Prenatal Diagnosis of Succinic Semialdehyde Dehydrogenase Deficiency: Increased Accuracy Employing DNA, Enzyme, and Metabolite Analyses

Hogema, Boris M.; Akaboshi, Shinjiro; Taylor, Mélissa; Salomons, G. S.; Jakobs, Cornelis; Schutgens, R. B. H.; Wilcken, Bridget; Worthington, Sharron; Maropoulos, George; Grompe, Markus; Gibson, K. Michael

doi:10.1006/mgme.2000.3145

Cited by 28 publications

(23 citation statements)

References 11 publications

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“…This table includes the six families of whom the mutations were previously published [Chambliss et al, 1998;Hogema et al, 2001a;Aoshima et al, 2002]. Only three alleles (in families 19, 25, and 29) could not be attributed to specific mutations at the genomic level, showing that the methods employed by us resulted in a high mutation detection rate (97%).…”

Section: Results Genotypingmentioning

confidence: 96%

“…The ¢gure is drawn to scale with the size of the introns reduced to 5% of the actual length for clarity. [Chambliss et al, 1998;Hogema et al, 2001a;Aoshima et al, 2002] are summarized in Table 3. Patients from 23 of the 55 different families were compound heterozygotes and in 32 families patients were homozygous.…”

Section: Results Genotypingmentioning

confidence: 99%

“…Although the disease is usually diagnosed during childhood it has been found in adults as well . EEG and MRI abnormalities have been described in some cases, but proper diagnosis can only be achieved by organic acid analysis of urine or plasma, followed by enzymatic determination of SSADH activity in leukocytes, and recently by DNA sequence analysis [Gibson et al, 1991[Gibson et al, , 1994Chambliss et al, 1998;Hogema et al, 2001a;Aoshima et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

“…Eight different pathologic mutations in the ALDH5A1 gene in patients from six different families have been described in the literature [Chambliss et al, 1998;Hogema et al, 2001a;Aoshima et al, 2002]. Mutant in vitro expression has not been performed in these studies, and the possibility that some of the mutations represent nonpathogenic polymorphisms could not be excluded.…”

Section: Introductionmentioning

confidence: 99%

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Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

et al. 2003

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Communicated by Johannes ZschockeSuccinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology. Hum Mutat 22:442-450,

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Section: Results Genotypingmentioning

confidence: 96%

Section: Results Genotypingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

et al. 2003

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“…The original assay employed to quantify SSADH enzyme activity in white blood cells utilized a coupled system (conversion of radiolabeled GABA to succinate, basically coupling the activities of GABA-transaminase with SSADH), which lacked sensitivity for heterozygote detection or for potential prenatal diagnostic studies (83,138). A significant methodological improvement in enzyme analysis came with the development and implementation of a sensitive fluorometric 692 KIM ET AL.…”

Section: B Human Ssadh Deficiency: Early Clinical Metabolic and Enmentioning

confidence: 99%

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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Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency

Gropman

2003

Ann Neurol.

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Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.

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Prenatal Diagnosis of Succinic Semialdehyde Dehydrogenase Deficiency: Increased Accuracy Employing DNA, Enzyme, and Metabolite Analyses

Cited by 28 publications

References 11 publications

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

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

Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency

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