Succinic Semialdehyde Dehydrogenase Deficiency

GUJHS. 2004 April; Vol. 1, No. 3

Emily Robbins NHS ‘06

elr24@georgetown.edu

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare autosomal recessive disorder identified in approximately 350 individuals worldwide is caused by an enzyme deficiency in the degradation of gaba-aminobutyric acid (GABA), the major inhibitory neurotransmitter.  Normally, GABA is converted to succinic semialdehyde, which is then, via succinic semialdehyde dehydrogenase, oxidized to succinic acid.  In the absence of succinic semialdehyde dehydrogenase, succinic semialdehyde is reduced to gaba-hydroxybutyrate (GHB), the neurotoxic agent that accumulates in the cerebrospinal fluid (CSF), urine, and serum of patients with SSADH deficiency, and is believed to cause the clinical manifestations of the disorder. About half of the SSADH deficiency patients suffer from seizures.  GHB, an addictive drug of abuse, has a wide range of applications, including the management of alcohol and opiate withdrawal, as well as to subdue victims for sexual assault.  I am participating in research at the National Institute of Health in the National Institute of Neurological Disorders and Stroke’s epilepsy lab with a murine model of this disorder, in which the gene encoding SSADH is disrupted.   Understanding SSADH deficiency will allow us to move towards treating this disease, and also, will provide a better understanding of GHB, and increase our understanding of many neuropsychiatric disorders involving substance abuse and psychosis.

Introduction

In 1981, three patients presented with 4-hydroxybutyric aciduria.  Although this type of organic aciduria was not yet understood, scientists hypothesized that it was caused by a genetic deficiency of succinic semialdehyde dehydrogenase (Jakobs et al., 1981).  Succinic semialdehyde dehydrogenase (SSADH) deficiency is one of the rare neurometabolic conditions known as pediatric neurotransmitter disorders (PNDs).  PNDs are divided into two categories: disorders of monoamine metabolism and disorders of gaba-aminobutyric acid (GABA) metabolism.  Of the GABA disorders, which also include pyridoxine dependent epilepsy and GABA transaminase deficiency, SSADH deficiency is the most common.  The diagnosis of PNDs requires a high degree of suspicion leading to cerebrospinal fluid and other biochemical analyses which make detection of these disorders difficult. (Pearl et al., in press).

Pathophysiology

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare autosomal recessive disorder identified in approximately 350 individuals worldwide, is caused by an enzyme deficiency in the degradation of gaba-aminobutyric acid (GABA), the major inhibitory neurotransmitter.  GABA action is mediated through GABAA and GABAB receptors, which have fast, ionotropic and slow, metabotropic (or protein-mediated) effects, respectively. Normally, GABA is converted to succinic semialdehyde, which is then, via succinic semialdehyde dehydrogenase, oxidized to succinic acid (Figure 1).  Succinic acid then enters the Krebs cycle where it is further metabolized, producing energy.  (Gropman 2003)

In the absence of succinic semialdehyde dehydrogenase, succinic semialdehyde is reduced to gaba-hydroxybutyrate (GHB).  GHB, a short-chain moncarboxylic fatty acid, is the putative neurotoxic agent that accumulates in the cerebrospinal fluid (CSF), urine, and serum of patients with SSADH deficiency, and is believed to cause the clinical manifestations of the disorder. (Pearl et al., 2003b) The SSADH gene has been mapped to chromosome locus 6p22, and over 35 mutations have been identified in the DNA sequence controlling the SSADH gene. (Trettel et al., 1997).

 

(drawn by Phillip L. Pearl, MD)

Diagnosis
Clinical Features

The most common clinical characteristics of SSADH deficiency are developmental delay, including language and motor delay, hypotonia, and mental retardation, which present between birth and age 25.  The clinical features of 60 SSADH deficiency cases are summarized in the table I.  Mental retardation, language delay, hypotonia, and motor delay are extremely common among patients suffering from SSADH deficiency.  About half of the patients exhibit ataxia, hyporeflexia, behavioral problems, and seizures.  These seizures include both absence and tonic-clonic seizures. (Pearl et al., 2003b).  These seizures may be caused by metabolic alterations in neurotransmitters, leading to a change in either the binding of neurotransmitters to receptors or the transport of neurotransmitters.  (Gibson et al., 2002).

Table 1. Clinical Findings in 60 Patients with SSADH DeficiencyNumber of individuals       Percent Mental retardation                  50                  83 Language delay                       49                   82 Hypotonia                                 48                  80Motor delay                              45                  75 Seizures                                     38                  63 Behavior problems                   30                  50Ataxia                                        29                  48 Hyporeflexia                             27                  45 Ocular findings                         15                  25 GI symptoms                             13                  22 Neonatal problems                     8                  13

From: Pearl et al., 2003b

Neuroimaging

Cranial computed tomography, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and flourodeoxyglucose positron emission tomography (FDG-PET) have been used as neuroimaging techniques for patients with SSADH deficiency.  The most common abnormalities, which are found in MRI studies, are increased T2-weighted signal abnormalities in the globus pallidi bilaterally and symmetrically, as well as abnormalities of the subcortical white matter.  Similar abnormalities have also been identified in the cerebellar dentate nucleus and brainstem, as well as atrophy of the cerebrum and cerebellum in some patients.  EEG studies show both generalized and focal epileptiform discharges, as well as background slowing in some patients with SSADH deficiency, although EEG findings are normal in about 50% of patients.  (Pearl et al., 2003a).

