Succinic semialdehyde dehydrogenase deficiency

Summary

Succinic semialdehyde dehydrogenase deficiency (MONDO:0010083) is a disease caused by ALDH5A1 (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALDH5A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 788
• Phenotypes (HPO): 9
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		450	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.2	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	succinic semialdehyde dehydrogenase deficiency
Mondo ID	MONDO:0010083
MeSH	C535803
OMIM	271980
Orphanet	22
DOID	DOID:0060175
SNOMED CT	49748000
UMLS	C0268631
MedGen	124340
GARD	0007695
NORD	1904
Is cancer (heuristic)	no

Also known as: 4-hydroxybutyric aciduria · gamma-hydroxybutyric aciduria · gamma-hydroxybutyricaciduria · SSADH deficiency · SSADHD · succinic semialdehyde dehydrogenase deficiency

Data availability: 788 ClinVar variants · 4 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › gamma-amino butyric acid metabolism disorder › succinic semialdehyde dehydrogenase deficiency

Related subtypes (2): homocarnosinosis, GABA aminotransaminase deficiency

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

600 retrieved; paginated sample, class counts are floors:

222 likely benign, 185 uncertain significance, 72 pathogenic, 48 likely pathogenic, 32 conflicting classifications of pathogenicity, 25 benign, 8 pathogenic/likely pathogenic, 7 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069046	NM_001080.3(ALDH5A1):c.1540C>T (p.Arg514Ter)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070800	NM_001080.3(ALDH5A1):c.318C>G (p.Tyr106Ter)	ALDH5A1	Pathogenic	criteria provided, single submitter
1070877	NM_001080.3(ALDH5A1):c.854C>G (p.Ser285Ter)	ALDH5A1	Pathogenic	criteria provided, single submitter
1070905	NM_001080.3(ALDH5A1):c.276del (p.Cys93fs)	ALDH5A1	Pathogenic	criteria provided, single submitter
1073790	NM_001080.3(ALDH5A1):c.967_968dup (p.Gln323fs)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075244	NM_001080.3(ALDH5A1):c.34dup (p.Ala12fs)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075603	NM_001080.3(ALDH5A1):c.896_897del (p.Ser299fs)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076224	NC_000006.11:g.(?24505087)(24533940_?)del	ALDH5A1	Pathogenic	criteria provided, single submitter
1323875	NM_001080.3(ALDH5A1):c.665del (p.Gly222fs)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334843	NM_001080.3(ALDH5A1):c.608C>T (p.Pro203Leu)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1346959	NM_001080.3(ALDH5A1):c.1576G>T (p.Glu526Ter)	ALDH5A1	Pathogenic	criteria provided, single submitter
1350850	NM_001080.3(ALDH5A1):c.424_425del (p.Ile142fs)	ALDH5A1	Pathogenic	criteria provided, single submitter
1355	NM_001080.3(ALDH5A1):c.1343+1G>T	ALDH5A1	Pathogenic	criteria provided, single submitter
1356	NM_001080.3(ALDH5A1):c.727-3298G>A	ALDH5A1	Pathogenic	criteria provided, single submitter
1357	NM_001080.3(ALDH5A1):c.612G>A (p.Trp204Ter)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1358	NM_001080.3(ALDH5A1):c.1234C>T (p.Arg412Ter)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1358625	NC_000006.11:g.(?24532327)(24533940_?)del	ALDH5A1	Pathogenic	criteria provided, single submitter
1359	NM_001080.3(ALDH5A1):c.1226G>A (p.Gly409Asp)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1419591	NM_001080.3(ALDH5A1):c.1592G>A (p.Cys531Tyr)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1429807	NM_001080.3(ALDH5A1):c.379_380del (p.Trp127fs)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1435168	NM_001080.3(ALDH5A1):c.660_666del (p.Ala221fs)	ALDH5A1	Pathogenic	criteria provided, single submitter
1452396	NM_001080.3(ALDH5A1):c.352A>T (p.Lys118Ter)	ALDH5A1	Pathogenic	criteria provided, single submitter
1452915	NM_001080.3(ALDH5A1):c.1015-1G>C	ALDH5A1	Pathogenic	criteria provided, single submitter
1691448	NM_001080.3(ALDH5A1):c.728_736del (p.Leu243_Ser245del)	ALDH5A1	Pathogenic	criteria provided, single submitter
1810825	NM_001080.3(ALDH5A1):c.667T>C (p.Cys223Arg)	ALDH5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810826	NM_001080.3(ALDH5A1):c.698C>T (p.Thr233Met)	ALDH5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1878435	NM_001080.3(ALDH5A1):c.278_298dup (p.Arg99_Ala100insGlyGlyValArgGluAlaArg)	ALDH5A1	Pathogenic	criteria provided, single submitter
1878439	NM_001080.3(ALDH5A1):c.375_378del (p.Lys126fs)	ALDH5A1	Pathogenic	criteria provided, single submitter
1878441	NM_001080.3(ALDH5A1):c.412C>T (p.Leu138Phe)	ALDH5A1	Pathogenic	criteria provided, single submitter
1878442	NM_001080.3(ALDH5A1):c.416C>A (p.Ala139Asp)	ALDH5A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ALDH5A1	Definitive	Autosomal recessive	succinic semialdehyde dehydrogenase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH5A1	Orphanet:22	Succinic semialdehyde dehydrogenase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH5A1	HGNC:408	ENSG00000112294	P51649	Succinate-semialdehyde dehydrogenase, mitochondrial	gencc,clinvar
GPLD1	HGNC:4459	ENSG00000112293	P80108	Phosphatidylinositol-glycan-specific phospholipase D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH5A1	Succinate-semialdehyde dehydrogenase, mitochondrial	Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
GPLD1	Phosphatidylinositol-glycan-specific phospholipase D	Hydrolyzes the inositol phosphate linkage of glycosylphosphatidylinositol (GPI)-anchored membrane proteins, thereby releasing them from the cell surface.

