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Disease Profile

Succinic semialdehyde dehydrogenase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Childhood

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ICD-10

E72.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

4-hydroxybutyric aciduria; Gamma-hydroxybutyricaciduria; SSADH deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a disorder that can cause a variety of neurological and neuromuscular problems. The signs and symptoms can be extremely variable among affected individuals and may include mild to severe intellectual disability; developmental delay (especially involving speech); hypotonia; difficulty coordinating movements (ataxia); and/or seizures. Some affected individuals may also have decreased reflexes (hyporeflexia); nystagmus; hyperactivity; and/or behavioral problems.[1][2] SSADH deficiency is caused by mutations in the ALDH5A1 gene and is inherited in an autosomal recessive manner.[2] Management is generally symptomatic and typically focuses on treating seizures and neurobehavioral issues.[3]

Symptoms

People with succinic semialdehyde dehydrogenase deficiency (SSADH) 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, 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 SSADH include uncontrollable movements of the limbs (choreoathetosis), involuntary tensing of the muscles (dystonia), muscle twitches (myoclonus), and a progressive worsening of ataxia.[2]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of metabolism/homeostasis
Laboratory abnormality
Metabolism abnormality

[ more ]

0001939
Ataxia
0001251
Global developmental delay
0001263
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Muscular hypotonia
Low or weak muscle tone
0001252
30%-79% of people have these symptoms
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

0000708
Bilateral tonic-clonic seizure
Grand mal seizures
0002069
Generalized myoclonic seizure
0002123
Status epilepticus
Repeated seizures without recovery between them
0002133
1%-4% of people have these symptoms
Cerebellar atrophy
Degeneration of cerebellum
0001272
Childhood onset
Symptoms begin in childhood
0011463
Delayed CNS myelination
0002188
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Hyporeflexia
Decreased reflex response
Decreased reflexes

[ more ]

0001265
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Juvenile onset
Signs and symptoms begin before 15 years of age
0003621
Motor delay
0001270
Seizure
0001250
Young adult onset
0011462
Percent of people who have these symptoms is not available through HPO
Abnormality of eye movement
Abnormal eye movement
Abnormal eye movements
Eye movement abnormalities
Eye movement issue

[ more ]

0000496
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness

[ more ]

0000718
Anxiety
Excessive, persistent worry and fear
0000739
Autism
0000717
Autosomal recessive inheritance
0000007
Decreased succinic semialdehyde dehydrogenase level
0032530
EEG abnormality
0002353
Elevated circulating gamma-aminobutyric acid concentration
0032529
Elevated CSF 4-hydroxybutyric acid concentration
0032532
Elevated CSF gamma-aminobutyric acid concentration
0032531
Elevated urinary 4-hydroxybutyric acid
0032528
Generalized non-motor (absence) seizure
Brief seizures with staring spells
0002121
Hallucinations
Hallucination
Sensory hallucination

[ more ]

0000738
Hyperactivity
More active than typical
0000752
Hyperkinetic movements
Muscle spasms
0002487
Increased level of gamma-aminobutyric acid in urine
0500253
Psychomotor retardation
0025356
Psychosis
0000709
Self-injurious behavior
Self-injurious behaviour
0100716

Cause

Succinic semialdehyde dehydrogenase deficiency (SSADH) is caused by mutations in the ALDH5A1 gene. This gene provides instructions for producing the succinic semialdehyde dehydrogenase enzyme which is involved in the breakdown of a chemical that transmits signals in the brain (neurotransmitter) called gamma-amino butyric acid (GABA). The primary role of GABA is to prevent the brain from being overloaded with too many signals. A shortage (deficiency) of succinic semialdehyde dehydrogenase leads to an increase in the amount of GABA and a related molecule called gamma-hydroxybutyrate (GHB) in the body, particularly the brain and spinal cord (central nervous system). It is unclear how an increase in GABA and GHB causes developmental delay, seizures, and other signs and symptoms of succinic semialdehyde dehydrogenase deficiency.[2]

Diagnosis

The diagnosis of succinic semialdehyde dehydrogenase (SSADH) deficiency is based upon a thorough clinical exam, the identification of features consistent with the condition, and a variety of specialized tests.[1] SSADH deficiency may first be suspected in late infancy or early childhood in individuals who have encephalopathy, a state in which brain function or structure is altered. The encephalopathy may be characterized by cognitive impairment; language deficit; poor muscle tone (hypotonia); seizures; decreased reflexes (hyporeflexia); and/or difficulty coordinating movements (ataxia). The diagnosis may be further suspected if urine organic acid analysis (a test that provides information about the substances the body discards through the urine) shows the presence of 4-hydroxybutyric acid. The diagnosis can be confirmed by an enzyme test showing deficiency of SSADH, or by genetic testing. ALDH5A1 is the only gene currently known to be associated with SSADH deficiency, and genetic testing can detect mutations in about 97% of affected individuals.[3]

Treatment

Treatment of succinic semialdehyde dehydrogenase deficiency (SSADH) is generally symptomatic and typically focuses on the treatment of seizures and neurobehavioral disturbances. Antiepileptic drugs (AEDs) that have proven to be effective in treating the seizures associated with this condition include carbamazepine and lamotrigine (LTG). Medications such as methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines appear to be effective at treating anxiety, aggressiveness, inattention, and hallucinations. Additional treatments may include physical and occupational therapy, sensory integration, and/or speech therapy.[3]

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Organizations Providing General Support

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • Genetics Home Reference (GHR) contains information on Succinic semialdehyde dehydrogenase deficiency. This website is maintained by the National Library of Medicine.
      • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Succinic semialdehyde dehydrogenase deficiency. Click on the link to view a sample search on this topic.

          Selected Full-Text Journal Articles

            References

            1. Succinic Semialdehyde Dehydrogenase Deficiency. NORD. 2003; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1113/viewAbstract. Accessed 9/25/2013.
            2. Succinic semialdehyde dehydrogenase deficiency. Genetics Home Reference. June 2008; https://ghr.nlm.nih.gov/condition/succinic-semialdehyde-dehydrogenase-deficiency. Accessed 9/25/2013.
            3. Pearl PL, Dorsey AM, Barrios ES, Gibson KM. Succinic Semialdehyde Dehydrogenase Deficiency. GeneReviews. September 19, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1195/. Accessed 9/25/2013.
            4. Crutchfield SR, Haas RH, Nyhan WL, Gibson KM.. Succinic semialdehyde dehydrogenase deficiency: phenotype evolution in an adolescent patient at 20-year follow-up. Developmental medicine and child neurology. November 2008; 50(11):880-881. https://www.ncbi.nlm.nih.gov/pubmed?term=18811705. Accessed 9/25/2013.

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