Succinic semialdehyde dehydrogenase deficiency

Neurogenetic Disorders

Updated 07.02.2024
Released 11.28.1994
Expires For CME 07.02.2027

Succinic semialdehyde dehydrogenase deficiency

Authors: Itay Tokatly Latzer MD, Phillip L Pearl MD

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Editor: Barry Wolf MD PhD

Succinic semialdehyde dehydrogenase deficiency

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Introduction

Overview

Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited disorder that interferes with the catabolism of the brain’s major inhibitory neurotransmitter, gamma-amino butyric acid (GABA). The absence of succinic semialdehyde dehydrogenase activity results in the accumulation of GABA and other GABA-related metabolites, such as gamma hydroxybutyric acid. Succinic semialdehyde dehydrogenase deficiency is caused by homozygous or compound heterozygous mutations in the ALDH5A1 gene. The clinical presentation ranges in severity with a broad range of symptoms, including developmental delays, intellectual disabilities, movement disorders (ataxia and dyskinesia), hypotonia, behavioral dysregulation, and epilepsy. The age of onset of symptoms is also variable, although most individuals with the disorder present in early childhood. In this article, the authors review the current literature on this topic.

Key points

	• Succinic semialdehyde dehydrogenase deficiency is an autosomal recessive disorder caused by pathological variants in the ALDH5A1 gene.
	• The clinical presentation typically consists of developmental delay identified in early childhood with or without hypotonia, and later with expressive language impairment, intellectual disabilities, seizures, and psychiatric and behavioral problems, such as anxiety, obsessive compulsive symptoms, hyperactivity, and inattention.
	• MR imaging shows T2-weighted hyperintensities in the globus pallidus, subthalamic nucleus, and cerebellar dentate nuclei, and spectroscopy shows elevated GABA as measured in voxels of basal ganglia and cerebral cortex.
	• The major diagnostic criterion is persistently elevated GHB in physiologic fluids and is usually detected on urine organic acids and confirmed via gene sequencing.
	• A focus on natural history studies has revealed a significant negative age correlation with GHB and GABA, as well as worsening of psychiatric symptoms and epilepsy during adolescence and adulthood.
	• Treatment of succinic semialdehyde dehydrogenase deficiency continues to be the treatment of symptoms, although there are ongoing preclinical trials assessing the feasibility of enzyme and gene replacement therapies.

Historical note and terminology

In 1981, the index patient was described with 4-hydroxybutyric aciduria, a previously unrecognized organic aciduria (41). Although definitive enzyme studies were lacking, these investigators hypothesized that 4-hydroxybutyric aciduria resulted from an inherited deficiency of succinic semialdehyde dehydrogenase, or SSADH (E.C. 1.2.1.24), an enzyme involved in the metabolism of the inhibitory neurotransmitter GABA. GABA is metabolized to succinic acid by the sequential action of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid). Jakobs and colleagues suggested that in response to an inherited deficiency of succinic semialdehyde dehydrogenase, accumulated succinic semialdehyde would undergo reduction to 4-hydroxybutyric acid in a reaction catalyzed by one or more 4-hydroxybutyrate dehydrogenases (E.C. 1.1.1.61). At that time, it was believed that eventual diagnosis of putative succinic semialdehyde dehydrogenase deficiency would be dependent on the availability of autopsied brain tissue. It is now understood that in the absence of succinic semialdehyde dehydrogenase, transamination of GABA to succinic semialdehyde is followed by its reduction to 4-hydroxybutyrate (gamma hydroxybutyrate, GHB), a short monocarboxylic fatty acid that accumulates in the urine, serum, and CSF of patients with succinic semialdehyde dehydrogenase deficiency. GHB, whose role is unclear, is an agonist towards both GHB and GABAB receptors (04) and has been considered to be a potential neurotoxic agent that contributes to the clinical manifestations of succinic semialdehyde dehydrogenase deficiency (68).

Biochemical interrelationships in SSADH deficiency

The enzyme defect is marked by the hatched arrow. Abbreviations: GABA, gamma-aminobutyric acid; GHB, gamma-hydroxybutyric acid; TCA, tricarboxylic acid. (Contributed by Dr. Phillip Pearl.)

Clinical manifestations

Presentation and course

Succinic semialdehyde dehydrogenase deficiency is suspected in individuals with slowly progressive or static encephalopathy of late-infantile to early-childhood onset. The disease is characterized by a nonspecific clinical presentation, including hypotonia, ataxia, speech disturbance, developmental delay, intellectual disability, behavioral dysregulation, hyporeflexia, and epilepsy (76). Although this entity is considered slowly progressive or static in nature, more acute or severe phenotypes that include onset with status epilepticus, acute encephalopathy, or a degenerative clinical course in infancy have been described (109; 37; 110). The clinical presentation of succinic semialdehyde dehydrogenase deficiency is not specific (101). Currently, approximately 190 succinic semialdehyde dehydrogenase–deficient patients are followed in a clinical registry of caregiver-reported information maintained at Boston Children’s Hospital and Harvard Medical School (67). Detailed information on common clinical features from 133 succinic semialdehyde dehydrogenase–deficient patients enrolled in the database has been published. The most common clinical features include developmental delay (75%), intellectual disability or cognitive deficit (57%), hypotonia (71%), and ataxia (52%). Seizures are reported in 49% of patients and are more prevalent in subjects 12 years and older (18). These are usually generalized seizures and absence seizures; the median age of onset for absence seizures was 2 years, and for generalized tonic-clonic seizures was 12 years (18). Some patients are known to have recurrent episodes of generalized convulsive status epilepticus (67). These seizures are often difficult to control, and sudden unexpected death in epilepsy (SUDEP) has been reported in 12% of adolescent and adult patients (18). Sleep disorders have been well documented and present as excessive daytime sleepiness as well as disorders of initiating and maintaining sleep (74). A study of 10 patients with overnight polysomnograms and diurnal multiple sleep latency tests showed prolonged latency to stage REM latency and reduced stage REM percentage (77). Also common and most prevalent among adolescents and adults are neuropsychiatric symptoms, including behavior problems and sleep disturbances (49; 18). Ataxia, when present, may improve with age (35). Aggressive, psychotic, hyperactive, and obsessive-compulsive behaviors have been reported (44; 27; 26; 80; 56; 14; 79). Younger patients present with high frequencies of ADHD and anxiety, with features of obsessive-compulsive disorder occurring in adolescence and adulthood (26; 18). Psychosis occurs in 5% to 21% of adult patients (14). No patients have reported symptoms other than those of the central nervous system (54).

