Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (Gamma-Hydroxybutyric aciduria)

CASE REPORT Significant Behavioral Disturbances in Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency (Gamma-Hydroxybutyric Aciduria) K. Michael Gibson, Maneesh Gupta, Phillip L. Pearl, Mendel Tuchman, L. Gilbert Vezina, O. Carter Snead III, Leo M.E. Smit, and Cornelis Jakobs Background: We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as ␥-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. Methods: To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Results: Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. Conclusions: We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients. Biol Psychiatry 2003;54:763–768 © 2003 Society of Biological Psychiatry Key Words: Behavioral disturbance, psychosis, GABA, From the Department of Molecular and Medical Genetics (KMG, MG), Oregon Health and Science University, Portland, Oregon; Departments of Neurology and Metabolism (PLP, MT) and Radiology (LGV), Children’s National Medical Center, Washington, DC; Department of Pediatrics, Division of Neurology and Program in Brain and Behavior (OCS), Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; the Departments of Pediatrics (LMES) and Clinical Chemistry (CJ), VU University Medical Center, Amsterdam, The Netherlands. Address reprint requests to K. Michael Gibson, Ph.D., OHSU Genetics Laboratories, 2525 SW 3rd Avenue, Portland OR 97201. Received July 22, 2002; revised October 23, 2002; accepted January 3, 2003.

© 2003 Society of Biological Psychiatry

succinic semialdehyde dehydrogenase deficiency, ␥-hydroxybutyric acid (GHB), benzodiazepines, dopamine, serotonin, homovanillic acid, 5-hydroxyindoleacetic acid

Introduction

S

uccinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively inherited defect in the catabolic pathway of GABA (␥-aminobutyric acid), the major central nervous system inhibitory neurotransmitter (Figure 1; Gibson and Jakobs 2001). Clinically, SSADH deficiency is very nonspecific, with most patients presenting a picture of global developmental delays, hypotonia, ataxia, and poorly developed to absent speech (Gibson et al 1997). Seizures occur in approximately 50% of patients, a paradoxical finding in view of increased neuroinhibitory GABA. SSADH deficiency is of interest because the defect leads to accumulation of ␥-hydroxybutyric acid (GHB), a compound with unusual neuropharmacologic properties that may be a neurotransmitter (Snead 2000). Because of its capacity to induce a state of perceived euphoria and sedation at low doses, perhaps related to alterations in GABA and dopamine release (Muller et al 2002), GHB has been popularized as a drug of abuse in recent years (Schneir et al 2001), while simultaneously employed therapeutically for treatment of cataplexy and withdrawal syndromes related to alcohol and opiate addiction (Colombo and Gessa 2000; Gessa et al 2000; Borgen et al 2002). A review of the growing number of clinical histories from confirmed patients has suggested that behavioral disturbances (aggression, hallucinations, hyperkinesis, disabling anxiety, and sleep disorder) may be prominent clinical features. Because benzodiazepines are commonly employed to treat GHB overdose in the emergency room (Bowles et al 2001), we hypothesized that benzodiazepines might be efficacious in patients manifesting behavioral disturbances. In this report, we present clinical features of two SSADH-deficient patients who manifested disabling behavioral abnormalities associated with psychosis. To identify a possible underlying metabolic basis 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00113-6

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Figure 1. Selected metabolic interconversions of ␥-aminobutyric acid (GABA), glutamine, and glutamate. The site of the block in succinic semialdehyde dehydrogenase deficiency is indicated by the cross-hatched box. Accumulated ␥-hydroxybutyrate (GHB) may lead to increased turnover of dopamine (DA) and serotonin (5-HT or 5-hydroxytryptamine), the metabolic end products of which are homovanillic (HVA) and 5-hydroxyindoleacetic (5HIAA) acids, respectively (these interactions are indicated by the T-lines). Trp, tryptophan; Tyr, tyrosine; TCA, tricarboxylic acid.

for behavioral disturbances in these and other patients, we analyzed amino acids in conjunction with selected neurotransmitters and biogenic amines in cerebrospinal fluid (CSF) from 13 unrelated SSADH-deficient patients. This report summarizes our findings.

