Succinic Semialdehyde Dehydrogenase Deficiency
What else is it called?
- 4-hydroxybutyric aciduria
- Gamma-hydroxybutyric acidemia
- gamma-hydroxybutyric aciduria
- SSADH deficiency
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What causes it?
SSADH deficiency is caused by mutations (changes) in the ALDH5A1 gene. This gene gives instructions for producing the succinic semialdehyde dehydrogenase enzyme which is involved in the breakdown of GABA (gamma-amino butyric acid), a chemical that transmits signals in the brain.
The main role of GABA is to avoid the brain from being overloaded with too many signals. A deficiency (lack) of succinic semialdehyde dehydrogenase causes an increase in the amount of GABA and a related molecule called GHB (gamma-hydroxybutyrate) in the body, mainly in the brain and the spinal cord. However, it is unclear how the increase in GABA and GHB causes the symptoms of SSADH deficiency.
How common is it?
Approximately 450 people have been reported with SSADH deficiency worldwide.
What are the signs and symptoms?
Initial symptoms may vary from patient to patient but usually include delays in achieving motor milestones (crawling, sitting unaided, unaided walking), reduced muscle tone and delays in intellectual or language development.
Symptoms usually start during infancy or childhood however, sometimes it does not get diagnosed until later in life and often not until adulthood.
SSADH symptoms can be mild, moderate or severe and usually differ greatly between patients.
Common symptoms (>70 % of patients):
- Delayed gross motor development (such as crawling, sitting, walking and running)
- Delayed fine motor skills development (such as movement of hands and fingers)
- Delayed speech and language development
- Hypotonia (floppy baby syndrome/low muscle tone)
Frequent symptoms (30-70% of patients)
- Hyporeflexia (below normal or absent reflexes)
- Ataxia (A group of disorders that affect coordination, balance and speech)
- Behavioural problems
- Hyperkinesis (muscle spasm)
- Sleep disturbance
Unusual Symptoms (<30% of patients)
- Neonatal problems
- EEG abnormalities
- Psychoses (A mental health problem causing people to perceive or interpret things differently from those around them, might involve hallucinations or delusions)
- MRI or CT abnormalities
- Oculomotor apraxia (the absence of or fault in controlled and voluntary eye movement)
- Microcephaly (a condition where the head circumference is smaller than normal)
- Macrocephaly (an overly large head)
- Hyperreflexia (overactive reflexes)
- Somnolence (sleepiness/drowsiness/sleeping for unusually long periods)
- Autistic features
- Choreoathetosis (involuntary movements)
- Myopathy (A disease in the muscles causing muscular weakness)
How is it diagnosed?
SSADH deficiency diagnosis is first based on a clinical examination looking for symptoms linked to the condition. It is usually first suspected in late infancy or early childhood in individuals who have encephalopathy, damage in the brain that alters the structure or function of the brain. This may be shown through cognitive impairment, language delays, poor muscle tone, seizures, decreased reflexes and difficulty in coordinating movements. Experts suggest that SSADH should be considered if two or more of these symptoms are present with unknown cause.
Specialised urine tests can be useful in the diagnosis of SSADH to show the presence of 4-hydroxybutyric acid.
The diagnosis can be confirmed by an enzyme test showing a deficiency of SSADH. It can also be confirmed using genetic testing as genetic testing can detect mutation of the ALDH5A1 gene in about 97% of affected individuals.
Can it be treated?
The treatment of SSADH is specific to treating the symptoms that are present in individual patients. In some patients, treatment may include the use of certain medication to control, reduce or prevent seizures.
Early intervention is very important in patients with SSADH to help them reach their potential. Other services that may be helpful for SSADH patients include physical therapy, speech therapy and occupational therapy.
Do my family need to be tested?
SSADH deficiency is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.
The pattern of inheritance of SSADH deficiency is autosomal recessive. This means that carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with SSADH deficiency are carriers.
When both parents are carriers, the risk to the baby in each pregnancy is
- 25% chance (1 in 4) of developing the condition
- 50% chance (1 in 2) for the baby to be a carrier of the condition
- 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier
Genetic counselling can be requested to get a full explanation.