Background

SSADH is an autosomal-recessive disorder that has a range of presentations, but typically manifests with a relatively non-progressive encephalopathy characterized by developmental delay, hypotonia, and a prominent expressive language deficit presenting in the first 2 years of life. Originally described in 1983 [1], a recent literature survey identified 182 confirmed published cases from 40 countries [2]. Based on laboratory experience, it is estimated that approximately 500 people have been diagnosed worldwide, and the disorder may well be underdiagnosed. SSADH is a mitochondrial protein in the aldehyde dehydrogenase family (subfamily 5A1), and encoded by ALDH5A1 on chromosome 6p22. At least 45 ALDH5A1 mutations have been published as pathogenic for SSADH deficiency [3]. In the absence of SSADH, the breakdown of GABA to succinic acid is altered. The result is a build-up of GABA, as well as gamma-hydroxybutyric acid (GHB; 4-hydroxybutyric acid), a neurotoxic agent that may contribute to the clinical manifestations. GHB is elevated in all physiological fluids, with the cerebral spinal fluid (CSF) showing up to a three-fold increase in GABA and 230-times increase in GHB in patients [4]. Although the excess GHB in all physiological fluids is the hallmark of the disease, there is no correlation between the severity of clinical features and GHB levels [5]. Recent longitudinal studies revealed a significant negative age correlation with GHB and GABA, with attainment of a nadir in GHB levels in red blood cells by 10 years of age and in GABA at 30–40 years of age [6]. Hair samples quantified for GHB levels from ten patients with SSADH deficiency showed significantly elevated concentrations in patients ages 3–7 years, with levels reaching the control range by 12–13 years [7]. Thus, the imbalance in GABA and GHB concentrations in this disorder fluctuate with age.

Clinical Manifestations

Detection is typically by urine organic acids for an elevated level, followed by confirmation using ALDH5A1 gene sequencing. Clinical features include developmental delay, intellectual disability with prominent impairment of expressive language, motor dysfunction, hypotonia, hyporeflexia, and non-progressive ataxia (Table 23.1). As patients enter adolescence and adulthood, more disabling symptoms tend to be behavioral and psychiatric manifestations, with a high prevalence of attention deficit hyperactivity disorder, anxiety disorder, autistic features, obsessive–compulsive disorder, and sometimes aggression and hallucinations [4, 8–10].

Sleep disturbances with excessive daytime somnolence have been reported, with polysmonography showing a reduced sleep latency as well as a prolonged latency to stage rapid eye movement (REM) with a reduced percentage of stage REM [11]. This is consistent with animal models demonstrating a reduction of REM-stage sleep, associated with hyperGABAergic states via inhibition of GABA transaminase [12]. Epilepsy is present in about half of affected individuals, and appears to be more prevalent over time [13]. There is a paradox of epilepsy in hyperGABAergic disorders, as GABA is the major inhibitory neurotransmitter of the brain. Our cohort of 128 patients demonstrates a 69% incidence of epilepsy in subjects of ages 12 and older, compared to 50% of the total population (p < 0.01) (Table 23.2). Generalized tonic–clonic and absence are the most common seizure types. We have observed a tendency to see more absence seizures in the younger patients compared to tonic–clonic in the older cohorts, which may correlate with the aforementioned age-related changes in GABA and GHB concentrations as well as the natural history of seizures in the null mouse model [14]. Sudden unexpected death in epilepsy patients (SUDEP) has occurred in four adult patients to our knowledge, which corresponds to a premature mortality rate of 13% in the adult population contained in our registry. The most common abnormal electrographic findings are generalized epileptiform discharges and diffuse background slowing [8, 9]. Electrographic status epilepticus of sleep and photosensitivity have also been observed in patients.

