Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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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 results in the accumulation of GABA and its neurotoxic metabolite, gamma hydroxybutyric acid. Succinic semialdehyde dehydrogenase deficiency is caused by homozygous or compound heterozygous mutations in the ALDH5A1 gene. The clinical presentation is nonspecific, with clinical hallmarks, including a nonprogressive course, ataxia, hypotonia, developmental delay, intellectual disability, behavioral dysregulation, hyporeflexia, and epilepsy. In this article, the authors review the current literature on this topic.
• Succinic semialdehyde dehydrogenase deficiency is an autosomal recessive disorder caused by pathological variants in the ALDH5A1 gene; over 60 pathological variants have been identified.
• The clinical presentation is typically an infantile-onset nonprogressive encephalopathy with early hypotonia and developmental delay, and later profound expressive language impairment, intellectual deficiency, hypotonia, epilepsy, and psychiatric morbidity especially manifest by anxiety and obsessive-compulsive symptoms; choreoathetosis, exertional dyskinesias, and ataxia may be present.
• 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.
• Therapy remains symptomatic, although clinical trials are in progress for more targeted treatments; vigabatrin will lower GHB levels but raise GABA further, and it has not shown a consistent benefit.
In 1981, the index patient was described with 4-hydroxybutyric aciduria, a previously unrecognized organic aciduria (52). 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. 126.96.36.199), 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 1 or more 4-hydroxybutyrate dehydrogenases (E.C. 188.8.131.52). 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 (03) and has been considered to be a potential neurotoxic agent that contributes to the clinical manifestations of succinic semialdehyde dehydrogenase deficiency (79).
The identification of succinic semialdehyde dehydrogenase activity in peripheral leukocytes and Epstein-Barr virus-transformed lymphoblasts allowed Gibson and colleagues to document succinic semialdehyde dehydrogenase deficiency in patients with 4-hydroxybutyric aciduria (36). Sensitive fluorometric and isotope dilution mass spectrometric methods have since then been developed to improve diagnostic accuracy in identifying succinic semialdehyde dehydrogenase deficiency (23; 33).
The Jakobs Laboratory developed a stable-isotope dilution liquid chromatography-tandem mass spectrometry method for the determination of succinic semialdehyde, an unstable metabolite, in urine and cerebrospinal fluid samples (103).
Molecular studies have enabled the elucidation of the complete succinic semialdehyde dehydrogenase amino acid sequence and its localization to chromosome 6p22 (106). The genomic structure of the succinic semialdehyde dehydrogenase gene has been identified, the promoter region sequenced, and the first inherited mutations responsible for succinic semialdehyde dehydrogenase deficiency were identified by Chambliss and colleagues in 1998 (15).
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 (85). 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 (117; 47; 118). The clinical presentation of succinic semialdehyde dehydrogenase deficiency is not specific (107). Currently, approximately 150 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 (78). 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 (19). 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 (19). Some patients are known to have recurrent episodes of generalized convulsive status epilepticus (78). These seizures are often difficult to control, and sudden unexpected death in epilepsy (SUDEP) was diagnosed in 6 cases: a 19-year-old female diagnosed posthumously (61), a male in his mid-20s, 2 additional adults who died at age 33 and 63 (67), and 2 adolescent males aged 12 and 14 years. Heterozygosity for succinic semialdehyde dehydrogenase deficiency has been reported in 1 family with a parent and sibling having generalized spike wave discharges, photosensitivity, and absence and myoclonic seizures (17). Sleep disorders have been well documented and present as excessive daytime sleepiness as well as disorders of initiating and maintaining sleep (83). 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 (87). Also common and most prevalent among adolescents and adults are neuropsychiatric symptoms, including behavior problems and sleep disturbances (60; 19). Ataxia, when present, may improve with age (43). Aggressive, psychotic, and hyperactive behaviors are reported (55; 28; 27). One set of siblings manifested nonspecific myopathy and ragged-red fibers in biopsied muscle (44). No patients have reported symptoms other than those of the central nervous system (65).
