Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency

Johansen, Sys Stybe; Wang, X.; Pedersen, Daniel Sejer; Pearl, Phillip L.; Roullet, Jean-Baptiste; Ainslie, Garrett R.; Vogel, Kara R.; Gibson, K. Michael

doi:10.1007/8904_2017_3

Cited by 11 publications

(6 citation statements)

References 23 publications

(34 reference statements)

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“…1 Recent longitudinal studies have demonstrated changes in GABA and GHB levels with age, with highest levels seen in the first years of life. 2,3 Clinical presentation is typically hypotonia and developmental delay. Nonprogressive ataxia, hyporeflexia, behavioral dysregulation, obsessive-compulsive disorder, anxiety disorder, and attention-deficit/hyperactivity disorder are additional signs and symptoms with high prevalence.…”

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confidence: 99%

Novel ALDH5A1 variants and genotype

et al. 2020

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Objective:To determine genotype-phenotype correlation in SSADH deficiency.Methods:ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.Results:Twenty-four subjects were enrolled (10M, 14F, median age 8.2y). There were 24 ALDH5A1 variants, including seven novel pathogenic variants: two missense, three splice site, two frameshift. Four previously reported variants were identified in >5% unrelated families. There was a correlation with age and presence (p=0.003) and severity (p=0.002) of epilepsy, and with OCD (p=0.016). The median IQ score was 53 (Q25 49–Q75 61). There was no overall correlation between the gene variants to the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only subject with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype.Conclusions:Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADHD. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find, however, a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.

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Novel ALDH5A1 variants and genotype

et al. 2020

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“…47,48 An age-dependent decrease in GABA and GHB levels toward more normal values follows. 49,50 This decrease in GABA and GHB levels, paired with downregulation of GABA-A and GABA-B receptors, 10,48 may explain the evolving phenotype seen in human subjects, who show more tendency toward compulsive behavior, sleep disturbance, and seizures with age. 5 The outcome measures we used, the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation parameters, may not have been sensitive enough to show therapeutic effects.…”

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confidence: 99%

A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency

et al. 2021

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We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 ( P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency. Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667

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“…GHB can be clinically assessed in whole blood, plasma, or dried blood spots 3,4 ; however, a negative correlation with age has been reported for GHB levels in dried blood spots, wherein the GHB concentrations for some patients previously diagnosed with SSADHD, when assessed at older ages, were below the threshold determined for newborn detection. 3,5 -7 These findings indicate that some individuals, when assessed at older ages, may be missed with current biomarker cutoffs, increasing the need to better understand variant pathogenicity. 3,5,6…”

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confidence: 99%

“…3,5 -7 These findings indicate that some individuals, when assessed at older ages, may be missed with current biomarker cutoffs, increasing the need to better understand variant pathogenicity. 3,5,6…”

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Assessing Prevalence and Carrier Frequency of Succinic Semialdehyde Dehydrogenase Deficiency

Martin

McConnell²,

Elsea

2021

J Child Neurol

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Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of ∼1/340, supporting a prevalence of SSADH deficiency of ∼1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease.

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Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency

Cited by 11 publications

References 23 publications

Novel ALDH5A1 variants and genotype

Novel ALDH5A1 variants and genotype

A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency

Assessing Prevalence and Carrier Frequency of Succinic Semialdehyde Dehydrogenase Deficiency

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