Movement disorders are not described universally in SSADH-deficient patients, although they are certainly reported and were even described in the index case report of gamma-hydroxybutyric aciduria as “short episodes of abnormal movements” between the ages of 6 months and 12 months, as well as ocular apraxia and a significant ataxia of the trunk and limbs by 20 months [15]. Although intermittent decompensation as seen in other metabolic disorders is not characteristic in the majority of patients, there is a subgroup (10%) with a more severe phenotype characterized by regression as well as prominent extrapyramidal manifestations [16, 17]. Basal ganglia signs, including choreoathetosis, dystonia, and myoclonus, as well as clinical onset in the first 6 months of life, are reported in these patients [18]. About half of the patients in this subgroup may show a progressive course with deterioration over time [17]. The varying degrees of severity have not been explained by genotype–phenotype correlation; in fact, there have been cases within the same family where the disorder in one sibling presents as an acute infantile encephalopathy with severe choreoathetosis and in another sibling with a more typical non-progressive appearance (Video 23.1) [19]. In addition, paroxysmal exertional dystonia has been described in SSADH deficiency, with clinical benefit from vigabatrin intervention [20]. The latter report revealed a prominent lurching gait. We have seen the same exertional lurching gait in a similarly aged adolescent with SSADH deficiency (Video 23.2). Alternatively, vigabatrin has been associated with basal ganglia, thalamic, and brainstem T2 hyperintensities on MRI [21] in addition to hyperkinetic movement disorders [22].

Imaging Findings

MRI demonstrates a fairly consistent pattern of distribution that may be characterized as a dentato-pallido-luysian pattern with increased T2-weighted and fluid-attenuated inversion recovery (FLAIR) signals involving the cerebellar dentate nuclei, globus pallidi (interna and externa), and subthalamic nuclei (Figure 23.2). This is usually, but not always, bilateral and symmetrical. Cerebral atrophy, cerebellar atrophy, delayed myelination and T2 hyperintensities in the subcortical white matter, thalami, and brainstem have also been found. MRS using single- and multivoxel-studies show normal spectra except for elevations of GABA and related compounds (including GHB and homocarnosine) on special editing techniques in affected patients, but not obligate heterozygotes [23]. Fluorodeoxyglucose brain positron emission tomography (PET) has demonstrated a decreased cerebellar glucose metabolism in patients with cerebellar atrophy on structural MRI [24]. PET using flumazenil to image the distribution of GABA-A receptors demonstrated a substantial reduction in binding in multiple regions in subjects compared to both parent heterozygote and healthy controls, consistent with overuse-dependent downregulation of GABA-A receptors (Figure 23.3) [25].

Figure 23.2 Dentato-pallido-luysian pattern in SSADH deficiency. Coronal short tau inversion recovery sections from MRI in a patient with SSADH deficiency showing bilateral symmetrical homogenous signal abnormalities in the globus pallidus (internal portion [black arrows, a], external portion [white arrows, a and b]), subthalamic nucleus (black arrows, b), and dentate nucleus (white arrows, c). Reproduced with permission from Pearl PL, Gibson KM, Quezado Z, Dustin I, Taylor J, Trzcinski S, et al. Decreased GABA-A binding on flumazenil PET in succinic semialdehyde dehydrogenase deficiency. Neurology. 2009;73(6):423–9.

Figure 23.3 Decreased GABA-A binding on flumazenil PET in SSADH deficiency. Flumazenil PET shows a marked reduction of cortical binding potential of ¹¹C-flumazenil in (a) a patient with SSADH deficiency versus (b) a heterozygote control. Reproduced with permission from Pearl PL, Gibson KM, Quezado Z, Dustin I, Taylor J, Trzcinski S, et al. Decreased GABA-A binding on flumazenil PET in succinic semialdehyde dehydrogenase deficiency. Neurology. 2009;73(6):423–9.

Treatment Strategies and Clinical Trials

Treatment for SSADH deficiency remains symptomatic, typically for seizure control and psychiatric manifestations. Options include targeted antiseizure drug therapy, anxiolytic agents, neuroleptics, and selective serotonin reuptake inhibitors. Antiseizure medications are generally selected to target generalized seizures, although valproate is typically avoided due to its ability to inhibit any residual SSADH enzymatic activity [26]. Lamotrigine, levetiracetam, topiramate, and zonisamide have been successful medications for maintenance therapy.