Methods and Materials Isotope-dilution combined gas chromatography–mass spectrometry was used to determine GHB and total and free GABA (Gibson et al 1990; Kok et al 1993). Homovanillic (HVA) and 5-hydroxyindoleacetic acids (5-HIAA) were quantified by highperformance liquid chromatography with electrochemical detection (Hyland et al 2002). Amino acids (including glutamine, glutamate, and homocarnosine) were quantified using standard ion-exchange chromatography with online ninhydrin derivitization (Slocum and Cummings 1991). The CSF samples were obtained from SSADH-deficient patients with informed consent.

Results Case Reports Patient 1, a 36-year-old woman for whom delivery and the neonatal period were uneventful, manifested delayed early motor milestones. Consanguinity was documented in the Turkish parents (Jakobs et al 1990). Delays in psychomotor development continued through adolescence into adulthood, predominantly psychomotor retardation with dysphasic language development. Hypotonia and ataxia were absent. Diagnosis of SSADH deficiency was ultimately

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Figure 2. T2-weighted magnetic resonance imaging scan of patient 1 demonstrating bilateral signal hyperintensity in the globus pallidus.

achieved at age 24 years, following multiple metabolic investigations, as the result of diagnosing two cousins with the same defect, both of whom were more developmentally delayed. The predominant clinical feature was a behavioral disorder. During childhood, patient 1 manifested hyperactivity, impulsiveness, and tantrums. In the second decade, the patient was institutionalized. In the third decade, there was a further deterioration of behavior, with aggressive episodes, incomprehensible language, spatial and temporal disorientation, stereotypical motor movements, and occasional catatonic posturing. She became isolated, demonstrated decreasing participation in the social environment, and developed a serious sleep disorder. Magnetic resonance imaging (MRI) revealed pronounced hyperintensity of the T2-weighted signal symmetrically in the globus pallidus (Figure 2). Pharmacologic intervention initially included Cisordinol (a thioxanthene-derivative antipsychotic), which decreased agitation but had minimal impact on the clinical presentation. Temazepam was added successfully for the sleep disorder. Following this, there was loss of contact for 10 years, after which time the patient was referred for consultation in relation to her behavioral disorder. A trial with vigabatrin (Gibson et al 1995), ranging from 250 up to 2500 mg/day was instituted, with little improvement in the clinical picture. Add-on therapy included oxazepam (75 mg/day), which led to significant improvement in the clinical picture. The patient became more socialized, less

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Metabolic Investigations

Figure 3. Midsaggittal (left) and axial (right) magnetic resonance image planar sections demonstrating cerebellar atrophy predominantly affecting the midline vermis of patient 2.

aggressive and more open to communication. Although there remained a minimum of interactive communication, language was more comprehensive. Eventually, the patient was weaned from vigabatrin, which did not lead to clinical deterioration. Patient 2 was a 22-year-old man with a history of developmental delay, subsequent mental retardation, autistic behavior, and hallucinations (Pearl et al 2001). He manifested more profound language impairment than nonverbal impairment. The patient talked to himself almost continuously during the waking state, and appeared to refer to visual and auditory hallucinations that were generally annoying to him. The content of these was undecipherable to observers, including his parents. At 19 years of age, he developed sporadic generalized tonic– clonic seizures, occasionally with status epilepticus. Electroencephalographic studies revealed diffuse background slowing with frontal predominance during the awake state and sleep spindle asynchrony, without epileptiform features. The primary clinical problem encompassed extreme attacks of apparent anxiety, without apparent provocation but leading to aggressive behavior and a frustrated effect. An MRI scan revealed cerebellar atrophy, primarily affecting the vermis (Figure 3). In addition, subtle increased T2-weighted intensity of the globus pallidus was noted, although without the prominence described in younger patients (Pearl et al 2001). Therapeutic trials included lamotrigine (200 mg/day), which was eventually tapered because of poor behavioral tolerance, and carbamazepine (800 mg/day), which was the optimal intervention for seizure control. Alprazolam (Xanax) (.75 mg/day) was begun, resulting in less agitation and aggressiveness and an improvement in social interaction. Beneficial effects of alprazolam waned within 3 months, coincident with introduction of lamotrigine. The patient receives alprazolam now as necessary for calming.

