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Succinic Semialdehyde Dehydrogenase Deficiency

Last updated Jan. 3, 2019

Approved by: Krish Tangella MD, MBA, FCAP

Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency is a condition characterized by low levels of the enzyme SSADH in the body. It is an inborn error of metabolism, a condition in which the metabolism (chemical reactions in our body) is affected due to a defective or absent enzyme or protein.


What are the other Names for this Condition? (Also known as/Synonyms)

  • 4-Hydroxybutyric Acidemia
  • GABA Metabolic Defect
  • Succinate-Semialdehyde:NAD+ Oxidoreductase Deficiency

What is Succinic Semialdehyde Dehydrogenase Deficiency? (Definition/Background Information)

  • Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency is a condition characterized by low levels of the enzyme SSADH in the body. It is an inborn error of metabolism, a condition in which the metabolism (chemical reactions in our body) is affected due to a defective or absent enzyme or protein
  • SSADH Deficiency is a rare genetic disorder, in which there is a mutation in the ALDH5A1 gene that encodes (contains the information necessary for the proper synthesis of) the SSADH enzyme
  • The individuals affected could have a number of nonspecific symptoms such as delayed developmental milestones, poor speech and language ability, improper gross and fine motor skill development, mental retardation, and behavioral disturbances
  • Though the symptoms begin to manifest in early infancy, SSADH Deficiency disorder is usually diagnosed only during childhood, or sometimes, only into adulthood
  • The treatment for SSADH Deficiency is mainly focused on the management of symptoms. The prognosis of the disorder depends upon many factors and it varies from one individual to another

Who gets Succinic Semialdehyde Dehydrogenase Deficiency? (Age and Sex Distribution)

  • Succinic Semialdehyde Dehydrogenase Deficiency is a very rare inherited disorder. Only around 400 cases of SSADH Deficiency have been identified so far. The diagnosed individuals are from many different countries and they include Turks, Indians, Caucasian Americans, Northern Europeans, Koreans, Palestinians, Syrians, Iranians, Pakistanis, Saudis, Chinese, and Inuits
  • This condition could likely be underreported due to its rare occurrence; with just a few cases reported worldwide and with its set of nonspecific symptoms
  • Infants, children, and adults have been diagnosed with this condition
  • Males and females are equally affected.

What are the Risk Factors for Succinic Semialdehyde Dehydrogenase Deficiency? (Predisposing Factors)

The risk factors for Succinic Semialdehyde Dehydrogenase Deficiency include:

  • Family history of this condition, since SSADH Deficiency is an autosomal recessive disorder: In an autosomal recessive disease, both the genes of the pair are defective and the disease is manifested. Such individuals inherit both defective genes from their parents, who are both carriers of the disorder
  • Consanguineous (closely-related by blood) parents, who are apparently healthy, have a higher chance to be carriers of the same defective gene

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Succinic Semialdehyde Dehydrogenase Deficiency? (Etiology)

  • Succinic Semialdehyde Dehydrogenase Deficiency is a genetic disorder that is inherited in an autosomal recessive manner. In SSADH Deficiency, there is a mutation in the ALDH5A1 gene that encodes the SSADH enzyme
  • As of now, this is the only gene mutation identified in individuals with this condition. This gene is located on the short arm (p) of chromosome 6 (6p22). SSADH is an enzyme involved in the metabolism of gamma-amino butyric acid (GABA)
  • GABA is a neuro-transmitter, a chemical compound which helps the nerve cells in the central nervous system to communicate with each other (through electrical activity). GABA inhibits or dampens the electrical activity of the nerve cells. Thus, it is a neuroinhibitory transmitter
  • Normally, GABA is broken down to Succinic Semialdehyde (SSA), which is further broken down by SSADH to produce succinate. When SSADH is deficient, SSA is converted into excess amounts of gamma-hydroxybutyrate (GHB), also known as 4-hydroxybutyricacid
  • An imbalance in the level of these chemical messengers causes abnormalities in the functioning of the nervous system. The signs and symptoms seen in SSADH are due to excess GABA and GHB (GABA-like). Elevated levels of GHB can be found in urine, plasma (fluid portion of blood) and cerebrospinal fluid (fluid covering the brain and spinal cord)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Succinic Semialdehyde Dehydrogenase Deficiency?