Vigabatrin, an irreversible inhibitor of GABA-T, is potentially a rational choice because it inhibits the conversion of GABA to GHB, yet exacerbates an already elevated GABA level [27–29]. In clinical use, vigabatrin has not been a reliable therapeutic, with many reports of a lack of effect, or worsening of symptoms, ranging from seizure control to alertness. In addition, other concerns regarding vigabatrin use include retinal toxicity with visual-field defects [30–32], MRI signal changes in the GABA-rich thalamus and basal ganglia [21], and a recent report of white matter spongiosis on a post-mortem study in a patient with polymicrogyria who died of SUDEP [33].

Therapeutic strategies in the animal model of SSADH deficiency have led to clinical trials that are ongoing [34]. Early promising results using taurine, based on the observation that suckling mice developed seizures as they weaned and that taurine was a principal component of murine breast milk, were followed by a single non-blinded, uncontrolled case report of improved gait, coordination, and energy in a 2-year-old boy with SSADH deficiency [35]. This was followed by an open-label study in 18 patients (age range 0.5–28 years, mean 12 years) without clinically meaningful improvement on the Adaptive Behavior Assessment Scale [36]. A crossover open-label study of seven patients (age range 12–33 years) on and off taurine assessed biomarkers, such as transcranial magnetic stimulation (TMS), CSF metabolites, and neuropsychological evaluations did not identify significant changes [37].

Benefit in the animal model from SGS 742, a GABA-B receptor antagonist, led to a current phase 2 double-blinded, placebo-controlled clinical trial in progress [38]. Preclinical work suggests potential efficacy and safety utilizing GHB antagonist NCS-382 [39–41].

Background

GABA-T is the initial key enzyme involved in GABA degradation. Deficiency of this enzyme is inherited in an autosomal-recessive pattern and was initially reported in 1984, with two cases reported in the same family suggesting mortality within the first 2 years of life [42]. Only a small number of affected individuals have been published although more cases are being identified with increasing use of phenotype-specific gene panels and whole-exome sequencing. The initial reports described neonatal or early-infantile onset encephalopathy although other phenotypes are emerging with increased recognition, including survival through the first decade [43]. Other common features are hypotonia, hyperreflexia, hypersomnolence, high pitched cry, and accelerated linear growth (Table 23.3) [42, 43]. The accelerated linear growth has been attributed to the growth hormone promoting effects of GABA.

Movement disorders may be very prominent when present, with choreoathetosis reported in one-third of patients [43]. A combined presentation of hypersomnolence and hyperkinetic movement disorder of distal extremities during wakefulness, superimposed upon hypotonia and impaired response to auditory and visual stimuli has been described [44]. Virtually constant choreoathetosis and myoclonus have been seen (Video 23.3); less excessive adventitious movements were observed in this patient after treatment with the GABA-receptor benzodiazepine-binding site antagonist, flumazenil [43].

GABA-T locates to the 4-aminobutyrate aminotransferase (ABAT) gene at chromosome 16p13.2. The concentration of free GABA in the CSF has been shown to be as high as 60 times greater (in the index case) than in controls. Diagnosis may be predicated on the measurement of CSF amino acid concentrations, with elevations in free and total GABA and beta-alanine. There is no CSF elevation of GHB. Metabolomic profiling may be informative by the detection of the GABA keto-analogue 2-pyrrolidinone in plasma, urine, or CSF [45]. The rarity of this disorder may be due to in utero death or the infrequency of recessive alleles, but diagnosis is likely impeded by the general lack of availability of CSF testing for GABA concentrations. Alternatively, the increasing use of MRS with special editing for small molecules and molecular testing will lead to more diagnosed cases [43, 46].

The ABAT enzyme has recently been discovered to have a dual function. ABAT deficiency results in both a neurometabolic disorder as described, as well as a mitochondrial genome depletion syndrome where there is a marked loss of mitochondrial genome (mtDNA) copy number. ABAT plays an essential role in mitochondrial nucleoside salvage by aiding in the production of deoxynucleotide triphosphate (dNTP) from deoxynucleotide diphosphate (dNDP) in the mitochondria, the building block for DNA [47].

Electroencephalography shows severe abnormalities including burst-suppression, modified hypsarrhythmia, multifocal spike discharges, generalized spike and wave, and diffuse background slowing and disorganization. Imaging has shown hypomyelination, T2- and diffusion-weighted hyperintensities involving the white matter including the internal and external capsules, and progressive cerebral atrophy (Figure 23.4) [48].

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