To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients.
The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families.
The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients.
Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.
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"Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessively inherited disorder that results in loss of activity in SSADH (an enzyme responsible for metabolism of GABA), reduced GABA breakdown, and excessive accumulation of both GABA and GHB in the cerebrospinal fluid  . Clinical symptoms are varied but include delayed intellectual, speech and language development, ataxia and, significantly, generalised absence seizures   . Using a recently developed SSADH knock-out (SSADH −/− ) mouse   , we have been able to demonstrate that in these animals, which replicate the epileptic phenotype displayed in humans with SSADH deficiency, there is a significant enhancement of tonic GABA A currents in TC neurons compared to their WT counterparts, Figures 3(a) and 3(c) . "
[Show abstract][Hide abstract] ABSTRACT: It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABA(A) receptors (eGABA(A)R) and augmented "tonic" GABA(A) inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABA(A)R gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABA(A)Rs in absence epilepsy.
Advances in Pharmacological Sciences 09/2011; 2011(1687-6334):790590. DOI:10.1155/2011/790590
"No standard therapy for SSADH deficiency exists, although vigabatrin is considered to be a logical choice because it inhibits the conversion of GABA–GHB . However, the laboratory and clinical reports of the effect of vigabatrin have been inconsistent . Moreover, vigabatrin is not currently available in Japan; thus, we administered PB to control severe seizures in our patient. "
[Show abstract][Hide abstract] ABSTRACT: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting γ-aminobutyric acid degradation. We describe here a boy with a severe phenotype of SSADH deficiency. He was referred because of a developmental delay at 4 months of age. At the age of 8 months, severe seizures developed. The diagnosis of SSADH deficiency was confirmed by an increase in 4-hydroxybutyric acid and heteroallelic mutation in the ALDH5A1 gene. His seizures were successfully treated with high-dose phenobarbital, and the electroencephalogram (EEG) abnormalities were ameliorated. However, the patient showed a degenerative clinical course with severe neurological deficits. A magnetic resonance imaging (MRI) scan revealed abnormal high intensities in the putamina and caudate nuclei on T2-weighted images, followed by marked atrophic changes. The clinical manifestation of our patient indicates the wide variety of SSADH deficiency phenotypes.
Brain & development 05/2011; 34(2):107-12. DOI:10.1016/j.braindev.2011.05.003 · 1.88 Impact Factor
"transa - minase inhibitor , remains the most widely used drug in SSADH deficiency with a variable success ( Uziel et al . , 1993 ; Gibson et al . , 1995 ; Gibson and Jakobs , 2001 ; Ergezinger et al . , 2003 ; Gropman , 2003 ) . The lack of a therapeutic efficacy of this antiepileptic drug reflects heterogeneity at the genetic or enzymatic level ( Gibson et al . , 1997 ) . On the other hand , Howells et al . ( 1992 ) have suggested that vigabatrin has limited use in SSADH deficiency because of differential effects on organ specific GABA transaminases . These investigators postulated that , although vigabatrin effectively inhibits brain GABA transaminase , limited inhibition of peripheral organ transam"
[Show abstract][Hide abstract] ABSTRACT: GHB is a naturally occurring compound in the central nervous system (CNS) whose tissue concentration are highly increased during drug abuse and in the inherited deficiency of succinic semialdehyde dehydrogenase (SSADH) activity. SSADH deficiency is a neurometabolic-inherited disorder of the degradation pathway of gamma-aminobutyric acid (GABA). It is biochemically characterized by increased concentrations of gamma-hydroxybutyric acid (GHB) in tissues, cerebrospinal fluid (CSF), blood and urine of affected patients. Clinical manifestations are variable, ranging from mild retardation of mental, motor, and language development to more severe neurological symptoms, such as hypotonia, ataxia and seizures, whose underlying mechanisms are practically unknown. In the present study, the in vitro and in vivo effects of GHB was investigated on some parameters of oxidative stress, such as chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), as well as the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in homogenates from cerebral cortex of 15-day-old Wistar rats. In vitro, GHB significantly increased chemiluminescence and TBA-RS levels, while TRAP and TAR measurements were markedly diminished. In contrast, the activities of the antioxidant enzymes SOD, CAT and GPX were not altered by GHB in vitro. Acute administration of GHB provoked a significant enhance of TBA-RS levels and a decrease of TRAP and TAR measurements. These results indicate that GHB induces oxidative stress by stimulating lipid peroxidation and decreasing the non-enzymatic antioxidant defenses in cerebral cortex of young rats. If these effects also occur in humans, it is possible that they might contribute to the brain damage found in SSADH-deficient patients and possibly in individuals who consume GHB or its prodrug gamma-butyrolactone.
Neurochemistry International 03/2007; 50(3):564-70. DOI:10.1016/j.neuint.2006.11.007 · 3.09 Impact Factor