Succinic semialdehyde dehydrogenase (SSADH) deficiency is an ultra-rare inborn error of metabolism that results in disrupted gamma-amino butyric acid (GABA) catabolism. In addition to developmental delay, intellectual disability, hypotonia, ataxia, and seizures, a variety of neuropsychiatric symptoms may occur, including psychosis. By highlighting all available and relevant case reports/series, this qualitative review seeks to characterize the prevalence, clinical manifestation, pathophysiology, and treatment of psychotic symptoms in this population. Psychosis occurs in a minority of SSADH-deficient individuals, and most commonly presents as auditory or visual hallucinations with an onset in adolescence or young adulthood. Although the pathophysiology underlying the development of psychosis in this context is not fully understood, it likely in part relates to increased GABA and/or gamma hydroxybutyric acid activity. Although antipsychotic medications should be used cautiously in SSADH deficiency, they may be effective at treating emergent psychotic symptoms.

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of γ-aminobutyric acid metabolism, leading to elevated levels of γ-aminobutyric acid and γ-hydroxybutyric acid in cerebrospinal fluid.
METHODS: We describe the neuroimaging findings of a previously healthy 6-month-old girl with acute onset of lethargy, hypotonia, and choreiform movements, and a subsequent diagnosis of SSADH deficiency. Magnetic resonance (MR) imaging of the brain revealed symmetric T2 hyperintense signal abnormalities and reduced diffusivity of the globus pallidi bilaterally. Arterial spin-labeling perfusion MR imaging suggested bilateral hyperperfusion of the globus pallidi. MR spectroscopy of the thalamus and frontal lobe white matter revealed increased signal intensity in the glutamate and glutamine region of the spectra between 2.1 and 2.4 ppm.
CONCLUSIONS: The unique early imaging findings described here may be attributable to bioenergetic failure and deficiency in mitochondrial energy metabolism and are consistent with SSADH-knockout mice studies.

OBJECTIVE: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a neurometabolic disease in which the degradation of γ-aminobutyric acid (GABA) is impaired. The purpose of this study was to report two novel ALDH5A1 mutations responsible for SSADH deficiency in a Chinese family and the prenatal diagnosis of an at-risk fetus with DNA sequencing.
RESULTS: Genetic analysis of ALDH5A1, in a child with SSADH deficiency, parents, and 10 weeks\' gestation at-risk fetus and 100 healthy unrelated volunteers, was performed. The coding sequence and the intron/exon junctions of ALDH5A1 were analyzed by bidirectional DNA sequencing. The proband was identified to have a compound heterozygous mutations with c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a deleterious mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier, but not affected, and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis. A study in 2003 described 35 mutations of ALDH5A1 in 54 unrelated families, and the current study and systematic literature review identified nine additional novel mutations in eight unrelated families bringing the total number of unique mutations of ALDH5A1 resulting in SSADH deficiency to 44, and the 44 mutations occur from exon 1 to exon 10. No mutational hotspots or prevalent mutations were observed, and all mutations appeared vital for the function of SSADH.
CONCLUSIONS: Two novel ALDH5A1 mutations likely responsible for SSADH deficiency were identified, and DNA sequencing provided an accurate diagnosis for an at-risk fetus whose sibling had SSADH deficiency.