autosomal dominant complex spastic paraplegia type 9B

Summary

autosomal dominant complex spastic paraplegia type 9B (MONDO:0018644) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007083	Hyperactive patellar reflex	Frequent (30-79%)
HP:0007178	Motor polyneuropathy	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0007350	Hyperreflexia in upper limbs	Frequent (30-79%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002987	Elbow flexion contracture	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0004373	Focal dystonia	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant complex spastic paraplegia type 9B
Mondo ID	MONDO:0018644
Orphanet	447757
UMLS	C5568979
MedGen	1800402
GARD	0021866
Is cancer (heuristic)	no

Also known as: AD-SPG9B

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant complex spastic paraplegia › autosomal dominant spastic paraplegia type 9 › autosomal dominant complex spastic paraplegia type 9B

Related subtypes (1): hereditary spastic paraplegia 9A

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 5 · 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
ALDH18A1	Definitive	Autosomal dominant	autosomal recessive complex spastic paraplegia type 9B	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa

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
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

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)
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase

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
ileal mucosa	1
jejunal mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH18A1	P54886	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Glutamate and glutamine metabolism	1	815.7×	0.002	ALDH18A1
Mitochondrial protein degradation	1	114.2×	0.009	ALDH18A1

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
L-ornithine biosynthetic process	1	16852.0×	3e-04	ALDH18A1
L-citrulline biosynthetic process	1	4213.0×	6e-04	ALDH18A1
L-proline biosynthetic process	1	2808.7×	6e-04	ALDH18A1
response to temperature stimulus	1	1532.0×	8e-04	ALDH18A1
glutamate metabolic process	1	1123.5×	9e-04	ALDH18A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH18A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ALDH18A1	3	Binding:3

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

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	ALDH18A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ALDH18A1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.