Neuropsychological evaluation of 21 patients showed a mean full-scale IQ of 53 (IQR 49-61, range 30 [floor value] to 87) (71).

Neuroimaging data reported in 30 patients revealed T2 hyperintensities in multiple regions, most commonly in the globus pallidus (43%) and dentate nucleus (17%) and occasionally in the white matter (10%) and brainstem (7%). Other noted abnormalities include cerebral atrophy (11%), cerebellar atrophy (7%), and delayed myelination (7%) (70; 01). A pallidal-dentate pattern of combined signal abnormalities involving the globus pallidus and cerebellar dentate nucleus has been reported (111). Involvement of the subthalamic nucleus has been described (72; 09). The basal ganglia abnormalities have been confirmed by pathology with demonstration of dark tan discoloration of the globus pallidus, thought to be suggestive of chronic excitotoxic neuronal injury (50). Normal cerebral imaging has been reported in about half of patients. MR spectroscopy for the standard neuronal markers of N-acetylaspartate, choline, and creatine, with the absence of lactate peak, is normal. An MR imaging and spectroscopy study of 18 patients with succinic semialdehyde dehydrogenase deficiency and 13 age-matched controls showed GABA increases in all examined regions, the posterior cingulate gyrus, the occipital lobe, and the basal ganglia, with GABA concentrations decreasing with age in the basal ganglia (02). Among the 25 patients that had an EEG as a part of the natural history study, 16 (64%) showed mild diffuse background slowing, one had generalized spike-and-wave, two had focal spikes (ages 5 and 9, and without history of seizures), and two had sharp waves (71).

The major diagnostic criterion of succinic semialdehyde dehydrogenase deficiency is persistently elevated GHB in urine, plasma, and CSF (29). However, quantification of this metabolite is difficult because of its volatility. Under routine extraction methods for organic acid analysis, acidification results in lactonization of 4-hydroxybutyric acid to gamma-butyrolactone (GBL), with considerable loss if care is not exercised (42). In a few specialized laboratories, accurate quantification of GHB is achieved using a stable-isotope dilution gas chromatography-mass spectrometry assay method, which employs deuterium labeled GHB the internal standard (22). The urinary concentration of GHB can, however, vary significantly in the same patient from day to day whereas the concentration of GHB in the CSF remains relatively constant (27). Although the hallmark of the disease is an excess of GHB in the physiological fluids, there is no correlation between GHB levels and severity of clinical features (05).

The natural history of succinic semialdehyde dehydrogenase deficiency largely remains unclear. A focus on natural history studies has revealed a significant negative age correlation with GHB and GABA. One study quantified GHB and GABA in plasma and red blood cells of 18 patients, finding a steady state of GHB in red blood cells by 10 years of age and GABA at 30 to 40 years of age (46). After this association was discovered, hair samples from 10 patients with succinic semialdehyde dehydrogenase deficiency were quantified for GHB concentrations, which showed concentrations reaching a normal range at 12 to 13 years of age with only younger patients showing GHB concentrations significantly above the control range (47). This GABA and GHB imbalance may correlate with onset of adolescent/adulthood neuropsychiatric findings and epilepsy (71). The decrease in GABA concentrations that occurs with age is associated with worsening of seizures and primary communications symptoms (93; 95).

Prognosis and complications

The prognosis in succinic semialdehyde dehydrogenase deficiency may be partly delineated by the specific homozygous or compound heterozygous pathogenic variants leading to different functional and structural impairments in semialdehyde dehydrogenase deficiency, as shown by in silico functional analyses (97). A variable degree of permanent psychomotor deficit and neuropsychiatric morbidity is typical. The age at diagnosis has ranged from the newborn period to 63 years (24; 75; 56), and death in the newborn period or very early childhood has been reported only rarely (83). A validated scoring system of succinic semialdehyde dehydrogenase deficiency may allow physicians to evaluate the clinical severity of individuals with succinic semialdehyde dehydrogenase deficiency using bedside examination (98). The most constant manifestations are developmental delay with emphasis in impaired expressive language, hypotonia, hyporeflexia, behavioral problems, and nonprogressive ataxia. Although resolution of cerebellar ataxia has been observed (35), ongoing problems of hyperkinesis and aggressive behavior, sleep disturbances, and hallucinations have been reported in older patients (28; 26; 44; 43; 40; 70). Disabling movement-induced dystonia has been described, and approximately 10% of patients have a more severe phenotype with prominent extrapyramidal manifestations and a more progressive course (69).

Clinical vignette

A 5-year-old boy presented with severe hyperactivity and a first generalized tonic-clonic seizure. Exam revealed a minimally verbal, nondysmorphic boy with mild hypotonia, hyporeflexia, and gait ataxia. Psychoeducational testing showed mild intellectual disability (Wechlser Intelligence Scales for Children: verbal 55, performance 65) and deficient adaptive behaviors on the Vineland Adaptive Behavioral Composite. EEG revealed mild background slowing during wakefulness but intermittent generalized spike-and-wave paroxysms during sleep. Valproate was begun but was associated with lethargy (possibly attributable to inhibition of any residual enzyme activity). MRI was obtained, demonstrating increased T2-weighted signal in the globus pallidus. Urine organic acids revealed 4-hydroxybutyric aciduria. This subsequently led to enzymatic quantitation of succinic semialdehyde dehydrogenase enzymatic activity in leukocytes, which confirmed the diagnosis. The patient was treated with lamotrigine, with fair seizure control, and has persistent problems with expressive aphasia, obsessive compulsive disorder, and anxiety.