Increased signal intensity in the globus pallidi has been noted in other organic acidurias, suggesting that this imaging finding is nonspecific in metabolic disorders.  (Bismar and Ozand 1994)  Differences in degree of signal intensity, with more subtle changes in older patients, are thought to suggest a change in metabolic environment with age. (Pearl et al., 2003b)

Laboratory Findings

The accumulation of GHB in the CSF, urine, and serum of patients with SSADH deficiency can be difficult to detect because GHB is volatile and often obscured on gas chromatography-mass spectrometry (GCMS) by a normal high amplitude urea peak.  Detection is possible with careful organic acid analysis of the urine, indicating high levels of GHB. (Pearl  et al., 2003b).  Other GABA metabolites, formed during its oxidation to succinic acid, have been identified, including 3,4-dihydroxybutyric acid, 3-oxo-4-hydroxybutyric acid, and glycolic acid.  An increase in glycolic acid may lead to an increase in glycine in CSF, urine, and serum, and thus may be found in laboratory tests.

In examining the cerebrospinal fluid from 13 unrelated patients with SSADH deficiency for selected neurotransmitters a significant increase in GHB and free GABA was shown in patients with SSADH deficiency compared to controls.  In addition, a linear relationship was noted between increased total GABA and the levels of homocarnosine, homovanillic acid (HVA), and 5-hydroyindoleacetic acid (5-HIAA).  As homocarnosine is a dipeptide molecule consisting of GABA coupled with histidine, this relationship could be anticipated.  GHB inhibits the release of presynaptic dopamine in the central nervous system.  The positive correlations between elevations in GABA and HVA plus 5-HIAA imply that there may be increased turnover of dopamine and serotonin.  HVA is the primary metabolic end product of dopamine, and 5-HIAA is the primary metabolic end product of serotonin.  An increased turnover of dopamine may be a compensatory response to the antidopaminergic release mediated by GHB.  A relationship between GABA, GHB, and serotonin is an area of ongoing investigation.

The primary precursor of GABA is glutamate, which is the major excitatory neurotransmitter in the brain.  There is a shuttle system between neurons and their supportive cells, astrocytes, involving glutamate and another amino acid, glutamine.  It is the astrocytic glutamine, which is then converted to glutamate in the neuron. (Behar et al., 1999 and Sonnewald U and McKenna 2002)  This neuron-astrocyte shuttle is required to maintain a pool of these vital neurotransmitters, glutamate and GABA.  Disruption of this shuttle has been suggested by the findings of decreased glutamine levels in both human  CSF studies and in the animal model of SSADH deficiency.  Hence, a disruption of this shuttle may lead to the disruption of normal balance between the glutamatergic excitatory and GABAergic inhibitory activities, which may cause seizures and the other widespread neurological manifestations of this disorder.  (Pearl et al., 2003b)

Pharmacological Treatment

There is no effective treatment for SSADH deficiency.  The treatments utilized are symptomatic, most often targeted at seizures and neurobehavioral disorders.  Vigabatrin, the most widely used pharmacological agent in the treatment of SSADH deficiency, is an irreversible inhibitor of GABA transaminase, and thus should inhibit the formation of succinic semialdehyde, and in turn, GHB.  (Howells et al., 1992; Gibson et al., 1995)  However, administration of vigabatrin has produced inconsistent results and has not been  effective in inhibiting peripheral GABA-transaminase outside of the central nervous system.  This could lead to unwanted accumulation of succinic semialdehyde and subsequently GHB in these patients  (Howells et al., 1992) Reports of visual loss due to retinal toxicity have prevented the FDA from approving vigabatrin  (Gross-Tsur V et al., 2002, Malmgren et al., 2001, Krauss  et al., 1998). Other antiepileptic drugs, including carbamazepine and lamotrigine, are also being used in attempts to prevent and control seizures in SSADH deficiency.

Neurobehavioral symptoms, such as anxiety, hallucinations, hyperkinesis, and aggressiveness are often controlled by the use of benzodiazepines, methylphenidate, thioridazine, risperidal and flouxetine.  (Gibson et al., In press; Scriver and Gibson et al., 1995; Pearl  et al., 2001).  Valproate, an anticonvulsant, may inhibit residual SSADH enzyme activity, and thus is contraindicated for patients with SSADH deficiency  (Pearl et al., 2003b)

Research

Research is underway in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health to find an effective treatment for SSADH deficiency, as well as to better understand the GABAergic and glutamateric systems.  Using gene-targeting methodology, Gibson and colleagues developed a murine model of this disorder, in which the gene encoding SSADH is disrupted (Hogema et al., 2001).  In the murine model, generalized tonic-clonic seizures, which almost always occur by 20 days of age, lead to death.  I am an active member of this research team, which is evaluating the administration of several anti-epileptic drugs in terms of their effectiveness to prolong the life of the knockout mice in which the SSADH gene has been removed by genetic manipulation by controlling their seizures.  The goal of the research is to find a treatment that will prolong and improve the quality of  life in the murine model, and then to evaluate the efficacy of the effective treatment in the animal model to control seizures in human SSADH patients.

There is still a great deal that is unknown about the pathology of SSADH deficiency.  This is a complex neurological disorder that manifests severe cognitive, behavioral, and epileptic disturbances and is biochemically manifest by alterations in several vital neurotransmitters, including GABA, GHB, glutamate, glutamine, dopamine, and serotonin.  As GHB is being increasingly used as a drug of abuse and addiction, the manifestations of patients having high endogenous levels of this compound have relevance throughout the fields of clinical neurology and psychiatry.  The murine model which biochemically and clinically simulates human SSADH deficiency allows us to progress in our ability to treat patients with this particular metabolic disorder and  may also provide information that is generalizable to a wide range of neuropsychiatric disorders.