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Succinic semialdehyde dehydrogenase deficiency


Other Names for this Disease
  • 4-hydroxybutyric aciduria
  • GABA metabolic defect
  • Gamma-hydroxybutyricaciduria
  • SSADH deficiency
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Overview



What is succinic semialdehyde dehydrogenase deficiency?

What are the symptoms of succinic semialdehyde dehydrogenase deficiency?

What causes succinic semialdehyde dehydrogenase deficiency?

How is succinic semialdehyde dehydrogenase deficiency inherited?

How is succinic semialdehyde dehydrogenase deficiency diagnosed?

How might succinic semialdehyde dehydrogenase deficiency be treated?

What is the prognosis for individuals with succinic semialdehyde dehydrogenase deficiency?


What is succinic semialdehyde dehydrogenase deficiency?

Succinic semialdehyde dehydrogenase (SSADH) deficiency is 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]
Last updated: 9/25/2013

What are the symptoms of succinic semialdehyde dehydrogenase deficiency?

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]
Last updated: 9/25/2013

What causes succinic semialdehyde dehydrogenase deficiency?

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]
Last updated: 9/25/2013

How is succinic semialdehyde dehydrogenase deficiency inherited?

Succinic semialdehyde dehydrogenase deficiency (SSADH) is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.[2]
Last updated: 9/25/2013

How is succinic semialdehyde dehydrogenase deficiency diagnosed?

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]
Last updated: 9/25/2013

How might succinic semialdehyde dehydrogenase deficiency be treated?

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]
Last updated: 9/25/2013

What is the prognosis for individuals with succinic semialdehyde dehydrogenase deficiency?

There has been very limited extended follow-up of this condition from childhood into adulthood, so little is known about the long-term prognosis for individuals with the condition. Because the nature and severity of signs and symptoms are so variable among affected individuals, the prognosis and quality of life likely depend on the specific features each affected individual has.

In the limited information available about SSADH deficiency in older individuals, it has been reported that the main neurobehavioral features present in adolescents and adults with the condition include attention deficit, hyperactivity, anxiety, obsession-compulsion, aggressive behavior, hallucinatory episodes, and autistic features.[4] One article discussing how SSADH deficiency affected a single individual over 20 years reported that hyperactivity in adolescence evolved into moderate psychopathology in adulthood, which consisted of depression and obsession-compulsion. The authors of this study report that features in this individual are similar to those seen in others. They also stated that the individual did not have any further neurological deterioration over the 20-year period.[4] However, this information about a single affected individual may not apply to other individuals with the condition.
Last updated: 9/25/2013

References
  1. Succinic Semialdehyde Dehydrogenase Deficiency. NORD. 2003; http://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; http://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; http://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. http://www.ncbi.nlm.nih.gov/pubmed?term=18811705. Accessed 9/25/2013.