Biological basis

Etiology and pathogenesis

Succinic semialdehyde dehydrogenase deficiency is an autosomal recessively inherited disorder of GABA metabolism (E.C. 1.2.1.24; OMIM #271980, *610045) (67). The gene that is abnormal in succinic semialdehyde dehydrogenase gene, ALDH5A1 (for aldehyde dehydrogenase 5A1), has been mapped to chromosome 6p22 (99).

The primary metabolic abnormality is excessive concentration of GHB in physiologic fluids with elevations up to 800-fold in urine and 200-fold in plasma, in comparison with control ranges (22; 44), and 65- to 230-fold elevation in CSF (26). Succinic semialdehyde dehydrogenase deficiency is not associated with systemic metabolic acidosis (87).

Patients with succinic semialdehyde dehydrogenase deficiency have elevated free and total GABA, homocarnosine, and GHB levels in CSF that have been shown to be detectable by nuclear magnetic resonance (21). Developed as an anesthetic and sedative agent, GHB has been employed experimentally to induce a rodent model of absence seizures (91; 15). Pharmacologic toxicity manifests as drowsiness, hypotonia, and seizure activity. In succinic semialdehyde dehydrogenase deficiency, GHB is present in concentrations that, in human as well as animal models, have been shown to affect neuropharmacology and neurophysiology, including seizures with arrested motor capacity, myoclonic jerks, and behavior disturbances (33; 89; 35; 45). GHB has been used therapeutically in alcohol withdrawal syndromes and is approved (sodium oxybate) by the FDA for the treatment of cataplexy, a disorder of abrupt hypotonia usually associated with narcolepsy. As a putative neurotoxic agent in succinic semialdehyde dehydrogenase deficiency, the role of GHB in the pathophysiology of the disorder is unclear. GHB is an endogenous metabolite (less than 1% of GABA levels) and may be a neurotransmitter (90; 60). GHB has been abused in humans as a recreational drug and to subdue victims for the purpose of sexual assault (63). The primary action of GHB in the CNS is inhibition of presynaptic dopamine release, and at high concentrations, it acts as a GABAb receptor agonist (27; 59; 07). Potential therapeutic uses of GHB have extended beyond the treatment of narcolepsy to alcohol and opiate withdrawal, fatal familial insomnia, difficult cases of labor and delivery, as sedation for controlled ventilation patients, and in the preservation of tissues for transplantation (24).

Data suggest a role for GHB as a neuromodulator or, perhaps, as a neurotransmitter. GHB is known to block monosynaptic and polysynaptic reflex arcs, depress firing of dopaminergic neurons, and depress cortical primary evoked potentials. GHB is also known to depress short-term memory, the mechanism of which remains unknown. GHB has been associated with its own high and low affinity binding sites; GHB binding sites that display different affinities appear distinct from GABA_B receptors, and binding of GHB to these sites (which is antagonized by NCS-382) produces effects similar to those observed with GABA_B receptor activation (39; 90; 92). Studies of [3H] GHB binding suggest that at least one of the specific GHB binding receptors is an isoform of a presynaptic GABA_B receptor (90). This raises the possibility that differing concentrations of GHB could interact with pre- and postsynaptic GABA_B receptors.

Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency has been obtained by determination of 4-hydroxybutyric acid concentration in amniotic fluid in conjunction with assays of succinic semialdehyde dehydrogenase activity in biopsied chorionic villi and cultured amniocytes (23). Increased accuracy is possible by combining metabolite and enzyme analysis with chorionic villus mutation analysis, utilizing reverse-transcription-polymerase chain reaction and genomic DNA amplification followed by sequencing (36).

The ALDH5A1 gene consists of 10 exons that code for 535 amino acids (05). About 100 different pathological variants have been identified, most commonly missense, as well as nonsense, splice mutations, and frameshift mutations. (30; 05; 10; 81; 61). Phenotypic variation is broad (48), and no clear genotype-phenotype relationship has been demonstrated to date (17). In silico studies have shown that a complete lack of or truncated succinic semialdehyde dehydrogenase enzyme, or functional impairment in its catalytic and stabilizing sites, are associated with worse outcomes compared to functional defects in the enzyme’s folding or oligomerization regions (97).

CSF data were reported in 13 patients, showing significant elevations in GHB (65- to 230-fold), high free and total GABA (up to 3-fold), and low glutamine (26). Postulates to explain the predisposition to generalized convulsive seizures in this hyper-GABAergic state include uncoupling of the glial-neuronal glutamine/glutamate/GABA shuttle, excessive GABA_B-mediated inhibition of inhibitory receptors, or reversal of the resting chloride membrane potential above the resting membrane potential so that the effects of GABA are depolarizing. Laboratory investigations demonstrate overexpression of the chloride transporter NKCC1 in an ALDH5A1-deficient mouse model, supporting a depolarizing role for GABA (106).

Further metabolic analysis in the homozygous deficient murine model revealed elevated GHB and total GABA in homogenate from kidney, pancreas, and heart, and elevated beta-alanine (a GABA homologue) in kidney and liver extracts (32). Amino acid analysis in mutant total brain homogenates and also regional sections revealed decreased glutamine concentrations, with normal glutamine synthetase protein and mRNA levels. Studies of oxidative metabolism demonstrated normal concentrations of Krebs cycle (tricarboxylic acid cycle) intermediates but increased 4,5-dihydroxyhexanoic acid, a postulated derivative of succinic semialdehyde (32). Increased oxidative stress and mitochondrial disturbances are indicated by decreased glutathione content in hippocampus and cortex and decreased activities of the respiratory chain in the hippocampus (85).

