Clinical spectrum of succinic semialdehyde dehydrogenase deficiency

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

“…PET with [18F]-fluorodeoxyglucose ([18F]-FDG PET) showed decreased cerebellar glucose metabolism in patients with known cerebellar atrophy on structural MRI. 1 Magnetic resonance spectroscopy (MRS) showed elevated occipital GABA in 5 affected subjects, but not in parents. 4 A mouse model of SSADH deficiency showed high GABA and GHB levels in neural tissue, altered GABA binding in cerebral cortex, and reduced expression of GABA A and GABA B receptors.…”

“…About 350 patients are known, with about 85% under 18, making this the most prevalent pediatric neurotransmitter disorder. 1 In the absence of SSADH, transamination of GABA to succinic semialdehyde is followed by its conversion to 4-hydroxybutryic acid (gamma-hydroxybutyric acid, or GHB), leading to CNS GABA and ␥-hydroxy butyrate (GHB) accumulation. 2 Major clinical manifestations include developmental delay, hypotonia, ataxia, and seizures.…”

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

“…Several publications have also presented many "expanded phenotypes" for genetic and metabolic conditions in association with ASDs' phenotypes. [10][11][12][13][14][15] These factors have led to an increase in the number of referrals to the clinical geneticist and an increase in the diagnostic yield.…”

Epilepsy and inborn errors of metabolism in children

“…The group of progressive myoclonic epilepsies usually starts in adolescence and comprises mitchochondrial disorders, especially MERRF, but also other disorders as Lafora body disease, CLN2, sialidosis type I and Unverricht-Lundborg disease. Appropriate genetic or histopathological testing is important if metabolic (Pearl et al 2003). Epilepsy is also part of the symptoms in hyperinsulinism/hyperammonaemia (HI/HA) syndrome and can present with myoclonic absences (Bahi-Buisson et al 2008).…”