4-hydroxybutyric aciduria

General Information (adopted from Orphanet):

Synonyms, Signs: SSADHD
4-&#64
HYDROXYBUTYRIC ACIDURIA
GAMMA-HYDROXYBUTYRIC ACIDURIA
SSADH DEFICIENCY
GABA METABOLIC DEFECT
Succinic semialdehyde dehydrogenase deficiency
Number of Symptoms 43
OrphanetNr: 22
OMIM Id: 271980
ICD-10: E72.8
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: 450 cases [Orphanet]
Inheritance: Autosomal recessive
[Orphanet]
Age of onset: Childhood
[Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases: Disorder of gamma-aminobutyric acid metabolism
 -Rare genetic disease
Metabolic neurotransmission anomaly with epilepsy
 -Rare neurologic disease
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease

Symptom Information: Sort by abundance 

1
(HPO:0001992) Organic aciduria Very frequent [Orphanet] 28 / 7739
2
(HPO:0000496) Abnormality of eye movement 79 / 7739
3
(HPO:0001265) Hyporeflexia 208 / 7739
4
(HPO:0000708) Behavioral abnormality Frequent [Orphanet] 212 / 7739
5
(HPO:0000750) Delayed speech and language development 197 / 7739
6
(HPO:0002133) Status epilepticus 59 / 7739
7
(HPO:0100716) Self-injurious behavior 43 / 7739
8
(HPO:0000717) Autism 108 / 7739
9
(HPO:0002487) Hyperkinesis 7 / 7739
10
(HPO:0001250) Seizures Frequent [Orphanet] 1245 / 7739
11
(HPO:0000718) Aggressive behavior 109 / 7739
12
(HPO:0001270) Motor delay 322 / 7739
13
(HPO:0002069) Generalized tonic-clonic seizures 96 / 7739
14
(HPO:0000709) Psychosis 61 / 7739
15
(HPO:0002121) Absence seizures 62 / 7739
16
(HPO:0002353) EEG abnormality 188 / 7739
17
(HPO:0001263) Global developmental delay 853 / 7739
18
(HPO:0002123) Generalized myoclonic seizures 62 / 7739
19
(HPO:0000739) Anxiety 67 / 7739
20
(HPO:0000752) Hyperactivity 140 / 7739
21
(HPO:0000738) Hallucinations 60 / 7739
22
(HPO:0001251) Ataxia 413 / 7739
23
(HPO:0001249) Intellectual disability 1089 / 7739
24
(HPO:0002066) Gait ataxia Very frequent [Orphanet] 327 / 7739
25
(HPO:0001939) Abnormality of metabolism/homeostasis 328 / 7739
26
(HPO:0008947) Infantile muscular hypotonia 482 / 7739
27
(HPO:0001252) Muscular hypotonia Very frequent [Orphanet] 990 / 7739
28
(HPO:0001324) Muscle weakness 859 / 7739
29
(HPO:0010547) Muscle flaccidity 466 / 7739
30
(OMIM) Psychosis in older patients 1 / 7739
31
(OMIM) Increased CSF and plasma GABA 1 / 7739
32
(HPO:0003593) Infantile onset 249 / 7739
33
(OMIM) MRI shows increased T2-weighted signals in the globus pallidi 1 / 7739
34
(OMIM) Approximately 30% of patients show normal early development 1 / 7739
35
(HPO:0012758) Neurodevelopmental delay Very frequent [Orphanet] 949 / 7739
36
(OMIM) Increased urinary excretion of gamma-aminobutyric acid (GABA) 1 / 7739
37
(OMIM) Delayed development, ranging from mild to severe 1 / 7739
38
(OMIM) Decreased activity of succinic semialdehyde dehydrogenase (SSADH, ALDH5A1), less than 5% of control values 1 / 7739
39
(OMIM) Increased urinary excretion of 4-hydroxybutyric acid (GHB) 1 / 7739
40
(HPO:0000007) Autosomal recessive inheritance 2538 / 7739
41
(OMIM) Autism, mild 1 / 7739
42
(OMIM) Increased CSF and plasma GHB 1 / 7739
43
(HPO:0003812) Phenotypic variability 129 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, ...
Diagnosis OMIM Pearl et al. (2003) noted that standard organic acid assays commonly miss increased urinary excretion of 4-hydroxybutyric acid because it is a highly volatile compound. The authors suggested that selective ion monitoring gas chromatography-mass spectrometry for specific compounds ...
Clinical Description OMIM Jakobs et al. (1981) reported a patient with neurologic abnormalities and urinary excretion of gamma-hydroxybutyric acid.

Gibson et al. (1983) demonstrated deficiency of the succinic semialdehyde dehydrogenase enzyme in lymphocyte lysates from 2 patients with gamma-hydroxybutyric ...

Molecular genetics OMIM In 4 patients from 2 unrelated families with SSADH deficiency, Chambliss et al. (1998) identified homozygosity for 2 different splice site mutations in the ALD5A1 gene (610045.0001; 610045.0002). Unaffected parents and sibs were heterozygous for the mutations. ...
Diagnosis GeneReviews Succinic semialdehyde dehydrogenase (SSADH) deficiency may be suspected in individuals with a late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by the following:...
Clinical Description GeneReviews SSADH deficiency is characterized by a relatively nonprogressive encephalopathy presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include intellectual disability, behavior problems, and motor dysfunction....
Genotype-Phenotype Correlations GeneReviews No genotype-phenotype correlations have been observed....
Differential Diagnosis GeneReviews Other disorders of GABA metabolism:...
Management GeneReviews To establish the extent of disease in an individual diagnosed with succinic semialdehyde dehydrogenase (SSADH) deficiency, the following evaluations are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....