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Succinate-semialdehyde dehydrogenase deficiency(SSADHD)

MedGen UID:
124340
Concept ID:
C0268631
Disease or Syndrome
Synonyms: 4-hydroxybutyric aciduria; Gamma-hydroxybutyricaciduria; SSADHD; Succinic Semialdehyde Dehydrogenase Deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Succinic semialdehyde dehydrogenase deficiency (49748000); 4--Hydroxybutyric aciduria (49748000); Gamma-hydroxybutyric acidemia (49748000); Succinate-semialdehyde dehydrogenase deficiency (49748000); GABAuria (49748000); gamma-Hydroxybutyric aciduria (49748000); GABA metabolic defect (49748000)
 
Gene (location): ALDH5A1 (6p22.3)
OMIM®: 271980
Orphanet: ORPHA22

Disease characteristics

Excerpted from the GeneReview: Succinic Semialdehyde Dehydrogenase Deficiency
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described. Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized. [from GeneReviews]
Authors:
Phillip L Pearl  |  Natrujee Wiwattanadittakul  |  Jean-Baptiste Roullet, et. al.   view full author information

Additional descriptions

From 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, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances (summary by Reis et al., 2012).  http://www.omim.org/entry/271980
From GHR
Succinic semialdehyde dehydrogenase deficiency is a disorder that can cause a variety of neurological problems. People with this condition typically have developmental delay, especially involving speech development; intellectual disability; and decreased muscle tone (hypotonia) soon after birth. About half of those affected experience seizures, difficulty coordinating movements (ataxia), decreased reflexes (hyporeflexia), and behavioral problems. The most common behavioral problems associated with this condition are sleep disturbances, hyperactivity, difficulty maintaining attention, and anxiety. Less frequently, affected individuals may have increased aggression, hallucinations, obsessive-compulsive disorder (OCD), and self-injurious behavior, including biting and head banging. People with this condition can also have problems controlling eye movements. Less common features of succinic semialdehyde dehydrogenase deficiency include uncontrollable movements of the limbs (choreoathetosis), involuntary tensing of the muscles (dystonia), muscle twitches (myoclonus), and a progressive worsening of ataxia.  https://ghr.nlm.nih.gov/condition/succinic-semialdehyde-dehydrogenase-deficiency

Clinical features

Abnormality of eye movement
MedGen UID:
99227
Concept ID:
C0497202
Finding
An abnormality in voluntary or involuntary eye movements or their control.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Fear and anxiety are part of life. You may feel anxious before you take a test or walk down a dark street. This kind of anxiety is useful - it can make you more alert or careful. It usually ends soon after you are out of the situation that caused it. But for millions of people in the United States, the anxiety does not go away, and gets worse over time. They may have chest pains or nightmares. They may even be afraid to leave home. These people have anxiety disorders. Types include. -Panic disorder . -Obsessive-compulsive disorder . -Post-traumatic stress disorder . -Phobias . -Generalized anxiety disorder . Treatment can involve medicines, therapy or both. NIH: National Institute of Mental Health .
Autistic disorder of childhood onset
MedGen UID:
13966
Concept ID:
C0004352
Mental or Behavioral Dysfunction
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS5 (606053), which maps to chromosome 2q; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; and AUTS18 (615032), associated with mutation in the CHD8 gene (610528). (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with mutation in the TMLHE gene (300777). Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
Ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Epilepsies, Myoclonic
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
A clinically diverse group of epilepsy syndromes characterized either by myoclonic seizures or by myoclonus in association with other seizure types. Myoclonic epilepsy syndromes are divided into three subtypes based on etiology: familial, cryptogenic, and symptomatic (i.e., occurring secondary to known disease processes such as infections, hypoxic-ischemic injuries, trauma, etc.).
Epilepsy juvenile absence
MedGen UID:
4989
Concept ID:
C0014553
Disease or Syndrome
Recurrent absence seizures are generalized seizures and are characterized by a loss of consciousness, thus, are a form of dialeptic seizures.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
Psychotic disorders are severe mental disorders that cause abnormal thinking and perceptions. People with psychoses lose touch with reality. Two of the main symptoms are delusions and hallucinations. Delusions are false beliefs, such as thinking that someone is plotting against you or that the TV is sending you secret messages. Hallucinations are false perceptions, such as hearing, seeing, or feeling something that is not there. Schizophrenia is one type of psychotic disorder. People with bipolar disorder may also have psychotic symptoms. Other problems that can cause psychosis include alcohol and some drugs, brain tumors, brain infections, and stroke. Treatment depends on the cause of the psychosis. It might involve drugs to control symptoms and talk therapy. Hospitalization is an option for serious cases where a person might be dangerous to himself or others.
Spasm
MedGen UID:
52431
Concept ID:
C0037763
Sign or Symptom
Motor hyperactivity with excessive movement of muscles of the body as a whole.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Seizures lasting for more than 30 minutes or longer or multiple seizures repeated frequently without regaining consciousness between seizures.
Self-mutilation
MedGen UID:
88371
Concept ID:
C0085271
Finding
Aggression towards oneself.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hallucinations, Sensory
MedGen UID:
115982
Concept ID:
C0235153
Sign or Symptom
Perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Excessive movement of muscles of the body as a whole, which may be associated with organic or psychological disorders.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Generalized tonic-clonic seizures
MedGen UID:
141670
Concept ID:
C0494475
Disease or Syndrome
Generalized tonic-clonic seizures are generalized seizures with bilateral symmetrical tonic contraction then bilateral clonic contractions of somatic muscles usually associated with autonomic phenomena.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28)
No development of motor milestones
MedGen UID:
892432
Concept ID:
C4020874
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSuccinate-semialdehyde dehydrogenase deficiency
Follow this link to review classifications for Succinate-semialdehyde dehydrogenase deficiency in Orphanet.

Professional guidelines

PubMed

Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee.
Genet Med 2013 May;15(5):399-407. Epub 2013 Mar 21 doi: 10.1038/gim.2013.32. PMID: 23519317

Recent clinical studies

Etiology

Aligianis IA, Farndon PA, Gray RG, Heath SK, Kilby M, Gibson KM, Akaboshi S
J Inherit Metab Dis 2002 Oct;25(6):517-8. PMID: 12555945

Diagnosis

Aligianis IA, Farndon PA, Gray RG, Heath SK, Kilby M, Gibson KM, Akaboshi S
J Inherit Metab Dis 2002 Oct;25(6):517-8. PMID: 12555945

Prognosis

Aligianis IA, Farndon PA, Gray RG, Heath SK, Kilby M, Gibson KM, Akaboshi S
J Inherit Metab Dis 2002 Oct;25(6):517-8. PMID: 12555945

Clinical prediction guides

Gupta M, Jansen EE, Senephansiri H, Jakobs C, Snead OC, Grompe M, Gibson KM
Mol Ther 2004 Apr;9(4):527-39. doi: 10.1016/j.ymthe.2004.01.013. PMID: 15093183
Aligianis IA, Farndon PA, Gray RG, Heath SK, Kilby M, Gibson KM, Akaboshi S
J Inherit Metab Dis 2002 Oct;25(6):517-8. PMID: 12555945

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