Cerebrospinal samples were investigated for amino acids, selected neurotransmitters, and biogenic amines. Although unavailable from patients 1 and 2, CSF samples were available from 13 unrelated patients. Metabolite analysis in these samples revealed significantly increased GHB (449 ⫾ 41 [SEM] umol/L; range 203–703, n ⫽ 13; control ⬍ 3) and free GABA (.37 ⫾ .11 ␮mol/L; range .12–1.33, n ⫽ 10; control ⬍ .17). There was no evidence for an age-dependent decrease in GHB or total GABA in CSF. Although absolute HVA and 5-HIAA concentrations were within the normal range, there was a significant correlation between GHB and both HVA and 5-HIAA (Figure 4), the end products of dopamine and serotonin metabolism, respectively (De Vivo et al 1988). Glutamine levels were low to borderline-low for 10 of 12 patients (Figure 4), whereas glutamate was not increased. It should be noted that glutamate is almost nondetectable in CSF. Total GABA (increased in 10 of 10 samples) and homocarnosine (elevated in 8 of 10 samples) displayed a significant linear correlation. Because total GABA is derived from esterified GABA that has been hydrolyzed (homocarnosine is a GABA-histidine dipeptide), this correlation is not unexpected.

Discussion Review of 51 published cases of SSADH deficiency, and our own cohort of 5 unpublished patients, reveals significant behavior problems in 43% (24 patients), usually referred to as hyperactivity or aggressiveness. In our own experience, six young adults (including patient two of this report) and one child manifest psychotic symptomatology. For example, the eldest sister in a female sibship (all patients in their early 20s; Gibson et al 1989) displays a profound obsessive– compulsive disorder with catatonia, whereas the younger sibs manifest extreme hyperactivity and aggression. A previously reported 22-year-old man suffered from hallucinations and self-injurious behavior, which was successfully treated with haloperidol (Gibson et al 1997; Neu et al 2002). An unrelated 22-year-old male patient displays what is described as “controlled” aggression (stopping when told to stop), is loud, euphoric, and enjoys physical contact with others (Dr. A. Boneh, personal communication, August, 2002; Haan et al 1985). The authors are also aware of a 6-year-old boy who has been described by his father as speaking to himself and hallucinating (K.M. Gibson, unpublished observation). These observations indicate that behavioral disturbances are a common finding in SSADH deficiency and, although psychosis appears frequently in adult patients, younger patients may also be affected.

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Figure 4. Correlation of ␥-hydroxybutyric acid (GHB) with 5-hydroxyindoleacetic acid (5-HIAA; top left) and homovanillic acid (HVA; top right) in cerebrospinal fluid (CSF) derived from succinic semialdehyde dehydrogenase-deficient patients. Bottom left, CSF glutamine in patient samples compared with the control range; bottom right, relationship between CSF total ␥-aminobutyric acid (GABA) and homocarnosine for patients and control subjects.

