In the early 1980s, a group of German pediatricians discovered a novel metabolic defect in children that caused severe developmental delays and neurological abnormalities. This defect was later found to be produced by mutations in the ALDH5A1 gene, which codes for the enzyme succinic semialdehyde dehydrogenase (SSADH). We showed in textbook Figure 16.4B that SSADH is responsible for converting succinic semialdehyde, the immediate product of GABA breakdown, to succinic acid. When SSADH activity is normal, almost all GABA metabolism flows through that pathway, with only a small amount flowing through the alternate pathway that produces GHB. However, when a mutation occurs in the ALDH5A1 gene that either causes no SSADH protein to be produced or causes the production of an inactive enzyme, GHB levels in the body rise markedly. Indeed, GHB concentrations in the plasma, urine, and cerebrospinal fluid (CSF) can reach hundreds of times the levels seen in healthy individuals. CSF concentrations of GABA are also elevated, but only 2- to 4-fold above the normal range.
The epidemiology and clinical features of SSADH deficiency are summarized in two recent reviews (Pearl et al., 2015; Malaspina et al., 2016). The disorder is quite rare, with fewer than 500 cases reported worldwide thus far. Diagnosis usually occurs during infancy, although roughly 10% of cases are not diagnosed until adolescence or adulthood. Late diagnosis may occur because of the nonspecific features of the neurological symptoms accompanied by a lack of testing for GHB in earlier urine screens performed on the patient. Once excessive GHB levels have been detected in the urine, the disorder can be confirmed by sequencing the mutant ALDH5A1 gene.
One of the hallmark symptoms of SSADH deficiency is global developmental delay. Depending on severity of the disorder, patients exhibit varying degrees of intellectual deficits, psychomotor retardation, and delayed speech and language development. Motor problems include hypotonia and hyporeflexia (poor muscle tone and impaired motor reflexes), and ataxia. Children are also at increased risk of developing an autism spectrum disorder. When they reach adulthood, patients may exhibit anxiety disorders (including obsessive-compulsive disorder), other neuropsychiatric symptoms, and sleep disturbances (Lapalme-Remis et al., 2015). Many patients also develop seizure disorders, either during childhood or later in life.
The mechanistic links between these various outcomes and the biochemical abnormalities of elevated GHB and GABA remain unclear. We saw in textbook Box 8.2 that GABA functions as an excitatory rather than an inhibitory transmitter during early brain development. Thus, abnormal brain development in infants with SSADH deficiency could be related, at least in part, to excessive neural excitation caused by chronically elevated GABA levels. Of course, the extremely high levels of GHB produced by SSADH deficiency probably also contribute to neural dysfunction, although the functional consequences of this biochemical abnormality are not yet fully understood.
Like other inborn errors of metabolism, SSADH deficiency is a lifelong disorder, at least until a future gene therapy is developed to correct the genetic anomaly. At present, the disorder cannot be cured, and the accompanying developmental deficits can have severe consequences for later functioning. Therefore, affected children should receive appropriate interventions (e.g., special education and physical, occupational, and speech therapies) to maximize their developmental potential. Adults with SSADH deficiency may be treated with drugs to ameliorate ongoing neurological (e.g., seizures) and neuropsychiatric symptoms.
Lapalme-Remis, S., Lewis, E. C., De Meulemeester, C., Chakraborty, P., Gibson, K. M., Torres, C., et al. (2015). Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology, 85, 861–865.
Malaspina, P., Roullet, J.-B, Pearl, P. L., Ainslie, G. R., Vogel, K .R., and Gibson, K. M. (2016). Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem. Int., 99, 72–84.
Pearl, P. L.,. Parviz, M., Vogel, K., Schreiber, J., Theodore, W. H., and Gibson, K. M. (2015). Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 identification. Dev. Med. Child Neurol., 57, 611–617.