Succinic semialdehyde dehydrogenase deficiency

This is part of Rare diseases.

Diagnosis: Succinic semialdehyde dehydrogenase deficiency

Synonyms: SSADH deficiency


Date of publication: 2014-10-16
Version: 2.0



The disease

Succinic semialdehyde dehydrogenase deficiency is an inherited, congenital metabolic disease caused by an absence of, or reduced levels of activity in, an enzyme called succinic semialdehyde dehydrogenase. This enzyme deficiency interferes with the metabolism of a chemical neurotransmitter in the central nervous system called gamma-aminobutyric acid (GABA). This affects the brain, resulting in varying levels of developmental impairment and also affecting speech, language and motor skills, and causing behavioural abnormalities. The disease is also known as SSADH deficiency, a term which will be used in the following information.

SSADH deficiency was described for the first time in 1981 by the Dutch paediatrician Cornelis Jakobs and his colleagues.


International medical literature shows that approximately 450 people around the world have been diagnosed with the disease, but the actual total of affected individuals is not known. As symptoms can vary greatly, it can be assumed that there are people with the disorder who have not received a diagnosis. In Sweden, only a few individuals have been identified.


The disease is caused by an absence of, or decreased activity in, the enzyme succinic semialdehyde dehydrogenase (SSADH). Enzymes are proteins which accelerate chemical reactions in the body. Normally SSADH works together with another enzyme, gamma-aminobutyric acid (GABA transaminase), to transform GABA into succinate. Reactions in the citric acid cycle release energy from succinate in the cell's mitochondria. Mitochondria are small units in the cells where chemical reactions take place which convert energy into forms that are usable by the organs.

Defects in the SSADH enzyme (the substance occurring in the last step of the process whereby GABA is broken down) allow it to accumulate, after which it is transformed into gamma hydroxy butyrate (GHB). GABA is an important neurotransmitter in the central nervous system. Elevated levels of GABA and GHB in the brain are thought to be the primary cause of the disease’s neurological symptoms. GHB is a by-product formed when GABA is broken down, but it is also found in certain pharmaceutical products. Abuse of GHB has led to its being classified as a controlled substance in Sweden.

SSADH deficiency is caused by a mutation in the ALDH5A1 gene located on chromosome 6 (6p22). ALDH5A1 controls the production of (codes for) the enzyme succinic semialdehyde dehydrogenase.


The inheritance pattern of SSADH deficiency is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


Symptoms vary greatly and can present at any time between birth and early adulthood. They also vary widely as regards severity. Although the disease is usually identified during infancy or when the individual is developing, symptoms may be so mild that the diagnosis is not made before adulthood.

Enzyme deficiency in newborns can present as apathy, feeding difficulties, breathing problems and low blood sugar (hypoglycaemia). Children may not cry or react to visual stimuli in the same way as other children.

The first sign in small children is often delayed development. Children do not learn to sit, crawl and walk at the usual times. They may have low muscle tone (hypotonia), difficulties controlling and co-ordinating muscle movements (ataxia), writhing, exaggerated, involuntary movements (choreoathetosis) and epileptic seizures. Abnormal patterns of movement tend to normalize over time. Seizures occur in approximately half of those affected and commonly take the form of periods of loss of awareness, or tonic-clonic seizures (epileptic seizures with convulsions and loss of consciousness, previously called grand mal).

Sometimes there are further neurological or neuromuscular symptoms. They can include impaired or sometimes wholly absent reflexes (hyporeflexia or areflexia) and abnormally high levels of physical activity (hyperkinesis). Involuntary, prolonged muscle contractions (dystonia) or brief, rhythmical twitching (myoclonus) may also occur.

The disease is characterised by a developmental impairment affecting cognitive, motor and language development. Speech and language abnormalities can vary greatly between different children with the disease. It is primarily the capacity for self-expression, including the ability to produce sounds and select the right word or way of communicating, which is affected. In severe cases speech may be almost entirely lacking or consist of only a couple of words or simple phrases, while in other individuals speech and language impairment may be almost undetectable.

