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GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and acc...

GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (summary by Koenig et al., 2017).

▼ Clinical Features
Jaeken et al. (1984) reported 2 sibs, born of consanguineous Flemish parents, who presented with severe hypotonia, psychomotor retardation, and hyperreflexia. The proband had accelerated linear growth associated with increased growth hormone. Cerebrospinal fluid showed high levels of free GABA, homocarnosine (a dipeptide of GABA and histidine), and beta-alanine (an alternative substrate for GABA-transaminase). Liver GABA-transaminase was deficient. Brain-evoked responses were suggestive of leukodystrophy. A brother, who showed a similar clinical picture, had died at 1 year of age. Postmortem showed leukodystrophy of the type seen in aminoacidopathies such as phenylketonuria (PKU; 261600). The proband died at age 25 months (Gibson et al., 1986).

Medina-Kauwe et al. (1999) described a second unrelated patient with GABA-aminotransferase deficiency and reviewed the patient reported by Jaeken et al. (1984). The phenotype in both included severe psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, high-pitched cry, and EEG abnormalities. The second patient did not have increased linear growth. Brain MRI of the second patient showed agenesis of the corpus callosum, cerebellar hypoplasia, a posterior fossa cyst, and abnormal gyration. GABA concentrations were significantly increased in all bodily fluids. He died at 5 months of age.

Tsuji et al. (2010) reported a 28-month-old Japanese female, born of nonconsanguineous parents, with GABA-aminotransferase deficiency. At age 7 months, the child showed psychomotor retardation, hypotonia, bilateral intermittent esotropia, hyperreflexia, and positive Babinski reflex. There was no dysmorphism. At age 8 months, she showed decreased consciousness after an acute febrile illness. Respiratory distress required mechanical ventilation and she experienced myoclonic jerks. EEG revealed diffuse slow spike and wave discharges with 1- to 2-s periods of suppression. Amino acid analysis showed elevated free GABA in the serum and cerebral spinal fluid. Proton MR spectroscopy showed significant elevation of GABA as well as a slight elevation of glutamine/glutamate complex in the basal ganglia and semioval center. GABA-transaminase deficiency was confirmed by enzyme studies in cultured lymphoblasts. Koenig et al. (2017) provided a follow-up of this patient at age 9.5 years. She was nonverbal, nonambulatory with spastic quadriparesis and dystonia, and dependent on gastrostomy tube feedings, but was relatively stable with rare convulsive seizures. EEG background was slow spike-wave.

Nagappa et al. (2017) reported a child, born of nonconsanguineous parents, who presented at 6 months of age with global developmental delay and hypersomnolence since birth. The duration of her sleep ranged from 18 to 20 hours a day. She had hypotonia, brisk muscle stretch reflexes, and Babinski reflex, and showed inconsistent visual tracking and response to sound stimulus. From age 8 months, she had a hyperkinetic movement disorder characterized by continuous arrhythmic movements of the distal extremities while awake. She also exhibited frequent tongue protrusions and eyebrow elevations. None of these movements were present during sleep. Brain MRI at 5 months of age showed restricted diffusion along the internal capsule and genu of corpus callosum, and EEG was normal. MRI at 10 months of age showed hyperintensities in the brainstem and external and internal capsules, a 'trilaminated' appearance of posterior limb of the internal capsule, and dysmyelination of subcortical white matter. MR spectroscopy from basal ganglia showed a prominent peak between 2.2 ppm and 2.4 ppm, indicating pronounced elevation of glutamine, glutamate, and GABA. EEG at 18 months of age showed recurrent multifocal epileptiform discharges, and she was treated with levetiracetam and clonazepan. Although the authors could not quantify GABA levels, they suggested that the MRS finding provided indirect evidence of reduced function of ABAT.

Koenig et al. (2017) reviewed a series of 10 cases of GABA-transaminase deficiency. Five patients were alive with age at last follow-up of 18 months to 9.5 years. All patients presented with neonatal/infantile-onset encephalopathy, hypotonia, and hypersomnolence. Median age at onset was 3 months, with 4 having neonatal presentations.

▼ Inheritance
Gibson et al. (1985) established autosomal recessive inheritance of GABA-transaminase deficiency by finding evidence of heterozygosity in both parents and a healthy sib and homozygosity for GABA-transaminase deficiency in the affected Flemish child reported by Jaeken et al. (1984).

▼ Clinical Management
Koenig et al. (2017) reported that 2 patients with GABA-transaminase deficiency were treated with continuous flumazenil. One patient, with a milder phenotype, began treatment at age 21 months and has continued 20 months with improved alertness and less excessive adventitious movements. Treatment in the second patient, with a more severe phenotype, was begun when he was 7 years old but was discontinued after 2 months due to increased wakefulness with agitation and no observed clinical benefit.

▼ Molecular Genetics
In 2 unrelated patients with GABA-aminotransferase deficiency, Medina-Kauwe et al. (1999) identified mutations in the ABAT gene (137150.0001 and 137150.0002).

In a 28-month-old Japanese female with GABA-aminotransferase deficiency, Tsuji et al. (2010) identified compound heterozygous mutations in the ABAT gene (137150.0003-137150.0004).

In a child with evidence of GABA-aminotransferase deficiency, Nagappa et al. (2017) identified compound heterozygous mutations in the ABAT gene (137150.0005-137150.0006). Her parents were each heterozygous for one of the mutations, and neither variant was present in the 1000 Genomes Project database.

In an 8-year-old boy, born of consanguineous parents of Mexican descent, with GABA-aminotransferase deficiency, Koenig et al. (2017) identified a homozygous mutation in the ABAT gene (R377W; 137150.0008). Each parent was heterozygous for the mutation, which was not present in the ExAC database.

Tags: 16p13.2



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