Increased mitochondrial numbers have been documented in hippocampal neurons of ALDH5A1-/- mice (64). Later, it was discovered that increased GABA concentration in S cerevisiae led to activation of mTOR, manifest as elevated mitochondrial numbers and enhanced oxidative stress. This was also documented in the brain and liver of ALDH5A1-/- mice and could be reversed with the mTOR inhibitor rapamycin (55). Mouse survival improved with a number of mTOR inhibitors. Torin2 did promote correction of GABA_A receptor downregulation but did not decrease seizure frequency or duration (102; 106). In addition, brain-derived neuronal stem cells have been developed from the animal model and showed preliminary positive results from intervention with mTOR inhibitors (103). Moreover, investigations underlying the mechanisms of the ultimately fatal status epilepticus in the mouse model have identified decreased GABA_A receptor antagonist binding at postnatal day 7 that was progressive until the third postnatal week of life. This corresponds to the time when generalized convulsive seizures emerge and rapidly evolve into status epilepticus. There was a substantial downregulation of the beta-2 subunit of GABA_A receptor, a reduction in GABA_A-mediated inhibitory postsynaptic potentials, and enhanced postsynaptic spikes recorded from hippocampal extracellular recordings (108). There was also decreased GABA_B receptor antagonist binding, especially in the hippocampus (11). The hypothesis is that use-dependent downregulation in the GABA_A receptor and GABA_B receptor, likely the result of high circulating GHB and GABA, underlies the predisposition to status epilepticus and may contribute to the pathophysiology of generalized epilepsy, transition from absence to generalized tonic-clonic seizures, and the phenotype found in the human condition (78). A flumazenil-PET study of GABAA receptor activity in human patients showed reduced benzodiazepine binding compared to healthy controls, supporting the hypothesized use-dependent downregulation (73). Reis and colleagues demonstrated that long interval intracortical inhibition was significantly reduced and cortical silent periods were shortened in patients with succinic semialdehyde dehydrogenase deficiency compared to heterozygous parents and controls using transmagnetic stimulation. Schreiber and colleagues found similarly shorter cortical silent periods in seven patients during a 2016 trial of taurine as a potential therapeutic agent. This pattern proposes that the human phenotype is consistent with the proposed mechanism in the murine model (84). However, the largest transmagnetic stimulation study to date performed on 18 patients and eight healthy controls found extended cortical silent periods and no significant difference in long-interval intercortical inhibition. Differences in the age of the cohort as well as different stimulation parameters, namely interstimulus interval duration and suprathreshold stimulation intensity, may explain this inconsistency (100).

Neuronal stem cells were derived from the hypothalamus of ALDH5A1 wild type and ALDH5A1 null mice at postnatal day 1 and day 20. Results indicated dysregulation in multiple epilepsy-related genes, including GABA_A receptor β-3 subunit, sodium-dependent glutamate/aspartate transporter 2, sodium potassium chloride transporter 1, neutral potassium chloride cotransporter, and tumor necrosis factor (103).

The ALDH5A1-/- mice also show downregulation for genes associated with myelin synthesis and compaction (19). These findings are especially significant in the hippocampus and cortex. It is thought that these myelin abnormalities may be caused by decreased phosphorylation of mitogen-activated protein kinase caused by low levels of neurosteroids due to overactivation of GABAergic systems.

These findings are supported by the histopathological postmortem analysis of a patient with succinic semialdehyde dehydrogenase deficiency, which revealed the presence of astrogliosis in the cortex, subcortical white matter, and hippocampus. Phospholipid analysis showed decreases consistent with myelination alterations seen in the murine model (107).

Differential diagnosis

The association of hypotonia, ataxia, hyporeflexia, and seizures are helpful clinical indications to pursue urine organic acid analysis for detection of 4-hydroxybutyric aciduria. This disorder does not typically present with intermittent decompensation or episodic hypoglycemia or acidosis that can occur spontaneously or be triggered by a systemic stressor, as is typical of other metabolic encephalopathies. Clinical findings associated with other organic acid disorders, such as metabolic stroke and megalencephaly, are not characteristic of succinic semialdehyde dehydrogenase deficiency. Basal ganglia signs, including choreoathetosis, dystonia, and myoclonus have been reported in a subgroup (10%) that have had phenotypes that present earlier and are more severe (83). About half of the patients in this subgroup may show a progressive clinical picture of deterioration (69).

Ataxia is suggestive of dysequilibrium syndrome, and a number of cases have been reported (18). Patients are also described as presenting with autism spectrum disorder or are reported to have "autistic features" (34; 43; 101; 82). In the natural history study cohort, 10 of the 20 assessed by neuropsychological evaluation met the criteria for autism spectrum disorder (71). The detection of abnormal signal intensity bilaterally in the globus pallidus by MRI has aided the differential diagnosis by suggesting a metabolic disorder (16; 88; 101; 111). However, abnormal signals bilaterally in the globus pallidus can be seen in other organic acidopathies. Dicarboxylic aciduria and 3-hydroxypropionic acid, detected in the urine of some patients, may suggest an abnormality of fatty acyl-CoA or propionyl-CoA metabolism, but the presence of highly elevated 4-hydroxybutyric acid in urine assists in the diagnosis of succinic semialdehyde dehydrogenase deficiency.

A much rarer autosomal recessively inherited disorder of GABA metabolism is 4-aminobutyrate aminotransferase (ABAT) deficiency or GABA-transaminase deficiency. ABAT is the key enzyme responsible for the catabolism of GABA, and therefore, deficiency of ABAT leads to an accumulation of GABA. Clinical hallmarks are much like those of succinic semialdehyde dehydrogenase deficiency, including ataxia, epilepsy, developmental delay, hypotonia, and hyporeflexia (52; 53). Diagnostic evaluation of organic acids will distinguish succinic semialdehyde dehydrogenase deficiency from ABAT deficiency as succinic semialdehyde dehydrogenase–deficient patients have elevated GHB concentrations, whereas ABAT-deficient patients will not (13). A dual function of the ABAT enzyme has been discovered, in which ABAT not only serves as a key enzyme for GABA metabolism but also serves an essential role in mitochondrial nucleoside salvage by facilitating the conversion of deoxynucleotide diphosphate (dNDP) to deoxynucleotide triphosphate (dNTP), the building block for DNA. ABAT deficiency results in both a neurometabolic disorder as described, as well as mitochondrial genome depletion syndrome (MDS) wherein there is a loss of mitochondrial genome (mtDNA) copy number (08).

Management

There are currently no targeted therapies for succinic semialdehyde dehydrogenase deficiency, and most strategies are directed toward symptomatic treatment as described in the Consensus Guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency (94; 96).

It is advisable that individuals with succinic semialdehyde dehydrogenase deficiency undergo neuropsychological assessments and attend specialized school systems according to their needs and deficits.

