Succinic semialdehyde dehydrogenase deficiency

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.^[2]

There is a wide variety in the range, severity and presentation of the symptoms of SSADH deficiency, so the time of diagnosis varies among affected individuals. Furthermore, some of the symptoms can be somewhat "nonspecific", potentially leading to difficulties with diagnosis.^[1] Studies have shown that the symptoms are first reported at a average age of 11 months (with a range of 0-44 months), and the average age at diagnosis is approximately 6.6 years of age.^[2] Although symptoms are usually noticed during infancy or childhood, the disorder sometimes has not been diagnosed until adulthood.^[1]

In some cases, a diagnosis of SSADH deficiency may be considered before a child is born, especially if an unborn child is known to be at a high risk for being affected with the condition (i.e. if there is a family history of the condition or both parents are known carriers). Specialized tests during the pregnancy such as amniocentesis or chorionic villus sampling (CVS) may detect increased amounts of 4-hydroxybutyric acid in the amniotic fluid or deficient SSADH enzyme activity in cells of the fetus or placenta.^[1]

Unfortunately, there is no way to predict how severely affected an individual might be. Unrelated affected individuals show a very wide range in nature and severity of signs and symptoms. There may be more consistency within families, but this is not always the case. Furthermore, there appears to be no consistent relationship between the level of the SSADH enzyme present (or the mutations present) and the signs and symptoms that an individual manifests. The degree of severity generally depends on the specific signs and symptoms that develop in each affected individual and generally becomes apparent as the child ages.^[3]

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.