The disease is also associated with behavioural abnormalities such as hyperactivity, aggression and self-destructive and autism-like behaviour patterns. This may mean, for example, that the child does not communicate, avoids social contact and shows stereotypical motor movements. Hallucinations may occur and a psychotic state may develop. Sleeping problems and extreme sleepiness are common.

Eye symptoms may also present. These may include involuntary eye movements (nystagmus) and difficulties in consciously coordinating eye movements and following an object with the eyes (ocular motor apraxia).

In individual cases, there are skull and facial (craniofacial) abnormalities such as an unusually small or large head (micro or macrocephaly).

Adults with the disease usually have behavioural, language and sleep disorders and most have epileptic seizures. They may have had these symptoms for some time without their leading to a diagnosis of this type of disease, and there may be delays and difficulties before the correct diagnosis is made.


The disease is indicated by characteristic symptoms including raised levels of GHB in urine, plasma and cerebrospinal fluid. GHB is an extremely volatile substance. For this reason, the test sample should be analysed using a combined gas chromatography-mass spectrometry (GC/MS) analysis. It is confirmed by measuring low SSADH activity in white blood cells. The activity of the damaged enzyme can be measured in its effect on white blood cells, and is often less than 5 per cent of normal levels.

Magnetic resonance imaging (an MRI scan) show changes in the brain. These include changes within some of the large central groups of nerve cells (the globus pallidus and dentate nucleus) as well as reduced quantities of white matter in both the cerebellum and cerebrum. An electroencephalogram (an EEG) of the brain can show changes associated with epilepsy as well as a characteristically slow background brainwave rhythm.

In most cases DNA analysis will show a genetic mutation. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with in vitro fertilization (IVF), are available to families where the mutation has been identified.


There is no cure for SSADH deficiency, and efforts are focused on alleviating symptoms and attempting to compensate for disabilities. Different specialists collaborate in medical treatment, which is primarily directed at controlling seizures and limiting behavioural abnormalities.

A neuropsychiatric evaluation should be carried out to assess autistic symptoms, concentration problems and other behavioural disorders. A neuropsychological investigation is included in this examination and is important for estimating levels of cognitive development. Hyperactivity, a lack of impulse control and temper tantrums are often difficult to deal with. Medication may be required to supplement pedagogical and psychological measures.

Epilepsy can be treated with medication. Lamotrigin is reported to have positive results. In theory, Vigabatrin should be beneficial in selectively inhibiting the GABA transaminase enzyme, but in practice it has not proved effective. Valproat is not used as it inhibits remaining activity in the succinic semialdehyde dehydrogenase enzyme. Benzodiazepines, risperidone, fluoxetine and ritalin are used to control behavioural problems.

Another treatment is the ketogenic diet. The diet includes a high proportion of fat and low amounts of protein and carbohydrates. It requires detailed instructions and careful monitoring of what the child consumes.


The extent of the child's disabilities determines which habilitation measures are required. In order to stimulate the child's development and help compensate for loss of function, action should be taken early. A habilitation team includes professionals with special expertise in different aspects of the disability and how they affect everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields.

Habilitation focuses on existing needs, may vary over time and occur in collaboration with individuals close to the child. Habilitation includes testing, treatment, the selection and supply of aids, information on the disability and counselling. It also includes information about support offered by Swedish public services as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support. The family may also require help in coordinating different forms of help.

In cases of speech and language impairment, it is important that a communication assessment is carried out. This will form the basis for systematic speech and language training. Alternative, complementary, communication methods which are not based on speech (Augmentative Alternative Communication - AAC) may be appropriate.

A program of motor training and support is designed with the child’s needs in focus.

The child's social environment is also important and people close to the child require knowledge of the best ways to approach children and young people with the condition. This is particularly important in the case of behavioural abnormalities. The team provides guidance for parents and others close to the child, with the aim of helping them stimulate the child and reinforce positive behaviour.

Local Swedish public agencies can offer different forms of support to facilitate the family's everyday life. Respite care can, for example, take the form of a contact family or short-term accommodation outside the home. Care assistance can help the family lead an active life despite the child or young person's extensive disabilities.