Seizures in succinic semialdehyde dehydrogenase deficiency have been shown to be responsive to levetiracetam or lamotrigine, either as monotherapy or in combination with other antiseizure medications, such as carbamazepine, oxcarbazepine, and clobazam. However, this information is based on case reports and relatively small case series and not on randomized control data. It should be noted that valproate is contraindicated in succinic semialdehyde dehydrogenase deficiency because it may inhibit residual succinic semialdehyde dehydrogenase activity.

Vigabatrin, an irreversible inhibitor of GABA-transaminase, inhibits the formation of succinic semialdehyde; therefore, use of this medication is aimed at reducing the formation of GHB. However, therapeutic intervention with vigabatrin has shown inconsistent results in patients with succinic semialdehyde dehydrogenase deficiency (101; 31; 87; 62; 20). Vigabatrin was reported as helpful in psychomotor and language development in an uncontrolled study of two unrelated children, aged 6 and 7 years old, with possible improvement or stabilization in the electroretinogram by supplemental taurine (38). Despite decreased GHB levels, vigabatrin is associated with increased GABA levels, which would not necessarily be desirable. Howells and colleagues suggested that vigabatrin was not effective at inhibiting peripheral GABA-transaminases, leading to a peripheral "resupply" of GHB to the brain and subsequent decrease in the efficacy of vigabatrin therapy (40). Although considered effective as an antiepileptic, specifically for the treatment of infantile spasms in children with tuberous sclerosis, clinical use of the drug has been associated with constriction of the visual fields due to retinal toxicity, and the medication is not approved by the FDA. Casarano and colleagues published a case report documenting a reduction in GHB concentrations in both urine and CSF with evidence of clinical improvement of communicative skills after 36 months of treatment in a patient with mild phenotypic expression (12). Visual field restriction was, however, apparent at the final ophthalmologic examination.

Methylphenidate, risperidone, fluoxetine, thioridazine, and benzodiazepines at standard dosages have been found to be effective therapies for anxiety, aggressiveness, hallucinations, and inattention (26).

Worsening obsessive-compulsive disorder behavior into adulthood is a primary concern of families. A report of a 26-year-old woman cites success in reducing obsessive-compulsive disorder symptoms with combined use of the serotonergic escitalopram and dopaminergic pramipexolehydrochloride (79). Namely, the patient demonstrated improvement in “obsessional slowness,” social engagement, and ability to perform daily tasks. Prior trials of risperidone, methylphenidate, and mirtazapine, all of which are often used to manage SSADH psychiatric symptoms, did not show improvement in this individual.

It is anticipated that therapeutic strategies in the murine model, as discussed above, along with prospective studies of the natural history of this disorder will lead to more successful treatments (71). Among these therapeutic options are different receptor antagonists, including GABA_B receptor antagonist SGS742, GHB antagonist NCS-382 (105), and dietary approaches such as taurine (72) or the ketogenic diet (52; 51). A double-blind, placebo-controlled trial of SGS-742 failed to show improvements in cognition or normalization of cortical excitability (86). NCS-382 has shown promising results in vivo in mice and in vitro using hepatocytes, adding support to the development of NCS-382 as a treatment consideration. Results indicated effectiveness in rescuing ALDH5A1-/- mice from premature lethality and blocking the motor deficits induced by GHB (104). This has not been tested in humans, but pilot in vitro studies have been conducted to test the toxicology in hepatocytes. Safety and toxicology studies support the potential for clinical application. Results indicated very little capacity to inhibit cytochrome P-450 and revealed little evidence of cytotoxicity at doses up to 1 mM (105; 106; 104).

Preliminary animal data suggested a role for the ketogenic diet, but this has not been confirmed with clinical experience (64; 65; 66; 51).

Preliminary evidence of enzyme replacement therapy in the original knockout murine model demonstrates improved survival and correction of several GABA_A receptor subunits, but the study was insufficiently powered for biochemical measures (106). The newest mouse model, created by Dr. Henry Lee, is inducible via tetracycline dosing, which allows for reversible SSADH expression through gene therapy, and is an improvement on the previous static disease model (57). The discovery and development of a succinic semialdehyde dehydrogenase-deficient murine model has led to ongoing studies showing that enzyme-replacement therapy and gene transfer (AAV-based) may result in reversal of symptoms and improved survival (58). These studies are the basis of future development of targeted treatments for humans with succinic semialdehyde dehydrogenase deficiency. This is further supported by molecular studies to better understand the disorder’s pathophysiology using highly enriched succinic semialdehyde dehydrogenase-deficient GABA-ergic neurons that are differentiated from induced pluripotent stem cells (iPSCs) taken from fibroblasts of succinic semialdehyde dehydrogenase-deficient individuals (03).

Conclusion. Since the initial discovery of succinic semialdehyde dehydrogenase deficiency in 1981, we have continued to gain a greater understanding of this unique inherited metabolic disorder. As the field of metabolic epilepsies and epilepsy genetics expands, our understanding will continue to grow and further therapeutic options will be available. Continued collaboration will be necessary as we strive to improve the quality of life of patients with this disorder.

