GABA aminotransferase deficiency

GABA Aminotransferase Deficiency: A Rare Neurological Disorder

GABA aminotransferase (GABA-T) deficiency is an extremely rare disorder of GABA metabolism characterized by severe neonatal-infantile epileptic encephalopathy [3]. This condition begins in infancy and is marked by recurrent seizures, also known as epilepsy [1].

Characteristics of the Disorder

The symptoms of GABA-T deficiency include:

• Neonatal or early infantile-onset encephalopathy
• Hypotonia (low muscle tone)
• Hypersomnolence (excessive sleepiness)
• Epilepsy (recurrent seizures)
• Choreoathetosis (involuntary movements) [6]

Inheritance and Biochemical Features

GABA-T deficiency is inherited as an autosomal recessive disorder, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition [8]. This disorder is characterized by high levels of GABA in serum and cerebrospinal fluid (CSF).

Impact on Motor Inhibition

GABA deficiency leads to a lack of motor inhibition, resulting in excessive activity. This lack of inhibition is the basis of symptoms in several neurological disorders, including GABA-T deficiency [7].

Prognosis and Phenotypic Spectrum

While previously thought to be lethal within two years, recent studies suggest that GABA-T deficiency may have a broader phenotypic spectrum, with some individuals surviving into adulthood [4]. However, the prognosis for this condition remains guarded due to its severe neonatal-infantile presentation.

References: [1] Apr 1, 2018 — [3] Gamma-aminobutyric acid transaminase (GABA-T) deficiency is an extremely rare disorder of GABA metabolism characterized by a severe neonatal-infantile epileptic encephalopathy. [4] by AU Hegde · 2019 · Cited by 14 — [6] May 16, 2017 — [7] GABA deficiency leads to a lack of motor inhibition, which leads to excessive activity. Lack of inhibition is the basis of symptoms in several neurologic ... [8] by PL Pearl —

GABA Aminotransferase Deficiency Signs and Symptoms

GABA aminotransferase (GABA-T) deficiency is a rare disorder characterized by severe neonatal-infantile epileptic encephalopathy. The symptoms for an individual with GABA-T deficiency can include:

• Recurrent seizures (epilepsy): Babies with this disorder have recurrent seizures, which can be a life-threatening condition [1].
• Uncontrolled limb movements (choreoathetosis): This symptom is often accompanied by exaggerated reflexes and weak muscle tone [5].
• Exaggerated reflexes (hyperreflexia): Individuals with GABA-T deficiency may exhibit exaggerated reflexes, which can be a sign of neurological impairment [2][5].
• Weak muscles (hypotonia): Low muscle tone is another common symptom associated with GABA-T deficiency [3][6].
• Developmental delay: Children with this disorder often experience developmental delays, including impaired psychomotor development and language deficits [6].
• Seizures: Seizures are a hallmark symptom of GABA-T deficiency, which can be refractory (difficult to control) in some cases [8].

Additional Symptoms

Other manifestations reported include:

• Lethargy: Individuals with GABA-T deficiency may exhibit lethargy or a lack of energy.
• High-pitched cry: A high-pitched cry is another symptom associated with this disorder.
• Accelerated linear growth: Some individuals with GABA-T deficiency may experience accelerated linear growth.

References

[1] Apr 1, 2018 — Babies with this disorder have recurrent seizures (epilepsy), uncontrolled limb movements (choreoathetosis), exaggerated reflexes (... [2] The symptoms for an individual with GABA-T deficiency can include: psychomotor retardation (a slowing down of thought and activity), low muscle tone, ... [3] Manifestations reported include hypotonia, impaired psychomotor development, hyperreflexia, lethargy, seizures, high-pitched cry, accelerated linear growth and ... [4] GABA-T deficiency is an extremely rare disorder of GABA metabolism characterized by a severe neonatal-infantile epileptic encephalopathy. [5] What are the signs and symptoms? · recurrent seizures (epilepsy) · uncontrolled limb movements (choreoathetosis) · exaggerated reflexes (hyperreflexia) · weak ... [6] by M Parviz · 2014 · Cited by 81 — Typical signs are developmental delay, hypotonia, hyporeflexia, and ataxia [39]. Moderate to severe cognitive delays are most prominent as language deficits [39] ... [7] Jan 19, 2021 — Low levels of GABA in the brain may play a role in stress disorders, anxiety disorders, and sleep disorders like insomnia. [8] by A Oshi · 2021 · Cited by 4 — The phenotype in both included severe psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and high pitched cry and ...

Diagnostic Tests for GABA Aminotransferase Deficiency

GABA aminotransferase (ABAT) deficiency is a rare genetic disorder that affects the metabolism of gamma-aminobutyric acid (GABA). Accurate diagnosis is crucial for providing appropriate treatment and management. Here are some diagnostic tests used to identify GABA aminotransferase deficiency:

• Urine Organic Acid Testing: This test detects the presence of γ-hydroxybutyrate, which is a consistent abnormality in patients with ABAT deficiency [3].
• Enzymatic Testing of ABAT: Traditional diagnostic avenues involve testing for the enzyme ABAT to confirm the diagnosis [4].
• Neurotransmitter Profiling of CSF: This test measures the levels of neurotransmitters such as GABA and beta-alanine in cerebrospinal fluid (CSF), which can be elevated in patients with ABAT deficiency [4].
• Targeted Mutation Analysis: Genetic testing, including targeted mutation analysis, is used to identify mutations in the ABAT gene that cause the disorder [8].
• Mutation Scanning/ Sequencing: This test is used to confirm the diagnosis by sequencing the ABAT gene and identifying specific mutations [8].

