Presentation and course
All patients presented with neonatal or early infantile onset developmental impairment, generalized tonic-clonic seizures, hypotonia, choreoathetosis, and subcortical myoclonus. Accelerated growth has been reported in 4 patients and delayed myelination was seen in 9 of 10 reported patients (34; 22).
Clinical findings in the index family were neonatal seizures, lethargy, hypotonia, hyperreflexia, poor feeding, severely retarded psychomotor development, and a high-pitched cry (16; 08; 15; 15; 06; 31; 18; 38). In both siblings, linear growth and head circumference were accelerated, with normal height and head circumference noted in both parents. Accelerated growth is consistent with the growth hormone-promoting effects of GABA (36). At 2 years of age, the female was 4 cm over the 97th percentile, and her head circumference was in the 75th percentile. The male showed a rapid increase in head circumference, from the 50th to 97th percentiles, during the last 6 weeks of his life. Adiposity and intermittent hepatomegaly were noted in the female proband. The first child of these parents died at the age of 5 days from an unknown cause; the second child is healthy. EEG in the female was normal at 2 weeks of age, revealed predominantly low-voltage beta-frequency activity with intermittent epileptiform discharges at 7 months, and showed generalized epileptiform paroxysms at 2 years. Visual, auditory, and somatosensory evoked potentials were absent at the age of 2 years. CT in both siblings revealed severe ventricular enlargement as well as increased cisternal and sulcal spaces.
The next reported patient was a 6745-gram female born to nonconsanguineous Japanese parents (44). Both parents and a 6-year-old sister were healthy, and there was no family history of neurologic disorders. The patient had an uncomplicated birth and normal early infancy but was evaluated at 7 months for hyperreflexia, psychomotor retardation, hypotonia, bilateral intermittent esotropia, and a positive Babinski reflex. No dysmorphic features were noted. At 8 months of age, the patient was hospitalized for decreased consciousness after the onset of a febrile illness, and she subsequently developed respiratory distress and required mechanical ventilation. She began to experience segmental myoclonic jerks that were not completely controlled by phenobarbital, clonazepam, valproate, or midazolam. EEG at 8 months revealed diffuse spike-and-wave activity with 1- to 2-second periods of background suppression. At 11 months, the patient was experiencing chronic respiratory failure, and the febrile illness resulted in neurodegeneration characterized by opisthotonic posturing with generalized dystonia and continued segmental myoclonus. Free GABA was elevated in serum, CSF, and cortical tissue, whereas GABA-transaminase activity was diminished. CT was normal, and the brain MRI suggested a mild delay in myelination, but no structural abnormalities. Follow-up was reported at 9 and a half years of age with profound neurodevelopmental impairment, active generalized tonic-clonic seizures, and a medication program of phenobarbital, clonazepam, diazepam, baclofen, dantrolene, and haloperidol.
Diagnostic findings include significantly elevated GABA (free and total) and beta-alanine levels in plasma and CSF, as well as diminished GABA-transaminase enzymatic activity. In both the female index patient and the unrelated case, CSF free-GABA was the most elevated biological marker at 60x and 16x elevated levels, respectively CSF bound, plasma bound, and plasma free GABA was also markedly elevated (at least 3 times normal levels) (16; 18; 44). Tsuji and colleagues used quantitative proton magnetic resonance spectroscopy (1H-MRS) to detect significantly increased GABA concentration in the basal ganglia of their living patient (44).
A 12-month-old male patient, diagnosed postmortem, was described in an abstract published in 2015 (25). He presented as a neonate with generalized tonic-clonic seizures, hypotonia, accelerated growth, lethargy, and cerebral atrophy without developmental progress. A 2015 paper discussed 2 siblings: a female who died at age 7 and a male who was alive at 7. Both presented at 3 months of age with profound impairment, seizures, hypotonia, lethargy, and cerebral atrophy (03). Free CSF GABA levels were more than twice the upper limit of normal (2.9 and 3.1 ULN = 1.4). A 2016 paper reported a third sibling of the above 2 patients, who presented at 2 months with a highly similar clinical presentation to the 2 siblings previously discussed and died at 12 months (02). This paper also reported a patient with a clinical presentation milder than the previously reported cases. The male patient presented at 6 months of age with hypotonia, hypersomnolence, developmental delay, and mild chorea. No structural brain abnormalities were noted, but a cranial MRI at 9 months showed delayed myelination. This patient had a milder presentation, without overt seizures, although EEG showed hypsarrhythmia. Unlike the previously reported patients, he reached developmental milestones and could control his head when sitting, track faces, smile appropriately, and eat and drink solid food by mouth by 18 months (02).