  • Succinic Semialdehyde Dehydrogenase Deficiency typically affects the central nervous system. The severity of the symptoms varies from one individual to another, even if affected individuals belong to the same family
  • The symptoms are nonspecific, meaning that many diseases or conditions can have such similar symptoms
  • Generally, children have symptoms of non-aggressive (somnolent) nature and adults have symptoms of aggressive nature. The symptoms usually stay the same, in terms of severity, over a period of time

The signs and symptoms of SSADH Deficiency include:

  • In infants, the developmental milestones may be delayed. For example, taking the first steps in walking, smiling, etc. may be delayed
  • Gross motor skill (activities that involve large muscles in the body) and fine motor skill (activities that involve small muscles in the body) development may be delayed
  • Language and speech development delays; some individuals may not speak much
  • Delayed mental development; individuals may also suffer from mental retardation
  • Psychomotor retardation: Learning skills that require both physical and mental coordination may be delayed
  • Decreased muscle tone (hypotonia)
  • Up to 50% of the affected individuals may have seizures /epilepsy
  • Behavioral disturbances may be observed in some individuals, such as increased aggression, unusual irritation, getting frustrated easily, autistic-like features, and self-injurious behavior
  • Ataxia, which is the decreased ability to coordinate voluntary movements. It is one of the symptoms that decrease in severity, as the individual gets older
  • Hyperkinesis (increased muscular activity)
  • Hyporeflexia or hyperreflexia (decreased or increased reflexes)
  • Involuntary eye movements (nystagmus), poor eye vision
  • Somnolence (increased sleepiness), hallucinations
  • Choreoathetosis (movement disorders)
  • Microcephaly or macrocephaly (smaller or larger than normal head size)

How is Succinic Semialdehyde Dehydrogenase Deficiency Diagnosed?

The diagnosis Succinic Semialdehyde Dehydrogenase Deficiency may include:

  • Thorough evaluation of the individual’s medical history and a complete physical examination. An increased suspicion is needed to diagnose SSADH Deficiency, due to its rarity, the nonspecific nature of symptoms, and variable presentation
  • Appropriate referral to pediatricians, pediatric neurologists, neurologists, and other healthcare providers may be necessary
  • Screening test: Detection of increased concentrations of GHB (gamma-hydroxybutyrate) in urine
  • Confirmatory test: Measurement of SSADH enzyme activity in white blood cells (leukocytes)
  • Imaging studies: MRI scan, electroencephalography (EEG), FDG-PET study, and MR spectroscopy may also be employed
  • Tests to check for developmental delays in the child
  • Genetic testing: Sequence analysis to detect mutations in the ALDH5A1 gene. This test is also done on individuals who have a family history of SSADH Deficiency and are planning to get pregnant

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Succinic Semialdehyde Dehydrogenase Deficiency?

The complications of Succinic Semialdehyde Dehydrogenase Deficiency include:

  • Psychiatric symptoms may cause the most disability
    • Children may have prominent attention deficit hyperactivity disorder (ADHD) and even aggression
    • Adolescents and adults may be affected by anxiety and obsessive-compulsive disorders
  • About 10% of the affected individuals have early-onset severe movement disorders
  • Fits (seizures) may progress to status epilepticus (continuous fits), which may even lead to death

How is Succinic Semialdehyde Dehydrogenase Deficiency Treated?

The treatment options of Succinic Semialdehyde Dehydrogenase Deficiency are mainly aimed at managing the symptoms and these include:

  • For seizures, antiepileptic drugs, such as lamotrigine, carbamazepine, and vigabatrin, may be prescribed
  • For anxiety, aggressive behavior, hallucinations, inattentiveness, and other related conditions, appropriate medication, such as benzodiazepines, fluoxetine, risperidone, or methylphenidate, may be given
  • Appropriate supportive therapy, such as speech therapy, physical and occupational therapy, may be provided as required, based on the most concerning symptoms of the affected individual

Medications that are currently being studied in the clinical trials are SGS-742, rapamycin, taurine, temsirolimus, everolimus, and other drugs.

How can Succinic Semialdehyde Dehydrogenase Deficiency be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Succinic Semialdehyde Dehydrogenase Deficiency disorder, since it is a genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

However, it is possible to diagnose SSADH Deficiency before birth, and hence, offer a choice to the parents as to how they want to proceed with the pregnancy. The tests used include:

  • Detection of raised levels of GHB (gamma-hydroxybutyrate)  in the amniotic fluid (fluid that surrounds the fetus in the womb)
  • Detection of decreased activity of the SSADH enzyme in certain fetal cells. This is done by removing placental tissue by chorionic villus sampling

What is the Prognosis of Succinic Semialdehyde Dehydrogenase Deficiency? (Outcomes/Resolutions)

The long-term prognosis of Succinic Semialdehyde Dehydrogenase Deficiency is not described, due to the limited number of cases reported worldwide, generic nature of the symptoms, and limited extended follow-up of affected individuals.

  • The prognosis of each individual depends on the major symptoms they are affected with
  • It is generally not a progressive disease and the symptoms usually remain the same (static) over a period of time
  • The disease-progression may vary between individuals depending on the primary symptoms they have

Additional and Relevant Useful Information for Succinic Semialdehyde Dehydrogenase Deficiency:

Banking DNA: Individuals affected with SSADH Deficiency can give a sample of their blood to be stored for future research, for their self-benefit and the benefit of others.

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


Helpful Peer-Reviewed Medical Articles:


Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: May 31, 2015
Last updated: Jan. 3, 2019