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21: Ethofer T, Seeger U, Klose U, et al. Proton MR spectroscopy in succinic semialdehyde dehydrogenase deficiency. Neurology 2004;62(6):1016-8. PMID 15037717
22: Gibson KM, Aramaki S, Sweetman L, et al. Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom 1990b;19(2):89-93. PMID 2407302
23: Gibson KM, Baumann C, Ogier H, Rossier E, Vollmer B, Jakobs C. Pre- and postnatal diagnosis of succinic semialdehyde dehydrogenase deficiency using enzyme and metabolite assays. J Inherit Metab Dis 1994;17(6):732-7. PMID 7707697
24: Gibson KM, Christensen E, Jakobs C, et al. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics 1997;99(4):567-74. PMID 9093300
25: Gibson KM, Goodman SI, Frerman FE, Glasgow AM. Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxybutyric and dicarboxylic acidurias: potential for clinical misdiagnosis based on urinary organic acid profiling. J Pediatr 1989;114:607-10. PMID 2926573
26: Gibson KM, Gupta M, Pearl PL, et al. Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psych 2003;54(7):763-8. PMID 14512218
27: Gibson KM, Hoffmann G, Hodson AK, Bottiglieri T, Jakobs C. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 1998;29(1):14-22. PMID 9553943
28: Gibson KM, Hoffmann G, Nyhan WL, et al. 4-Hydroxybutyric aciduria in a patient without ataxia or convulsions. Eur J Pediatr 1988;147(5):529-31. PMID 3409929
29: Gibson KM, Hoffmann G, Rating D. Acidemia, gamma-hydroxybutyric. In: Buyse ML, editor. Birth defects encyclopedia. Cambridge, Massachusetts: Blackwell Scientific, 1990a:17-8.
30: Gibson KM, Jakobs C. Disorders of beta- and gamma-amino acids in free and peptide linked forms. In: Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The metabolic and molecular bases of inherited disease, 8th ed. McGraw-Hill: New York, 2001a:2079-105.
31: Gibson KM, Jakobs C, Ogier H, et al. Vigabatrin therapy in six patients with succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 1995;18(2):143-6. PMID 7564230
32: Gibson KM, Schor DS, Gupta M, et al. Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. J Neurochem 2002;81(1):71-9. PMID 12067239
33: Godschalk M, Dzoljic MR, Bonta IL. Slow wave sleep and a state resembling absence epilepsy induced in the rat by gamma-hydroxybutyrate. Eur J Pharmacol 1977;44(2):105-11. PMID 407087
34: Haan EA, Brown GK, Mitchell D, Danks DM. Succinic semialdehyde dehydrogenase deficiency-a further case. J Inherit Metab Dis 1985;8:99. PMID 2433500
35: Hodson AK, Gibson KM, Jakobs C. Developmental resolution of ataxia in succinic semialdehyde dehydrogenase deficiency. Ann Neurol 1990;28:438.
36: Hogema BM, Akaboshi S, Taylor M, et al. Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: increased accuracy employing DNA, enzyme, and metabolite analyses. Mol Genet Metab 2001a;72(3):218-22. PMID 11243727
37: Horino A, Kawawaki H, Fukuoka M, et al. A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression. Brain Dev 2016;38(9):866-70. PMID 27117035
38: Horvath GA, Hukin J, Stockler-Ipsiroglu SG, Aroichane M. Eye findings on vigabatrin and taurine treatment in two patients with succinic semialdehyde dehydrogenase deficiency. Neuropediatrics 2016;47(4):263-7. PMID 27104484
39: Hosford DA, Wang Y, Liu CC, Snead OC. Characterization of the antiabsence effects of SCH 50911, a GABA-B receptor antagonist, in the lethargic mouse, gamma-hydroxybutyrate and pentylenetetrazole models. J Pharmacol Exp Ther 1995;274:1399-1403. PMID 7562514
40: Howells D, Jakobs C, Kok RM, Wrennall J, Thompson GN. Vigabatrin therapy in succinic semialdehyde dehydrogenase deficiency. Mol Neuropharmacol 1992;2:181-4.
41: Jakobs C, Bojasch M, Moench E, Rating D, Siemes H, Hanefeld F. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta 1981;111:169-78. PMID 7226548
42: Jakobs C, Jaeken J, Gibson KM. Inherited disorders of GABA metabolism. J Inherit Metab Dis 1993;16:704-15. PMID 8412016
43: Jakobs C, Michael T, Jaeger E, Jaeken J, Gibson KM. Further evaluation of vigabatrin therapy in 4-hydroxybutyric aciduria. Eur J Pediatr 1992;151:466. PMID 1628679
44: Jakobs C, Smit LM, Kneer J, Michael T, Gibson KM. The first adult case with 4-hydroxybutyric aciduria. J Inherit Metab Dis 1990;13:341-4. PMID 2122097
45: Jansen EE, Stuys E, Jakobs C, Hager E, Snead OC, Gibson KM. Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development. BMC Dev Biol 2008;8:112. PMID 19040727
46: Jansen EE, Vogel KR, Salomons GS, Pearl PL, Roullet JB, Gibson KM. Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis 2016;39(6):795-800. PMID 27686230
47: Johansen SS, Wang X, Sejer Pedersen D, et al. Gamma-hydroxybutyrate (GHB) content in hair samples correlates negatively with age in succinic semialdehyde dehydrogenase deficiency. JIMD Rep 2017;36:93-8. PMID 28213850
48: Julia-Palacios NA, Kuseyri Hübschmann O, Olivella M, et al. The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 2024;47(3):447-62. PMID 38499966
49: Knerr I, Gibson KM, Jakobs C, Pearl PL. Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency in patients. CNS Spectr 2008;13(7):598-605. PMID 18622364
50: Knerr I, Gibson KM, Murdoch G, et al. Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol 2010;42(4):255-8. PMID 20304328
51: Knerr I, Pearl PL. Ketogenic diet: stoking energy stores and still posing questions. Exp Neurol 2008;211(1):11-3. PMID 18374334
52: Knerr I, Pearl PL, Bottiglieri T, Snead OC, Jakobs C, Gibson KM. Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (gamma-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1-/- mice and characterization of gamma-hydroxybutyric acid pharmacology. J Inherit Metab Dis 2007;30(3):279-94. PMID 17457693
53: Koenig MK, Hodgeman R, Riviello JJ, et al. Phenotype of GABA-transaminase deficiency. Neurology 2017;88(20):1919-24. PMID 28411234
54: Kolker S, Sauer SW, Hoffmann GF, Muller I, Morath MA, Okun JG. Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 2008;31:194-204. PMID 18392748
55: Lakhani R, Vogel KR, Till A, et al. Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition. EMBO Mol Med 2014;6(4):551-66. PMID 24578415
56: Lapalme-Remis S, Lewis EC, De Meulemeester C, et al. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology 2015;85(10):861-5. PMID 26268900
57: Lee HHC, Pearl PL, Rotenberg A. Enzyme replacement therapy for succinic semialdehyde dehydrogenase deficiency: relevance in γ-aminobutyric acid plasticity. J Child Neurol 2021;36(13-14):1200-9. PMID 33624531
58: Lee HHC, McGinty GE, Pearl PL, Rotenberg A. Understanding the molecular mechanisms of succinic semialdehyde dehydrogenase deficiency (SSADHD): towards the development of SSADH-targeted medicine. Int J Mol Sci 2022;23(5):2606. PMID 35269750
59: Lingenhoehl K, Brom R, Heid J, et al. Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. Neuropharmacology 1999;28(11):1667-73. PMID 10587082
60: Maitre M, Andriamampandry C, Kemmel V, et al. Gamma-hydroxybutyric acid as a signaling molecule in brain. Alcohol 2000;20(3):277-83. PMID 10869870
61: Martin K, McConnell A, Elsea SH. Assessing prevalence and carrier frequency of succinic semialdehyde dehydrogenase deficiency. J Child Neurol 2021;36(13-14):1218-22. PMID 34882073
62: Matern D, Lehnert W, Gibson KM, Korinthenberg R. Seizures in a boy with SSADH deficiency treated with vigabatrin (gamma-vinyl-GABA). J Inherit Metab Dis 1996;19:313-8. PMID 8803774
63: Nicholson KL, Balter RL. GHB: a new and novel drug of abuse. Drug Alcohol Depend 2001;63(1):1-22. PMID 11297827
64: Nylen K, Likhodii S, Velasquez JL, Burnham WM, Gibson KM, Snead OC. The ketogenic diet rescues the lethal phenotype and restores synaptic activity in succinic semialdehyde dehydrogenase deficient mice. Clin Neurophysiol 2007;118:e187.
65: Nylen K, Velazquez JL, Likhodii SS, et al. A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exp Neurol 2008;210(2):449-57. PMID 18199435