Protein-family classification

Druggable: 2 · 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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH5A1	Enzyme (other)	yes	1.2.1.24	Succ_semiAld_DH, Aldehyde_DH_dom, Ald_DH_CS_CYS
GPLD1	Enzyme (other)	yes	3.1.4.50	Gprt_PLipase_D, FG-GAP, Int_alpha_beta-p

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
vastus lateralis	1
liver	1
penis	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH5A1	273	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, vastus lateralis
GPLD1	222	broad	marker	secondary oocyte, penis, liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH5A1	4,219
GPLD1	928

Intra-cohort edges

A	B	Sources
ALDH5A1	GPLD1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH5A1	P51649	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GPLD1	P80108	87.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Degradation of GABA	1	2855.0×	0.002	ALDH5A1
GABA synthesis, release, reuptake and degradation	1	317.2×	0.009	ALDH5A1
Neurotransmitter release cycle	1	219.6×	0.009	ALDH5A1
Post-translational modification: synthesis of GPI-anchored proteins	1	84.0×	0.018	GPLD1
Transmission across Chemical Synapses	1	38.1×	0.031	ALDH5A1
Neuronal System	1	22.1×	0.045	ALDH5A1

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
positive regulation of alkaline phosphatase activity	1	8426.0×	0.003	GPLD1
GABA catabolic process	1	4213.0×	0.003	ALDH5A1
positive regulation of high-density lipoprotein particle clearance	1	2808.7×	0.003	GPLD1
cellular response to triglyceride	1	2808.7×	0.003	GPLD1
hematopoietic stem cell migration	1	2106.5×	0.003	GPLD1
succinate metabolic process	1	1685.2×	0.003	ALDH5A1
hematopoietic stem cell migration to bone marrow	1	1685.2×	0.003	GPLD1
negative regulation of triglyceride catabolic process	1	1404.3×	0.003	GPLD1
positive regulation of glucose metabolic process	1	1203.7×	0.003	GPLD1
cellular response to pH	1	1053.2×	0.003	GPLD1
regulation of cellular response to insulin stimulus	1	766.0×	0.004	GPLD1
positive regulation of triglyceride biosynthetic process	1	648.1×	0.004	GPLD1
transepithelial transport	1	601.9×	0.004	GPLD1
complement receptor mediated signaling pathway	1	561.7×	0.004	GPLD1
glutamate metabolic process	1	561.7×	0.004	ALDH5A1
positive regulation of membrane protein ectodomain proteolysis	1	468.1×	0.004	GPLD1
cellular response to cholesterol	1	421.3×	0.005	GPLD1
phosphatidylcholine metabolic process	1	401.2×	0.005	GPLD1
cell migration involved in sprouting angiogenesis	1	324.1×	0.005	GPLD1
synaptic transmission, GABAergic	1	247.8×	0.007	ALDH5A1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.008	GPLD1
chondrocyte differentiation	1	150.5×	0.010	GPLD1
protein secretion	1	131.7×	0.010	GPLD1
response to glucose	1	127.7×	0.010	GPLD1
positive regulation of endothelial cell migration	1	125.8×	0.010	GPLD1
cellular response to xenobiotic stimulus	1	120.4×	0.011	GPLD1
ossification	1	113.9×	0.011	GPLD1
insulin receptor signaling pathway	1	110.9×	0.011	GPLD1
post-embryonic development	1	102.8×	0.011	ALDH5A1
cellular response to insulin stimulus	1	85.1×	0.013	GPLD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH5A1	0	0
GPLD1	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
ALDH5A1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH5A1	1.2.1.24	succinate-semialdehyde dehydrogenase (NAD+)
GPLD1	3.1.4.50	glycosylphosphatidylinositol phospholipase D

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	ALDH5A1
D	Druggable family + AlphaFold only, no drug	1	GPLD1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH5A1	5	—
GPLD1	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
NCT03758521	Not specified	RECRUITING	Natural History Study of Patients With Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
NCT00246870	Not specified	COMPLETED	PET Imaging of GABA Receptors in Succinic Semialdehyde Dehydrogenase Deficiency