Succinic semialdehyde dehydrogenase deficiency has rarely been described in association with other syndromes. One patient was identified with both succinic semialdehyde dehydrogenase deficiency and partial WAGRO syndrome due to a deletion in the short arm of chromosome 11 (Wilms tumor, aniridia, genital abnormalities, mental retardation, obesity) (59). A second patient with hypersomnolence, failure to thrive, global developmental delay, dysmorphic facies, and cardiovascular anomalies was diagnosed with succinic semialdehyde dehydrogenase deficiency and Williams syndrome (63).
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%) (81; 02). A pallidal-dentate pattern of combined signal abnormalities involving the globus pallidus and cerebellar dentate nucleus has been reported (119). Involvement of the subthalamic nucleus has been described (82; 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 (61). Normal cerebral imaging has been reported in about half of patients, and MR spectroscopy for the standard neuronal markers of N-acetylaspartate, choline, and creatine, with the absence of lactate peak, is normal. Edited MR spectroscopy that measures specific neurotransmitters has determined elevated GABA and homocarnosine levels in brain parenchyma of patients with succinic semialdehyde dehydrogenase deficiency (73; 22).
EEG data are published in approximately 58 cases and reveal epileptiform activity in approximately 59% (77; 107; 90; 70; 25; 28; 05; 51; 84; 81; 59; 78). Electroencephalographic findings also include background slowing (24%), epileptiform abnormalities (22%; typically generalized but sometimes multifocal), and occasionally photosensitivity (5%) and electrographic status epilepticus of sleep (2%) (88; 78).
The major diagnostic criterion of succinic semialdehyde dehydrogenase deficiency is persistently elevated GHB in urine, plasma, and CSF (30). 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 (53). 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 (23). 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 (28). 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 (04).
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 (57). 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 (58). This GABA and GHB imbalance may correlate with onset of adolescent/adulthood neuropsychiatric findings and epilepsy.
Sgaravatti and colleagues studied the effect of 1,4-butanediol, a precursor to GHB, in rats and found that this compound induces oxidative stress, which may contribute to the human brain damage found in succinic semialdehyde dehydrogenase deficiency (97).
Although diagnosis in adults is rare, Lapalme-Remis and colleagues reviewed a cohort of adult patients, including the oldest known diagnosed case at age 63 (67). This patient was born to nonconsanguineous parents with a family history of a deceased sister with developmental delay and seizures. The patient presented with global developmental delay in late infancy and generalized tonic-clonic seizure onset from 19 years of age. Until age 46, he reported seizures every 2.5 years. From age 46, his neurologic symptoms progressed to include tremors, horizontal nystagmus, disorientation, and increased frequency of clustering generalized tonic-clonic seizures. Metabolic investigations revealed increased urine GHB at age 62. The patient died at age 63 after diagnosis of succinic semialdehyde dehydrogenase deficiency. A cross-sectional analysis of patients above 18 years of age identified 31 patients between 18 to 29 years, 7 patients including 1 deceased between 30 to 39 years, 1 patient of 46 years, and the reported patient of 63 years. Of the adult patients reviewed, 3 were diagnosed with semialdehyde dehydrogenase deficiency after age 18. Among the reviewed adult patients, 60% had a history of epilepsy, as compared with 47% of the total patient population.
The prognosis in succinic semialdehyde dehydrogenase deficiency is difficult to assess. A variable degree of permanent psychomotor deficit and neuropsychiatric morbidity is typical. The age at diagnosis has ranged from the newborn period to 25 years (25; 84), and death in the newborn period or very early childhood has been reported only rarely (90). 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 (43), ongoing problems of hyperkinesis and aggressive behavior, sleep disturbances, and hallucinations have been reported in older patients (29; 27; 55; 54; 50; 81). 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 (80).
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.
Succinic semialdehyde dehydrogenase deficiency is an autosomal recessively inherited disorder of GABA metabolism (E.C. 184.108.40.206; OMIM #271980, *610045) (78). The gene that is abnormal in succinic semialdehyde dehydrogenase gene, ALDH5A1 (for aldehyde dehydrogenase 5A1), has been mapped to chromosome 6p22 (106).