66: Nylen K, Velazquez JL, Sayed V, et al. The effects of a ketogenic diet on ATP concentrations and the number of hippocampal mitochondria in Aldh5a1(-/-) mice. Biochim Biophys Acta 2009;1790(3):208-12. PMID 19168117
67: Parviz M, Vogel K, Gibson KM, Pearl PL. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies. J Pediatr Epilepsy 2014;3(4):217-27. PMID 25485164
68: Pearl PL, Acosta MT, Gibson KM, et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 2003a;60(9):1413-7. PMID 12743223
69: Pearl PL, Acosta MT, Wallis DD, et al. Dyskinetic features of succinate semialdehyde dehydrogenase deficiency, a GABA degradative defect. Paediatric movement disorders. Fernandez-Alvarez E, Arzimanoglou A, Tolosa E, editors. John Libbey Eurotext, 2005a.
70: Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem 2005b;38:1051-8. PMID 16298354
71: Pearl PL, DiBacco ML, Papadelis C, et al. Succinic semialdehyde dehydrogenase deficiency: review of the Natural History Study. J Child Neurol 2021;36(13-14):1153-61. PMID 33393837
72: Pearl PL, Gibson KM, Cortez MA, et al. Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis 2009a;32(3):343-52. PMID 19172412
73: Pearl PL, Gibson KM, Quezado Z, et al. Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency. Neurology 2009c;73(6):423-9. PMID 19667317
74: Pearl PL, Jakobs C, Gibson KM. Disorders of beta- and gamma-amino acids in free and peptide-linked forms. In: Valle D, Beaudet A, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, editors. Online Molecular and Metabolic Bases of Inherited Disease, 2007b. Available at:http://www.ommbid.com.
75: Pearl PL, Novotny EJ, Acosta MT, Jakobs C, Gibson KM. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003b;54(Suppl 6):S73-80. PMID 12891657
76: Pearl PL, Parviz M, Vogel K, Schreiber J, Theodore WH, Gibson KM. Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification. Dev Med Child Neurol 2015;57(7):611-7. PMID 25558043
77: Pearl PL, Shamim S, Theodore WH, et al. Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency. Sleep 2009b;32(12):1645-8. PMID 20041601
78: Pearl PL, Taylor JL, Trzcinski S, et al. 11C-Flumazenil PET imaging in patients with SSADH deficiency. J Inherit Metab Dis 2007a;30(Suppl 1):43.
79: Phakey S, Rego T, Gaillard F, et al. OCD symptoms in succinic semialdehyde dehydrogenase (SSADH) deficiency: a case report. BMC Psychiatry 2020;20(1):395. PMID 32758201
80: Philippe A, Deron J, Geneviève D, et al. Neurodevelopmental pattern of succinic semialdehyde dehydrogenase deficiency (gamma-hydroxybutyric aciduria). Dev Med Child Neurol 2004;46(8):564-8. PMID 15287248
81: Pop A, Smith DEC, Fbiomarkers T, et al. Functional analysis of thirty-four suspected pathogenic missense variants in ALDH5A1 gene associated with succinic semialdehyde dehydrogenase deficiency. Mol Genet Metab 2020;130(3):172-8. PMID 32402538
82: Posar A, Visconti P. Syndromic autism spectrum disorder: let us not forget about succinic semialdehyde dehydrogenase deficiency. A case report with literature review. J Pediatr Neurosci 2020;15(3):297-300. PMID 33531951
83: Rahbeeni A, Ozand PT, Rashed M, et al. 4-Hydroxybutyric aciduria. Brain Dev 1994;16:S64-71. PMID 7726383
84: Reis J, Cohen LG, Pearl PL, et al. GABAB-ergic motor cortex dysfunction in SSADH deficiency. Neurology 2012;79(1):47-54. PMID 22722631
85: Sauer SW, Kolker S, Hoffmann GF, et al. Enzymatic and metabolic evidence for a region specific mitochondrial dysfunction in brains of murine succinic semialdehyde dehydrogenase deficiency (Aldh5a1-/- mice). Neurochem Int 2007;50(4):653-9. PMID 17303287
86: Schreiber JM, Wiggs E, Cuento R, et al. A randomized controlled trial of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, for succinic semialdehyde dehydrogenase deficiency. J Child Neurol 2021;36(13-14):1189-99. PMID 34015244
87: Scriver CR, Gibson KM. Disorders of beta- and gamma-amino acids in free and peptide-linked forms. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 7th ed. New York: McGraw-Hill, 1995.
88: Shih VE, Younes MC, Gotoff JM, Dooling EC, Gibson K. Transient increase in CSF glycine in a patient with succinic semialdehyde dehydrogenase deficiency (SSADH). Am J Hum Genet 1990;47:A166.
89: Snead OC 3rd. Gamma hydroxybutyrate in the monkey. I. Electroencephalographic, behavioral, and pharmacokinetic studies. Neurology 1978;28(7):636-42. PMID 97574
90: Snead OC 3rd. Relation of the [3H] gamma-hydroxybutyric acid (GHB) binding site to the gamma- aminobutyric acid B (GABAB) receptor in rat brain. Biochem Pharmacol 1996;52(8):1235-43. PMID 8937431
91: Snead OC 3rd, Furner R, Liu CC. In vivo conversion of gamma-aminobutyric acid and 1,4 butanediol to gamma-hydroxybutyric acid in rat brain: studies using stable isotopes. Biochem Pharmacol 1989;38(24):4375-80. PMID 2604740
92: Ticku MK, Mehta AK. Characterization and pharmacology of the GHB receptor. Ann N Y Acad Sci 2008;1139:374-85. PMID 18991884
93: Tokatly Latzer I, Bertoldi M, DiBacco ML, et al. The presence and severity of epilepsy coincide with reduced γ‐aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency. Epilepsia 2023c;64(6):1516-26. PMID 36961285
94: Tokatly Latzer I, Bertoldi M, Blau N, et al. Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency. Mol Genet Metab 2024a;142(1):108363. PMID 38452608
95: Tokatly Latzer I, Hanson E, Bertoldi M, et al. Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency. Dev Med Child Neurol 2023d;65(12):1596-606. PMID 37246331
96: Tokatly Latzer I, Roullet JB, Afshar-Saber W, et al. Clinical and molecular outcomes from the 5-year natural history study of SSADH deficiency, a model metabolic neurodevelopmental disorder. J Neurodev Disord 2024b;16(1):21. PMID 38658850
97: Tokatly Latzer I, Roullet JB, Cesaro S, et al. Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants. Hum Genet 2023a;142(12):1755-76. PMID 37962671
98: Tokatly Latzer I, Roullet JB, Gibson KM, Pearl PL. Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 2023b;46(5):992-1003. PMID 37219411
99: Trettel F, Malaspina P, Jodice C, et al. Human succinic semialdehyde dehydrogenase. Molecular cloning and chromosomal localization. Adv Exp Med Biol 1997;414:253-60. PMID 9059628
100: Tsuboyama M, Liu J, Kaye H, DiBacco M, Pearl PL, Rotenberg A. Transcranial magnetic stimulation in succinic semialdehyde dehydrogenase deficiency: a measure of maturational trajectory of cortical excitability. J Child Neurol 2021;36(13-14):1169-76. PMID 34058900
101: Uziel G, Bardelli P, Pantaleoni C, Rimoldi M, Savoiardo M. 4-Hydroxybutyric aciduria: clinical findings and vigabatrin therapy. J Inherit Metab Dis 1993;16:520-2. PMID 7609441
102: Vogel KR, Ainslie GR, Jansen EE, Salomons GS, Gibson KM. Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. Biochim Biophys Acta Mol Basis Dis 2017a;1863(1):33-42. PMID 27760377
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104: Vogel KR, Ainselie GR, McConnell A, Roullet J_B, Gibson KM. Toxicologic/transport properties of NCS-382 a γ-hydroxybuterate (GHB) receptor ligand, in neuronal and epithelial cells: therapeutic implications for SSADH deficiency, a GABA metabolic disorder. Toxicol In Vitro 2018b;46:203-12. PMID 29031482
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106: Vogel KR, Ainselie GR, Walters DC, et al. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. J Inherit Metab Dis 2018a;41(4):699-708. PMID 29460030
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109: Yamakawa Y, Nakazawa T, Ishida A, et al. A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency. Brain Dev 2012;34(2):107-12. PMID 21612881
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111: Ziyeh S, Berlis A, Korinthenberg R, Spreer J, Schumacher M. Selective involvement of the globus pallidus and dentate nucleus in succinic semialdehyde dehydrogenase deficiency. Pediatr Radiol 2002;32:598-600. PMID 12136353

