Diagnostic challenges in a severely delayed infant with hypersomnolence, failure to thrive and arteriopathy: A unique case of γ‐hydroxybutyric aciduria and Williams syndrome

Knerr, Ina; Gibson, K. Michael; Ganesh, Jaya; Bennett, Michael J.; Salomons, Gajja S.; Jakobs, Cornelis; Myers, Scott M.

doi:10.1002/ajmg.b.30553

Cited by 4 publications

(2 citation statements)

References 17 publications

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“…The clinical features include global developmental delay, hypotonia, epilepsy, extrapyramidal manifestations, and hyporeflexia (Pearl et al 2003; 2003, 2005; 2009; Novotny et al 2003; Knerr et al 2007, 2008, 2010; Kim et al 2011; Vogel et al 2013). Diagnosis of autism spectrum disorder occurs disproportionately (Gibson et al 2003).…”

Section: Succinic Semialdehyde Dehydrogenase Deficiency (Ssadhd)mentioning

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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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: Succinic Semialdehyde Dehydrogenase Deficiency (Ssadhd)mentioning

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

View full text Add to dashboard Cite

show abstract

“…SSADH deficiency has rarely been detected in association with a second genetic disorder, e.g. in a patient with WAGRO syndrome (Wilms_ tumour, aniridia, genital abnormalities, mental retardation, and obesity) (Jung et al 2006) and Williams-Beuren syndrome (Knerr et al 2007).…”

mentioning

confidence: 99%

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1^−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

Knerr

Pearl

Snead

et al. 2007

J of Inher Metab Disea

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We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (gamma-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of gamma-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH-/- (e.g. Aldh5a1-/-) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1-/- mice accumulate GHB and gamma-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1-/- mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.

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Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose

Amsterdam

Brunt

McMaster

et al. 2012

Neuroscience & Biobehavioral Reviews

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Diagnostic challenges in a severely delayed infant with hypersomnolence, failure to thrive and arteriopathy: A unique case of γ‐hydroxybutyric aciduria and Williams syndrome

Cited by 4 publications

References 17 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

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1^−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose

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Diagnostic challenges in a severely delayed infant with hypersomnolence, failure to thrive and arteriopathy: A unique case of γ‐hydroxybutyric aciduria and Williams syndrome

Cited by 4 publications

References 17 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

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose

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Product

Resources

About

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1^−/− mice and characterization of γ‐hydroxybutyric acid pharmacology