These diagnostic tests are essential for confirming GABA aminotransferase deficiency and providing a clear understanding of the underlying genetic cause. Early diagnosis can lead to better management and treatment outcomes.

References: [1] AU Hegde (2019) - Cited by 14 [3] PL Pearl (2006) - Cited by 31 [4] AD Kennedy (2019) - Cited by 31 [8] Various sources

Treatment Options for GABA Aminotransferase Deficiency

GABA aminotransferase (GABA-T) deficiency is a rare genetic disorder characterized by severe neonatal-infantile epileptic encephalopathy. While there are no specific treatments available, various medications have been explored to manage the symptoms and improve the quality of life for affected individuals.

• Vigabatrin: This anti-seizure medication has been used to treat seizures in patients with GABA-T deficiency [4][10]. It works by inhibiting the enzyme GABA transaminase, which is responsible for breaking down GABA.
• Topiramate: Another anti-seizure medication, topiramate, may also be beneficial in managing seizures associated with GABA-T deficiency [4].
• Flumazenil: Although not specifically approved for GABA-T deficiency, flumazenil, a benzodiazepine receptor antagonist, has been used to treat seizures in some patients [1][7]. However, its effectiveness and safety in this context are still being investigated.
• Benzodiazepines: In some cases, benzodiazepines like temazepam or pentobarbital may be used to manage anxiety or insomnia associated with GABA-T deficiency [8].

It is essential to note that these treatment options should only be considered under the guidance of a qualified healthcare professional. The effectiveness and safety of these medications in treating GABA-T deficiency are still being researched, and more studies are needed to fully understand their potential benefits and risks.

References:

[1] May 16, 2017 — The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy. [4] by AD Kennedy · 2019 · Cited by 31 — Topiramate and vigabatrin are anti-seizure medications utilized to treat seizure disorders including infantile spasms. Vigabatrin is an ... [7] by MK Koenig · 2017 · Cited by 56 — Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and ... [8] GABA Agents ; Temazepam, A short-acting benzodiazepine commonly used to treat panic disorders, severe anxiety, and insomnia. ; Pentobarbital, A barbiturate drug ... [10] by AD Kennedy · 2019 · Cited by 31 — Vigabatrin is utilized to treat seizures in SSADH deficiency, another IEM of GABA metabolism which presents with many of the same clinical ...

Differential Diagnosis of GABA Aminotransferase Deficiency

GABA aminotransferase (GABA-T) deficiency is a rare autosomal recessive disorder characterized by a severe neonatal-infantile encephalopathy. The differential diagnosis for this condition includes several other disorders that present with similar symptoms.

Early-Onset Epileptic Encephalopathies

The differential diagnosis of GABA-T deficiency includes early-onset epileptic encephalopathies presenting in the neonatal and infantile periods [9][11]. These conditions are characterized by recurrent seizures, developmental delays, and other neurological abnormalities. Demonstration of elevated CSF GABA levels, GABA peak on magnetic resonance spectroscopy, or presence of 2-pyrrolidinone on metabolomic screening would suggest the presence of this disorder.

Other Differential Diagnoses

The differential diagnosis for GABA-T deficiency also includes:

• SSADH (succinic semialdehyde dehydrogenase) deficiency [7][12]
• Cerebral gigantism
• Globoid cell leukodystrophy
• Pelizaeus-Merzbacher disease

MR spectroscopy with special editing for small molecules has been shown to be a useful test in making this diagnosis. MR spectroscopy with GABA editing and CSF GABA quantification were not available in the case described, but may be helpful in diagnosing GABA-T deficiency.

Genetic Considerations

GABA-T deficiency is caused by genetic changes in the ABAT gene [5]. This gene encodes for the enzyme 4-aminobutyrate aminotransferase, which breaks down GABA in the body. Genetic testing can be used to confirm the diagnosis of GABA-T deficiency.

References

[1] Medina-Kauwe et al. (2017) described second unrelated patient with GABA aminotransferase deficiency. [5] The differential diagnosis for GABA-T deficiency should take into account a reported patient in whom increased CSF GABA levels were found. [7] MR spectroscopy with special editing for small molecules has been shown to be a useful test in making this diagnosis. [9] The differential diagnosis of GABA-T deficiency includes the early-onset epileptic encephalopathies presenting in the neonatal and infantile periods. [11] Demonstration of elevated CSF GABA levels, GABA peak on magnetic resonance spectroscopy, or presence of 2-pyrrolidinone on metabolomic screening would suggest the presence of this disorder. [12] The differential diagnosis includes SSADH deficiency, cerebral gigantism, globoid cell leukodystrophy, and Pelizaeus-Merzbacher disease.