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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

Definition

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 GTR]

Additional descriptions

From GeneReviews
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.  https://www.ncbi.nlm.nih.gov/books/NBK1195
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
A verbal or physical act of hostility.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable stimulus.
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.
Cerebellar 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).
Myoclonic seizures
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
Seizures with sudden, brief (< 100 msec) involuntary single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb, distal).
Epilepsy juvenile absence
MedGen UID:
4989
Concept ID:
C0014553
Disease or Syndrome
Epilepsy characterized by very brief episodes of sudden cessation of activity, usually associated with eye blinking. There is no loss of the muscle tone.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes of personality and thought patterns often accompanied by hallucinations and delusional beliefs.
Muscle spasms
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
A life-threatening situation in which the brain is in a continuous state of seizure.
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.
Sensory hallucination
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
A generalized tonic-clinic seizure, characterized by loss of consciousness. This type of seizure may be preceded by an aura and is frequently followed by a period of confusion and lethargy (post-ictal state).
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. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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
A condition of decreased tone of the skeletal muscles and 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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