Nagappa and colleagues described a female neonate that presented with global developmental delay, hypersomnolence, and hypotonia (30). The patient also presented with a hyperkinetic movement disorder, including choreoathetosis, with movements that subsided during sleep. EEG initially was normal at 6 months, but showed multifocal epileptiform spikes at 18 months. MRI showed increased T2/FLAIR signal with T1 hypointensity, interpreted as dysmyelination, affecting the medulla, dorsal pons, cerebellar dentate nucleus, and internal capsule (anterior limb and genu). A trilaminated appearance was present based on central hypointensity and hyperintense margins involving the posterior limb of the internal capsule. Morales-Briceño and colleagues described previously unreported findings of paroxysmal dyskinesias associated with drowsiness and T2 thalamic hyperintensities in 2 adult siblings, 32- and 25-year-old sisters with history of mild developmental delays and seizures (29).
A series published in 2017 reported a boy born to consanguineous parents who presented at 5 months with developmental delay, hypotonia, hypersomnolence, choreoathetosis, and focal seizures (22). Seizure types expanded to include generalized tonic-clonic at 2 years and absence as well as generalized convulsive status epilepticus at 6 years. Cranial MRI showed progressive atrophy at 4 years.
In the case series by Koenig and colleagues, of the 10 patients reported with confirmed GABA-transaminase deficiency, 4 were deceased by age 25 months and 1 survived to age 7 years. The 5 surviving reported cases are ages 18 months to 9 and a half years. In recent years, milder phenotypes are emerging and are associated with higher residual enzymatic activity and survival into adulthood (13; 29).
In 2020, another genetically confirmed GABA-transaminase deficiency case was reported (32). The description of this case included a neonate who presented with severe neonatal epileptic encephalopathy, lethargy, hypotonia, hyperreflexia, and poor feeding. An MRI of this neonate revealed extensive intraventricular hemorrhage (which could be coincidental). At 14 days of age, he developed polyuria and hypernatremia and had a low antidiuretic hormone serum level, corresponding to diabetes insipidus. He was treated with desmopressin until his death at 7 months. A whole exome study detected homozygosity of the c.316G > A (p.Gly106Ser) variant in the ABAT gene. Both his parents, who were consanguineous, were heterozygous carriers of this variant.
Increasing the use of sequencing of the ABAT gene is expected to identify new cases. CSF quantification of GABA-free and total levels is recommended to confirm the pathogenic sequencing findings. Definitive diagnosis can also be made by measurement of GABA-T activity in the liver, lymphocytes isolated from whole blood, or Epstein-Barr virus-transformed cultured lymphoblasts (09).
Prognosis and complications
Patients have uniformly presented with neonatal or early infantile encephalopathy, often accompanied by hypotonia, lethargy, seizures, and extrapyramidal manifestations. In the first reported family, 1 child died at 5 days of age from an unknown cause without sufficient clinical history to establish a retrospective diagnosis. GABA-transaminase deficiency appears to be extremely rare, although it is possible that the inborn error is lethal in utero or very early in the neonatal period, before a metabolic diagnosis is made. Additionally, CSF GABA levels in CSF are not measured routinely measured in patients with epileptic encephalopathies, and the disorder may be undetected.
Clinical vignette
An 8-year-old boy born to first cousin parents presented at 5 months of age with hypotonia, excessive daytime somnolence, and virtually continuous movements in the awake state consistent with choreoathetosis. Generalized seizures ensued by age 2 years, and EEGs showed multifocal discharges and diffuse slowing. MRI demonstrated progressive atrophy. Whole exome sequencing demonstrated a novel homozygous variant in ABAT (c.1129C> T; p.R377W). Parents were confirmed as heterozygous carriers.