Déficit de succínico semialdehído deshidrogenasa. Disminución de los niveles de 4 OH butírico con dosis bajas de vigabatrina

Escalera, G. Iglesias; Ferrer, I; Ml, Carrasco-Marina; Ruíz-Sala, Pedro; Salomons, Gajja S.; Jakobs, C.; Pérez‐Cerdá, Celia

doi:10.1016/j.anpedi.2009.09.018

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…As an example, we can see the potential outcome of multifactorial linkages in the treatment of SSADHD with vigabatrin. Biochemical data in the cerebrospinal fluid of patients receiving high-dose vigabatrin supports the biochemical effect (lowered GHB, elevated GABA; Gibson et al 1995), yet the clinical response to vigabatrin is highly variable, with some patients showing benefit, others not showing benefit, and even some patients demonstrating clinical deterioration on this agent (Good 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). The recent identification of another aldehyde dehydrogenase in addition to ALDH5A1 (e.g., ALDH1A1) which mediates GABAergic neurotransmission pathway in non-GABAergic neurons of mammalian brain adds another layer to the complexity of understanding of the pathophysiology of SSADHD (Kim et al 2015).…”

Section: Discussionmentioning

confidence: 94%

“…However, treatment with VGB has resulted in mixed outcomes in SSADHD (Vogel et al 2013). Further, long-term treatment with VGB is contraindicated due to marked and permanent visual-field impairments (Singh et al 2013; Froger et al 2014; Good et al 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). Of further concern is the predicted expectation that VGB will augment brain GABA (Ergezinger et al 2003; Pearl et al 2014a; 2014b), which is a relevant observation in light of recent studies (described above) highlighting GABA-induced impairment of autophagic processes (Vogel et al 2015).…”

Section: Treatment Of Ssadhdmentioning

confidence: 99%

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Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Malaspina

Roullet

Pearl

et al. 2016

Neurochemistry International

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Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

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Section: Discussionmentioning

confidence: 94%

Section: Treatment Of Ssadhdmentioning

confidence: 99%

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Malaspina

Roullet

Pearl

et al. 2016

Neurochemistry International

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“…While the pallidal hyperintensity is usually homogeneous and equally affects the internal and external portions, we have had occasional patients with heterogeneous and even asymmetric involvement. Magnetic resonance spectroscopy will show spectra for routine single and multi-voxel studies of N-acetyl aspirate, choline, and lactate, but specialized protocols that allow editing for small molecules has shown elevated levels of GABA and related compounds (including GHB and homocarnosine) in patients but not obligate heterozygotes [12, 13]. Fluorodeoxyglucose PET studies have shown decreased cerebellar glucose metabolism in patients with cerebellar atrophy demonstrated on structural MRI [1, 14].…”

Section: Human Phenotypementioning

confidence: 99%

Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Pearl

Shukla

Theodore

et al. 2011

Brain and Development

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Objectives Succinic semialdehyde dehydrogenase (SSADH) deficiency is a gamma-aminobutyric acid (GABA) degradative defect. Epilepsy affects half of patients. The murine model is associated with a transition from absence to convulsive seizures in the third week, with fatal status epilepticus. Methods The clinical phenotype is reported from a patient database. Flumazenil-Positron Emission Topography (FMZ-PET) and Transcranial Magnetic Stimulation (TMS) were used to study GABA neurotransmission. Electrocorticography, single cell electrophysiology, and radioligand binding studies are reported from animal studies. Results Generalized seizures predominate, including tonic-clonic, atypical absence, and myoclonic. EEG discharges are typically generalized spike-wave. MRI shows a dentatopallidoluysian pattern. Sudden Unexpected Death in Epilepsy Patients (SUDEP) has occurred and the associated neuropathology reveals chronic excitotoxic injury in gloubus pallidus. Investigations using FMZ-PET and TMS support downregulation of GABAA and GABAB activity, respectively, in patients. Gamma-hydroxybutyrate (GHB) induces spike-wave discharges in homozygous null mice via GHB and GABAB-mediated mechanisms. These resemble absence seizures and are abolished by a GABAB receptor antagonist. Decreased binding of GABAA and GABAB receptor antagonists has been demonstrated in P19 and P14 null mice, respectively. Downregulation of GABAA and GABAB receptor subunits is observed by P14. GABAA and GABAB mediated potentials are reduced from P8–P14. Conclusion Generalized epilepsy and epileptiform discharges are characteristic of SSADH deficiency. Spontaneous absence seizures appear in null mice by the third week, which may be induced by GHB or GABAB activity. Subsequent overuse dependent downregulation of GABAA and GABAB receptor activity may be associated with hyperexcitability concomitant with the transition to generalized seizures.

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Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency

et al. 2016

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The incidence of succinic semialdehyde dehydrogenase (SSADH) deficiency, an autosomal recessive inherited disorder of GABA degradation, is unknown. Upon a recent diagnosis of a new family of affected fraternal twins from the Punjabi ethnic group of India, case ascertainment from the literature and our database was done to determine the number of confirmed cases along with their geographic distribution. The probands presented with global developmental delay, infantile onset epilepsy, and a persistent neurodevelopmental disorder upon diagnosis at 10 years of age with intellectual disability, expressive aphasia, and behavioral problems most prominent for hyperactivity. Gamma-hydroxybutyric aciduria and homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations were confirmed. Identification of all available individual cases with clinical details available including geographic or ethnic origin revealed 182 patients from 40 countries, with the largest number of patients reported from the USA (24%), Turkey (10%), China (7%), Saudi Arabia (6%), and Germany (5%). This study provides an accounting of all published cases of confirmed SSADH deficiency and provides data useful in planning further studies of this rare inborn error of metabolism.

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Déficit de succínico semialdehído deshidrogenasa. Disminución de los niveles de 4 OH butírico con dosis bajas de vigabatrina

Cited by 6 publications

References 24 publications

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency

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