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Itay Tokatly Latzer MD

Dr. Tokatly Latzer of Boston Children's Hospital has no relevant financial relationships to disclose.
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Phillip L Pearl MD

Dr. Pearl of Boston Children's Hospital and Harvard Medical School received a research grant from PTC Therapeutics.
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Editor

Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
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Former Authors

Sanjiv Sahoo MD
Emily L Robbins
Heather D Bennett BA
Philip K Capp MD
Jessica L Cabalza BA
Jacob Taylor MD
Ina Knerr MD
Katherine Forester BA
Jennifer M Pettiford
John Schreiber MD
Mahsa Parviz MD PhD
Ryan Hodgeman BS
Melissa L DiBacco MD
Jasmine Gite BS
Madalyn N Brown
Jean-Baptiste Roullet PhD
K Michael Gibson PhD
Deniz Aygun BA

Patient Profile

Age range of presentation: 0 months to 65+ years
Sex preponderance: male=female
Heredity: autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Acidosis: E87.2

Disorder of amino-acid metabolism, unspecified: E72.9
ICD-11: Cerebral organic aciduria: 5C50.E1
OMIM: Succinic semialdehyde dehydrogenase (SSADH) deficiency: #271980

Aldehyde dehydrogenase 5 family, member A1; ALDH5A1: *610045

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Succinic semialdehyde dehydrogenase deficiency

Associated Disorders

Hypotonia

Differential Diagnosis

other forms of mental retardation
other metabolic encephalopathies
other organic acid disorders
hereditary ataxias
infantile autism
- abnormality of fatty acyl-CoA metabolism
- abnormality of propionyl-CoA metabolism

Also Relevant

2-Hydroxyglutaric acidurias
Ataxia
Epilepsy
GABA-transaminase deficiency
Intellectual disability

Clinical Categories

Neurogenetic Disorders

Succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Succinic semialdehyde dehydrogenase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

This is an article preview.
Start a Free Account
to access the full version.