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 (23; 55), and 65- to 230-fold elevation in CSF (27). Succinic semialdehyde dehydrogenase deficiency is not associated with systemic metabolic acidosis (96).
In addition to GHB, other abnormal compounds are detected in physiological fluids derived from patients with succinic semialdehyde dehydrogenase deficiency. Urinary metabolites indicative of beta-oxidation of GHB include 3,4-dihydroxybutyric, 3-oxo-4-hydroxybutyric, and glycolic acids (52; 42; 10; 29; 26; 77; 98). Increased urinary 2,4-dihydroxybutyric (and its lactone) and 3-hydroxypropionic acids suggest metabolism of GHB via alpha-oxidation (10). Struys and colleagues investigated 3 succinic semialdehyde dehydrogenase deficiency patients for the likelihood of having simultaneous D-2- hydroxyglutaric aciduria and, therefore, 2 inborn errors of metabolism. Cultures and gene studies did not support this hypothesis, and the authors concluded that D-2- hydroxyglutaric aciduria is a common metabolite found in succinic semialdehyde dehydrogenase deficiency. Succinic semialdehyde and D-2- hydroxyglutaric aciduria results from the oxidation of GHB by hydroxyacid-oxoacid transhydrogenase (104). Threo- and erythro-4,5-dihydroxyhexanoic acids (and the corresponding lactones) have been identified in the urine of some patients (10; 77). Brown and colleagues suggest these compounds result from the condensation of succinic semialdehyde with a 2-carbon intermediate involved in pyruvate metabolism.
Dicarboxylic aciduria has been noted and may indicate a secondary inhibition of mitochondrial fatty acid beta-oxidation or propionyl-CoA metabolism by succinic semialdehyde or its related metabolites (10; 26). A case report from Niemi and colleagues demonstrated elevated levels of urine dicarboxylic acids and persistently low levels of glutathione, further supporting mitochondrial dysfunction in patients (72). Several patients manifested glycinuria in their urine and plasma, and 1 displayed a transient CSF glycine elevation (42; 92; 18; 26; 98). Elevated urinary glycolic acid resulting from beta-oxidation of GHB is consistent with the observation that isolated rat liver mitochondria generate glycolyl-CoA when incubated with GHB (108). Although glycolic acid may be metabolized to glycine, a significant increase in the glycine pool via glycolic acid generated from the beta-oxidation of GHB seems unlikely (26). The cause of glycinuria in succinic semialdehyde dehydrogenase deficiency remains unclear. The widening scope of metabolic aberrations suggests that succinic semialdehyde dehydrogenase deficiency has deleterious effects on both neural and non-neural (eg, glial) metabolic pathways.
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 (22). Developed as an anesthetic and sedative agent, GHB has been employed experimentally to induce a rodent model of absence seizures (101; 16). Pharmacologic toxicity manifests as drowsiness, hypotonia, and seizure activity, similar to symptoms observed in succinic semialdehyde dehydrogenase deficiency. 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 (38; 99; 43; 56). 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 (100; 69). GHB has been abused in humans as a recreational drug and to subdue victims for the purpose of sexual assault (71). 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 (28; 68; 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 (25).
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 GABAB receptors, and binding of GHB to these sites (which is antagonized by NCS-382) produces effects similar to those observed with GABAB receptor activation (49; 100; 105). Studies of [3H] GHB binding suggest that at least 1 of the specific GHB binding receptors is an isoform of a presynaptic GABAB receptor (100). This raises the possibility that differing concentrations of GHB could interact with pre- and postsynaptic GABAB 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 (24). 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 (45).
The ALDH5A1 gene consists of 10 exons that code for 535 amino acids (04). Over 60 different pathological variants have been identified in patients, including missense, nonsense, and splice mutations (31; 04; 59). Frameshift mutations (duplication, deletion, or insertion) have been described in a handful of cases. Phenotypic variation is broad, and no clear genotype-phenotype relationship has been demonstrated to date.
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 (27). 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 GABAB-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 (114).
