submitter
979210	NM_032756.4(HPDL):c.503G>A (p.Cys168Tyr)	HPDL	Likely pathogenic	criteria provided, single submitter
982397	NM_032756.4(HPDL):c.788C>T (p.Thr263Met)	HPDL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
982398	NM_032756.4(HPDL):c.342_345dup (p.Ala116fs)	HPDL	Likely pathogenic	criteria provided, single submitter
1028872	NM_000817.3(GAD1):c.1184+17G>A	GAD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
332227	NM_000817.3(GAD1):c.265C>T (p.Arg89Trp)	GAD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
332229	NM_000817.3(GAD1):c.380A>T (p.Tyr127Phe)	GAD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
HPDL	Strong	Autosomal recessive	neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	5
GAD1	Limited	Autosomal recessive	neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPDL	Orphanet:528084	Non-specific syndromic intellectual disability
HPDL	Orphanet:631076	Autosomal recessive spastic paraplegia type 83
HPDL	Orphanet:641353	Infantile neurodegeneration-progressive spasticity-intellectual disability-white matter lesions syndrome
GAD1	Orphanet:210141	Inherited congenital spastic tetraplegia

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HPDL	HGNC:28242	ENSG00000186603	Q96IR7	4-hydroxyphenylpyruvate dioxygenase-like protein	gencc,clinvar
GAD1	HGNC:4092	ENSG00000128683	Q99259	Glutamate decarboxylase 1	gencc,clinvar
GAD1-AS1	HGNC:40250	ENSG00000235934		GAD1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPDL	4-hydroxyphenylpyruvate dioxygenase-like protein	Iron-dependent dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate (4-HPPA) to 4-hydroxymandelate (4-HMA) in the mitochondria, one of the steps in the biosynthesis of coenzyme Q10 from tyrosine.
GAD1	Glutamate decarboxylase 1	Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5’-phosphate as cofactor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPDL	Other/Unknown	no		4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase, VOC_core
GAD1	Enzyme (other)	yes	4.1.1.15	PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
GAD1-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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
bone marrow cell	1
cortical plate	1
nucleus accumbens	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPDL	152	broad	marker	primordial germ cell in gonad, mucosa of transverse colon, ileal mucosa
GAD1	199	broad	marker	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
GAD1-AS1	101		yes	bone marrow cell, nucleus accumbens, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GAD1	4,362
HPDL	1,149
GAD1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GAD1	Q99259	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HPDL	Q96IR7	91.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GABA synthesis	1	2855.0×	0.001	GAD1
MECP2 regulates transcription of genes involved in GABA signaling	1	1903.3×	0.001	GAD1
Ubiquinol biosynthesis	1	439.2×	0.003	HPDL
GABA synthesis, release, reuptake and degradation	1	317.2×	0.003	GAD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	4213.0×	8e-04	GAD1
aromatic amino acid metabolic process	1	4213.0×	8e-04	HPDL
L-glutamate catabolic process	1	2106.5×	0.001	GAD1
GABA biosynthetic process	1	1053.2×	0.002	GAD1
locomotory exploration behavior	1	495.6×	0.003	GAD1
social behavior	1	135.9×	0.009	GAD1
chemical synaptic transmission	1	38.6×	0.026	GAD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPDL	0	0
GAD1	0	0
GAD1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	GAD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HPDL, GAD1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HPDL	0	—
GAD1	1	—
GAD1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.