autosomal recessive complex spastic paraplegia type 9B

Summary

autosomal recessive complex spastic paraplegia type 9B (MONDO:0014702) is a disease caused by ALDH18A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALDH18A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 43
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007350	Hyperreflexia in upper limbs	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002445	Tetraplegia	Frequent (30-79%)
HP:0031064	Impaired continence	Frequent (30-79%)
HP:0000016	Urinary retention	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002371	Loss of speech	Occasional (5-29%)
HP:0002476	Primitive reflex	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006938	Impaired vibration sensation at ankles	Occasional (5-29%)
HP:0007371	Corpus callosum atrophy	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0100515	Pollakisuria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive complex spastic paraplegia type 9B
Mondo ID	MONDO:0014702
OMIM	616586
Orphanet	447760
DOID	DOID:0110825
UMLS	C5568980
MedGen	1800403
GARD	0017770
Is cancer (heuristic)	no

Also known as: ALDH18A1 autosomal recessive complex spastic paraplegia · AR-SPG9B · autosomal recessive complex spastic paraplegia caused by mutation in ALDH18A1 · hereditary spastic paraplegia type 9B · spastic paraplegia 9B, autosomal recessive · SPG9B

Data availability: 43 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › autosomal recessive complex spastic paraplegia type 9B

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, 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, 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

43 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 8 benign, 8 conflicting classifications of pathogenicity, 4 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333373	NM_002860.4(ALDH18A1):c.1596_1600del (p.Val533fs)	ALDH18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344210	NM_002860.4(ALDH18A1):c.1111C>T (p.Arg371Ter)	ALDH18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217120	NM_002860.4(ALDH18A1):c.1910T>C (p.Leu637Pro)	ALDH18A1	Pathogenic	no assertion criteria provided
217259	NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2253522	NM_002860.4(ALDH18A1):c.250C>T (p.Arg84Ter)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2924294	NM_002860.4(ALDH18A1):c.1321C>T (p.Arg441Ter)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1333680	NM_002860.4(ALDH18A1):c.1481C>T (p.Ala494Val)	ALDH18A1	Likely pathogenic	criteria provided, single submitter
217115	NM_002860.4(ALDH18A1):c.2143G>C (p.Asp715His)	ALDH18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431929	NM_002860.4(ALDH18A1):c.377G>A (p.Arg126His)	ALDH18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1227179	NM_002860.4(ALDH18A1):c.-29+188_-29+211del	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679568	NM_002860.4(ALDH18A1):c.89-1G>C	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878569	NM_002860.4(ALDH18A1):c.1931T>A (p.Ile644Asn)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217121	NM_002860.4(ALDH18A1):c.383G>A (p.Arg128His)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392663	NM_002860.4(ALDH18A1):c.991A>C (p.Thr331Pro)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424961	NM_002860.4(ALDH18A1):c.1867G>A (p.Asp623Asn)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633462	NM_002860.4(ALDH18A1):c.1273C>T (p.Arg425Cys)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
689652	NM_002860.4(ALDH18A1):c.2177G>A (p.Arg726His)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013572	NM_002860.4(ALDH18A1):c.743G>A (p.Ser248Asn)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029647	NM_002860.4(ALDH18A1):c.1078+6T>C	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299693	NM_002860.4(ALDH18A1):c.1926A>G (p.Val642=)	ALDH18A1	Uncertain significance	criteria provided, single submitter
1523847	NM_002860.4(ALDH18A1):c.1078+5A>G	ALDH18A1	Uncertain significance	criteria provided, single submitter
2442115	NM_002860.4(ALDH18A1):c.1691T>C (p.Val564Ala)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2505531	NM_002860.4(ALDH18A1):c.41A>G (p.Asn14Ser)	ALDH18A1	Uncertain significance	criteria provided, single submitter
2928043	NM_002860.4(ALDH18A1):c.1780G>A (p.Val594Ile)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2932585	NM_002860.4(ALDH18A1):c.34C>G (p.Pro12Ala)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3108824	NM_002860.4(ALDH18A1):c.86C>T (p.Ser29Phe)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377370	NM_002860.4(ALDH18A1):c.2312T>C (p.Val771Ala)	ALDH18A1	Uncertain significance	criteria provided, single submitter
3598737	NM_002860.4(ALDH18A1):c.1784A>G (p.Asp595Gly)	ALDH18A1	Uncertain significance	criteria provided, single submitter
441102	NM_002860.4(ALDH18A1):c.1942C>T (p.Pro648Ser)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
623751	NM_002860.4(ALDH18A1):c.1351G>A (p.Val451Met)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts

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,clinvar

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.