Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

Pearl, Phillip L.; Gibson, K. Michael; Cortez, Miguel A.; Wu, Ying; Snead, O. Carter; Knerr, Ina; Forester, K.; Pettiford, J. M.; Jakobs, Cornelis; Theodore, William H.

doi:10.1007/s10545-009-1034-y

Cited by 104 publications

(104 citation statements)

References 37 publications

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“…A pattern of dentate-pallidal hyperintensity has been described. 3 There are also areas of abnormal T2-weighted signal in cerebral white matter and brainstem. PET with [18F]-fluorodeoxyglucose ([18F]-FDG PET) showed decreased cerebellar glucose metabolism in patients with known cerebellar atrophy on structural MRI.…”

mentioning

confidence: 99%

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

Pearl¹,

Gibson²,

Quezado³

et al. 2009

Neurology

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Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gammahydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utiliz- Succinic semialdehyde dehydrogenase (SSADH) deficiency, also called 4-hydroxybutyric aciduria (McKusick 279180) and aldehyde dehydrogenase 5a1 (Aldh5a1), is an autosomal recessive disorder. 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. Hyperkinetic behavior, aggression, self-injurious behaviors, and hallucinations have also been described; EEG abnormalities include generalized and focal epileptiform discharges, photosensitivity, and background slowing.

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mentioning

confidence: 99%

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

Pearl¹,

Gibson²,

Quezado³

et al. 2009

Neurology

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“…Murphy and coworkers employed competition, inhibition, and immunoblotting studies to demonstrate that SSADH, in rat brain, was the major aldehyde dehydrogenase responsible for 4-HNE disposition, but only a minor contributor to its metabolism in liver. This raises the possibility that 4-HNE may accumulate in neural tissue of SSADH-deficient patients and might contribute to pathophysiology (144)(145)(146).…”

Section: B Role Of Ssadh In 4-hydroxynonenal Metabolismmentioning

confidence: 99%

“…Utilization of electroretinography and ocular Doppler ultrasonography technology for assessment of optic nerve fiber layer thickness remains preliminary at this time for such applications. MRI signal changes, particularly prominent in the GABA-rich thalamus and basal ganglia, in infants treated with relatively high doses of vigabatrin pose additional concerns regarding vigabatrin use in SSADH deficiency (145,146). While vigabatrin will lead to at least transient decreases in CSF GHB levels (50), there may be a deleterious effect related to attendant increases in CSF (and brain) GABA levels (142).…”

Section: Treatment Strategies and Challengesmentioning

confidence: 99%

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Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Kim

Pearl

Jensen

et al. 2011

Antioxidants & Redox Signaling

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADHdeficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation=reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691-718.

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“…Mild developmental delay, psychomotor retardation, hypotonia, ataxia are observed along with extrapyramidal symptoms such as dystonia, choreoathetosis and myoclonus. More than 50% of affected individuals develop seizures (64)(65)(66)(67). Neuroimaging screening generally reveals hyper intensities in globus pallidus, sub cortical white matter, cerebellar dentate nucleus and brain stem (68).…”

Section: Succinic Semialdehyde Dehydrogenase (Ssd) Deficiencymentioning

confidence: 99%

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

Naik¹,

Prasad²,

Cucullo³

2012

Dehydrogenases

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Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

Cited by 104 publications

References 37 publications

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

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

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

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