A murine model of ALDH5A1-deficiency has been developed utilizing genetic recombination techniques. This model is characterized by failure to thrive, development of ataxia, and then rapidly fatal generalized convulsive seizures at postnatal day 16 to 22 (46; 41; 102). Hippocampal gliosis as well as increased GHB and total GABA levels in urine, brain, and liver homogenates are noted in these ALDH5A1-/- mice. Conversely, Gln is decreased in brain tissue of ALDH5A1-/- mice, which is suggestive of a disruption of the glutamine/glutamate/GABA shuttle between glial cells and neurons (41; 63). GABA and GHB have been found to be elevated at all embryonic stages of the ALDH5A1-/- mice, suggesting a heightened excitatory state during development in this disorder (56). Data suggest that 24-hour distribution of spontaneous tonic-clonic seizures in these adult mutant mice may be related to the natural circadian rhythm, as they occur with greater frequency around the early dark phase of the photocycle, a time of day associated with increasing levels of arousal (102).
Therapeutic intervention has been attempted in this model, with absence of survival prolongation utilizing the traditional antiepileptic agents phenobarbital and phenytoin, but with therapeutic efficacy utilizing vigabatrin, a GABA-transaminase inhibitor, and CGP 35348, an experimental GABAB receptor antagonist. Survival was also prolonged with a treatment utilizing taurine, selected because of its high concentration in murine breast milk because neurologic deterioration coincided with weaning of the suckling mice. Further therapeutic intervention studies showed maximal survival prolongation with intraperitoneal administration of NCS-382, a specific GHB receptor antagonist (40). Measurements of GABA and GHB levels in ALDH5A1-/- mice receiving vigabatrin revealed the expected elevation of brain GABA, but no corresponding decrease in brain GHB (40). This may correlate with the poor clinical response to vigabatrin in succinic semialdehyde dehydrogenase-deficient patients.
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 (34). 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 (34). 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 (94).
Increased mitochondrial numbers have been documented in hippocampal neurons of ALDH5A1-/- mice (74). 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 (66). Mouse survival improved with a number of mTOR inhibitors. Torin2 did promote correction of GABAA receptor downregulation, but did not decrease seizure frequency or duration (110; 114). In addition, brain-derived neuronal stem cells have been developed from the animal model and showed preliminary positive results from intervention with mTOR inhibitors (111). Moreover, investigations underlying the mechanisms of the ultimately fatal status epilepticus in the mouse model have identified decreased GABAA 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 GABAA receptor, a reduction in GABAA-mediated inhibitory postsynaptic potentials, and enhanced postsynaptic spikes recorded from hippocampal extracellular recordings (116). There was also decreased GABAB receptor antagonist binding, especially in the hippocampus (13). The hypothesis is that use-dependent downregulation in the GABAA receptor and GABAB 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 (89). 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. This proposes that the human phenotype is consistent with the proposed mechanism in the murine model (91).
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 GABAA receptor β-3 subunit, sodium-dependent glutamate/aspartate transporter 2, sodium potassium chloride transporter 1, neutral potassium chloride cotransporter, and tumor necrosis factor (111).
The ALDH5A1-/- mice also show downregulation for genes associated with myelin synthesis and compaction (20). 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.
Although the number of known cases was previously based on estimates from lab surveillance, an epidemiologic survey confirmed 182 subjects with succinic semialdehyde dehydrogenase deficiency published in the literature or followed in our database (06). These patients were reported from 40 different countries, with United States of America (24%), Turkey (10%), China (7%), Saudi Arabia (6%), and Germany (5%) representing approximately half of all reported patients.
Consanguinity has been reported in 37% of published cases (84). Due to the nonspecific nature of the clinical presentation, as well as wide spectrum of severity and poor detection rate of 4-hydroxybutyric aciduria on laboratory testing, the disorder may be significantly underdiagnosed. Hence, its true frequency in the general population is undetermined.
