Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity

Jung, Ronny; Rauch, Anita; Salomons, Gajja S.; Verhoeven, Nanda M.; Jakobs, Cornelis; Gibson, K. Michael; Lachmann, Ehrenfried; Sass, Jörn Oliver; Trautmann, Udo; Zweier, Christiane; Staatz, Gundula; Knerr, Ina

doi:10.1016/j.ymgme.2006.02.003

Cited by 21 publications

(14 citation statements)

References 30 publications

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“…Loss of this cysteine residue has been previously demonstrated dramatically to reduce enzyme activity 40. A patient with combined ALDH5A1 deficiency and incomplete WAGR (aniridia, hemihypertrophy, and Wilms' tumour) syndrome was described by Jung and collaborators 45. Absence of enzyme activity in the proband's leukocytes was associated with homozygosity for a novel c.587G > A missense mutation (p.G196D).…”

Section: Human Aldh5a1 Deficiencymentioning

confidence: 96%

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

et al. 2009

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for g-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1 -/-knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or g-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB,. Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.

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Section: Human Aldh5a1 Deficiencymentioning

confidence: 96%

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

et al. 2009

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“…We report the presence of two rare heritable disorders (or one heritable disorder and a probable new mutation). In only a single instance has SSADH deficiency been detected in association with a second disorder, a patient with WAGRO syndrome (Wilms' tumor, aniridia, genital abnormalities, mental retardation, and obesity) [Jung et al, 2006]. Conversely, WS has been described with phosphoserine phosphatase deficiency, Rieger's syndrome, craniosynostosis, Crohn and chronic granulomatous disease, and Burkitt lymphoma [Balacco‐Gabrieli et al, 1985; Jaeken et al, 1997; Morimoto et al, 2003; Gilbert‐Barness et al, 2004; Thornburg et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

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

Gibson

Ganesh

et al. 2007

American J of Med Genetics Pt B

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Metabolic work-up, pursued in a 5-month-old female infant with hypersomnolence, failure to thrive, and global developmental delay, led to the identification of gamma-hydroxybutyric aciduria (GHB). Succinic semialdehyde dehydrogenase deficiency (SSADH deficiency) was confirmed enzymatically and molecularly. Characteristic dysmorphic facies, cardiovascular anomalies, and hypercalcemia led to clinical suspicion of Williams-Beuren syndrome (WS), confirmed by cytogenetic studies. This rare occurrence of two unrelated genetic conditions highlights the importance of instituting comprehensive metabolic studies despite the presence of syndromic findings, even in the absence of other metabolic abnormalities that may be indicative of metabolic disease such as hyperammonemia, hypoglycemia, ketonuria, and metabolic acidosis.

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“…The main characteristics are stated in the acronym: Wilms tumor (an embryonic malignancy of the kidney), aniridia, genitourinary malformations and mental retardation or ID. Obesity or severe hyperphagia has also been described in a subgroup of these patients, in which case the condition is often called WAGRO . Secondary features often seen in WAGR patients are renal problems, cardiopulmonary defects and behavioral difficulties like autism .…”

Section: Wilms Tumor Aniridia Genitourinary Malformations and Mentamentioning

confidence: 99%

“…Obesity or severe hyperphagia has also been described in a subgroup of these patients, in which case the condition is often called WAGRO. [156][157][158][159][160][161][162] Secondary features often seen in WAGR patients are renal problems, cardiopulmonary defects and behavioral difficulties like autism. 160,163 Due to the specific combination of manifestations, the differential diagnosis of WAGR is very limited.…”

Section: Bardet-biedl Syndromementioning

confidence: 99%

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

2018

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Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.

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Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity

Cited by 21 publications

References 30 publications

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

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

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

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