Pharmacologically, GHB acts primarily by inhibition of presynaptic dopamine release with corresponding alterations in dopaminergic transmission (Maitre 1997; Maitre et al 2000). In a murine knockout of SSADH deficiency (Hogema et al 2001), which also manifests significant GHB and total GABA elevations in tissues and physiologic fluids (Gibson et al 2002), we have documented significantly increased levels of brain HVA without a corresponding increase in 5-HIAA (T. Bottiglieri and K.M. Gibson, unpublished results). Increased dopamine turnover may result in decreased subcortical dopaminergic neurotransmission, perhaps explaining hyperkinetic movement disorders frequently seen in patients. This situation might be exacerbated by defective GABAergic nuerotransmission. The preponderance of current pharmacologic data suggests that GHB at physiologic concentrations acts on GHB receptors, whereas at nonphysiologic levels (i.e., SSADH deficiency) GHB acts predominantly at the GABAB receptor (Banerjee and Snead 1995; Carai et al 2001; Colombo et al 1998, 2000; Nava et al 2001; Snead 2000). High concentrations of GHB and GABA likely lead to down-regulation of both pre- and postsynaptic GABAB receptor-mediated function (Mehta et al 2002), which would compound hyperkinetic movements if altered GABAergic inhibition occurred in midbrain dopamine cell groups. Our data provide the first demonstration of lowered glutamine coupled to elevated homocarnosine in CSF of SSADH-deficient patients. Decreased glutamine may be linked to abnormalities of intermediary metabolism, which may correlate with the globus pallidi and cerebellar

abnormalities seen in our patients (Figures 2, 3; Larnaout et al 1998). Elevated free and total GABA coupled to decreased glutamine points to disruption of the “glutamine-glutamate” shuttle, a key cycle providing astrocytic glutamine as precursor for neuronal glutamate and GABA (Behar et al 1999; Sonnewald and McKenna 2002). Trafficking of glutamine between glia and neurons is essential for neuronal neurotransmitter (GABA/glutamate) pool maintenance. The level of metabolite compartmentalization is underscored by the fact that glutamine synthetase is exclusively localized to glia, while L-glutaminase (producing glutamate) is neuron-specific. Decreased glutamine with elevated GABA implies disrupted glutamate homeostasis; elevated glutamatergic excitatory activity coupled to decreased GABAergic inhibition may be responsible for convulsive activity in SSADH deficiency. The role of homocarnosine in pathology of SSADH deficiency (if any) remains to be determined. Metabolic disorders featuring accumulation of homocarnosine are extremely rare (Gibson and Jakobs 2001). Nonetheless, in those disorders (GABA-transaminase deficiency and homocarnosinosis), neurologic impairment was a dominant feature (Gibson and Jakobs 2001). Our CSF studies also provide the first evidence for a correlation between GHB and serotonin turnover in humans, which had previously been suggested in rodent models (Gibson et al 1998; Gobaille et al 2002). Because serotonin levels are important in the regulation of sleep, mood, and anxiety, altered serotonergic neurotransmission may underlie the aggression, sleep disorders, anxiety, and symptoms of psychosis observed in many SSADH-deficient patients.

Behavioral Disturbance in Human SSADH Deficiency

The phenotype of human SSADH deficiency is that of nonspecific neurologic disease, which may result in considerable diagnostic delay and underrecognition (Pearl et al 2001). Currently, there is no effective treatment, although interventions targeting dopamine and serotonin levels may hold promise (Anderson et al 2001, 2002). Although benzodiazepines proved efficacious, long-term use is not feasible (Wallace et al 2001). In the limited number of case reports currently available, it appears that the SSADH-deficient phenotype evolves with age, which suggests that treatment strategies may need to be tailored to the developmental stage of the disease. Thus, accurate cross-sectional and longitudinal studies of human SSADH-deficient patients, both metabolically and clinically, will be important to estimate the relative importance of pathologic mechanisms that may be present at specific stages of development. Supported in part by NIH Grant No. NS 40270 and National March of Dimes Birth Defects Foundation Grant No. 1-FY00-352. The authors are indebted to E.E.W. Jansen and A. Bakkali for excellent technical assistance in determination of metabolites in physiologic fluids of patients.

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