Only mating between heterozygotes for succinic semialdehyde dehydrogenase deficiency could give rise to an affected child, with each pregnancy having a 1 in 4 chance of producing an affected fetus. Genetic counseling for a family with a previously documented proband is recommended. 4-hydroxybutyric acid may be measured accurately in amniotic fluid by use of a sensitive stable-isotope dilution, gas chromatography-mass spectrometry assay method employing deuterium labeled 4-hydroxybutyric acid as internal standard (23). Succinic semialdehyde dehydrogenase activity can be measured in cultured amniocytes and biopsied chorionic villus tissue (30). Mutation analysis in chorionic villus adds increased accuracy in diagnosis, especially when enzyme activity and metabolite analysis results are discordant (45).
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 (90). About half of the patients in this subgroup may show a progressive clinical picture of deterioration (80).
Ataxia is suggestive of dysequilibrium syndrome, but ataxia is not a consistent finding in succinic semialdehyde dehydrogenase deficiency (37). The patient described by Uziel and colleagues was treated for infantile autism, which is consistent with other patients who were reported to have "autistic features" (42; 54; 107). The detection of abnormal signal intensity bilaterally in the globus pallidus by MRI has aided the differential diagnosis by suggesting a metabolic disorder (18; 98; 107; 119). 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 more rare autosomal recessively inherited disorder of GABA metabolism is 4-aminobutyrate aminotransferase (ABAT) 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 (63; 64). 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 (15). 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).
Prenatal diagnosis. Only mating between heterozygotes for succinic semialdehyde dehydrogenase deficiency could give rise to an affected child, with each pregnancy having a 1 in 4 chance of producing an affected fetus. Genetic counseling for a family with a previously documented proband is recommended. GHB may be measured accurately in amniotic fluid by use of a sensitive stable-isotope dilution, gas chromatography-mass spectrometry assay method employing deuterium labeled GHB as internal standard (23). Succinic semialdehyde dehydrogenase activity can be measured in cultured amniocytes and biopsied chorionic villus tissue (30). Mutation analysis in chorionic villus adds increased accuracy in diagnosis, especially when enzyme activity and metabolite analysis results are discordant (45).
Succinic semialdehyde dehydrogenase deficiency does not present with metabolic abnormalities generally suggestive of an inherited organic aciduria. There is not typically episodic metabolic decompensation, hypoglycemia, metabolic acidosis, ketosis, or hyperammonemia. The key is a persistently elevated level of GHB in urine, plasma, and CSF, which can be detected through accurate organic acid analysis (23). Quantitative organic acid analysis in a frozen, nonpreserved urine specimen should be requested. However, this general observation requires qualification. The concentration of GHB in urine may be only slightly elevated, making the correct diagnosis difficult (55). The utilization of specific ion monitoring allows for a greater detection rate of GHB (79).
The detection of elevated quantities of other metabolites through organic acid analysis may assist in arriving at the correct diagnosis. Elevated urinary 3,4-dihydroxybutyric, 3-oxo-4-hydroxybutyric, 2,4-dihydroxybutyric, glycolic, 3-hydroxypropionic, 4,5-dihydroxyhexanoic, and dicarboxylic acids (ie, glutaric, adipic, and suberic acids) may suggest 4-hydroxybutyric aciduria (53). In addition, elevated plasma glycine has been detected in physiologic fluids from some patients (26; 98). The presence of consistently increased GHB in urine would warrant determination of succinic semialdehyde dehydrogenase activity in lymphocytes isolated from whole blood or cultured fibroblasts or, more typically, gene sequencing.
Preliminary studies suggest that succinic semialdehyde dehydrogenase deficiency may be identified through newborn screening via quantification of gamma-hydroxybutyric acid in newborn dried bloodspots (11). In postnewborn bloodspots a significant negative age-dependent correlation was noted, consistent with previous reports of decreasing concentrations in plasma with age (57). Under further examination, there is a significant reduction of ornithine, short-chain acylcarnitines (C2-, C3-, C4, and C4-OH), and creatine in newborn blood spots, suggesting a specific metabolic profile with the potential to integrate succinic semialdehyde dehydrogenase deficiency screening into the current newborn screening panel. In addition, based on postnewborn studies, reduced histidine has the potential to be a biomarker. Histidine is conjugated with GABA to form homocarnosine in the central nervous system, which is elevated in the CSF of succinic semialdehyde dehydrogenase deficiency patients (12). The specific metabolic profile or “bio-signature” could possibly be a first-tier screening test (ornithine, C2-, C3-, C4, C4-OH, and creatine) for early diagnosis. Gamma-hydroxybutyric acid quantification could be used as second-tier screening.