Adults with the disease may require continued individual habilitation and support in their daily lives. Those people who develop symptoms as adults require different medical and rehabilitation measures depending on the nature and severity of their symptoms and disabilities.

Practical advice


National and regional resources in Sweden

Children’s and young people’s clinics at Sweden’s university hospitals investigate and treat cases of SSADH deficiency.

Hällsboskolan in Sigtuna is a special state school for children with severe language impediments, and has affiliates in several areas of Sweden. Contact Elisabeth Ångström, tel: +46 10 473 53 46, email: elisabeth.angstrom@spsm.se. Many local authorities also have special classes for children with language and speech impediments

Resource personnel

Associate Professor Niklas Darin, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: niklas.darin@vgregion.se.

Associate Professor Mårten Kyllerman, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: marten.kyllerman@vgregion.se.

Senior Physician Karin Naess, Paediatric Neurology and Habilitation, The Astrid Lindgren Children’s Hospital, Huddinge, and The Center for Inherited Metabolic Diseases, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: karin.naess@karolinska.se.

Dr Gunilla Rejnö-Habte Selassie, MD and speech therapist.The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, tel: +46 31 343 40 00, email: gunilla.rejno-habte-selassie@vgregion.se.

Dr Gerd Viggedal, MD and psychologist, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: gerd.viggedal@vgregion.se

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations etc.

There are currently no special associations for people with SSADH deficiency in Sweden, but the following organizations are involved with developmental and language disorders.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Industrivägen 7 (visitors address), Box 1181, 171 23 Solna Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Talknuten, Parent Association, The Aphasia Association in Sweden. Tel: +46 8 545 663 60 or +46 8 545 663 74, email: talknuten@afasi.se, www.afasi.se.

DHB, The Swedish National Association for Deaf, Hearing-Impaired and Language-Impaired Children, Klostergatan 15, SE-703 61 Örebro, Sweden. Tel: +46 19 17 08 30, text tel: dial +46 19 19 68 90 and give the number 019122146*, videophone: see website. Email: kansliet@dhb.se, www.dhb.se.

There is an association for children and families with SSADH in the US,

Courses, exchanges of experience for personnel


Research and development

International research is currently investigating taurine treatment and the effects of an antagonist on GABA receptors.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under "Mer hos oss" in the right hand column.)

Ågrenska has published information on severe language impairments, no. 345 (2009). In Swedish only. These newsletters are edited summaries of lectures delivered at family and adult stays at Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.


Jakobs C, Bojasch M, Mönch E, Rating D, Siemes H, Hanefeld F. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities: the probability of a new inborn error of metabolism. Clin Chim Acta 1981; 111: 169-178.

Knerr I, Pearl PL, Bottiglieri T, Snead OC, Jakobs C, Gibson KM. Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (gamma-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1-/- mice and characterization of gamma-hydroxybutyric acid pharmacology. J Inherit Metab Dis 2007; 30: 279-294.

Knerr I, Gibson KM, Jakobs C, Pearl PL. Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients. CNS Spectr 2008; 13: 598-605.

Pearl PL, Gibson KM, Cortez MA, Wu Y, Carter Snead O 3rd, Knerr I et al. Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis 2009; 32: 343-352.

Pearl PL, Gibson KM, Acosta MT, Vezina LG, Theodore WH, Rogawski MA et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 2003; 60: 1413-1417.

Pearl PL, Novotny EJ, Acosta MT, Jakobs C, Gibson KM. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003; 54: 73-80.

Spilioti M, Evangeliou AE, Tramma D, Theodoridou Z, Metaxas S, Michailidi E et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci 2013; 7: 858.

Vogel KR, Pearl PL, Theodore WH, McCarter RC, Jacobs C, Gibson KM. Thirty years beyond discovery – clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. J Inherit Metab Dis 2013; 36: 401-410.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: succinic semialdehyde dehydrogenase deficiency

GeneReviews (University of Washington)
www.genetests.org (select "GeneReviews", then "Titles")
search: succinic semialdehyde dehydrogenase deficiency

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Mårten Kyllerman, The Queen Silvia Children's Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-10-16
Version: 2.0
Date of publication of Swedish version: 2014-06-23

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.