There is no standard therapy for succinic semialdehyde dehydrogenase deficiency, and most strategies are directed toward symptomatic treatment of seizures or neurobehavioral disturbances (39). Murine studies have shown positive results with vigabatrin, GHB and GABAB receptor antagonists, and taurine (46; 41; 81). 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 (107; 32; 96; 70; 21). 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 (50). 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 (14). Visual field restriction was, however, apparent at the final ophthalmologic examination. Vigabatrin was, however, reported as helpful in psychomotor and language development in an uncontrolled study of 2 unrelated children, ages 6 and 7 years, with possible improvement or stabilization in the electroretinogram by supplemental taurine (48).
Lamotrigine, which blocks voltage-sensitive sodium channels resulting in inhibition of the presynaptic release of glutamate, has been successfully used and well tolerated in a patient in whom vigabatrin led to seizures (35). Although valproic acid has been thought to be contraindicated due to its inhibition of residual succinic semialdehyde dehydrogenase activity, a case report demonstrated improvement in seizures and behavior with the use of magnesium valproate (MgVPA). This suggests that valproic acid as well as magnesium may have a role in treatment (109). Methylphenidate, risperidone, fluoxetine, thioridazine, and benzodiazepines at standard dosages have been found to be effective therapies for anxiety, aggressiveness, hallucinations, and inattention (27).
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. Among these therapeutic options are different receptor antagonists, including GABAB receptor antagonist SGS742, GHB antagonist NCS-382 (113), and dietary approaches such as taurine (82) or the ketogenic diet (63; 62). A double-blind, placebo-controlled trial of SGS-742 has concluded, with results pending. 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 (112). 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 (113; 114; 112).
Taurine showed initial benefit in murine studies and a single uncontrolled case report, but failed to show improvement in adaptive behavior, cognitive testing, and transcranial magnetic stimulation (TMS)-derived biomarkers in a study of 18 patients (93; 41; 86; 95). Preliminary animal data suggested a role for the ketogenic diet but this has not been confirmed with clinical experience (74; 75; 76; 62). Further information on pharmacologic management is available in reviews by Abanades and colleagues and Knerr and colleagues (01; 63; 115).
Preliminary evidence of enzyme replacement therapy in the murine model demonstrates improved survival and correction of several GABAA receptor subunits, but the study was insufficiently powered for biochemical measures (114). Nonpharmacologic treatments important in patient management include special educational services and therapies. These include physical therapy directed at strength, endurance, and balance; occupational therapy for improvement of fine motor skills, feeding, and sensory integration; and speech therapy for articulation and modalities for total communication.
Conclusion. Since the initial discovery of succinic semialdehyde dehydrogenase deficiency in 1981, we have continued to gain a greater understanding of this entity. 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 disease.
Phillip L Pearl MD
Dr. Pearl of Boston Children's Hospital and Harvard Medical School received research funding from PTC Therapeutics.See Profile
Melissa DiBacco MD
Dr. DiBacco of Boston Children’s Hospital has no relevant financial relationships to disclose.See Profile
Jasmine Gite BS
Ms. Gite of Oakland University William Beaumont School of Medicine has no relevant financial relationships to disclose.See Profile
Madalyn N Brown
Ms. Brown of Washington State University College of Pharmacy has no relevant financial relationships to disclose.See Profile
Jean-Baptiste Roullet PhD
Dr. Roullet of Washington State University College of Pharmacy has no relevant financial relationships to disclose.See Profile
K Michael Gibson PhD
Dr. Gibson of Washington State University College of Pharmacy has no relevant financial relationships to disclose.See Profile
Barry Wolf MD PhD
Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.See Profile
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