GABA-transaminase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

GABA-transaminase deficiency is a brain disease (encephalopathy) that begins in infancy. Babies with this disorder have recurrent seizures (epilepsy), uncontrolled limb movements (choreoathetosis), exaggerated reflexes (hyperreflexia), weak muscle tone (hypotonia), and excessive sleepiness (hypersomnolence). Affected babies may grow faster in length than usual (accelerated linear growth), even though they have feeding problems and may not gain weight as quickly as expected (faltering weight).

Children with GABA-transaminase deficiency have profoundly impaired development. Most do not achieve normal developmental milestones of infancy such as following others' movement with their eyes or sitting unassisted. Individuals with this disorder usually do not survive past the first 2 years of life, but some live longer into childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

GABA-transaminase deficiency is caused by mutations in the ABAT gene, which provides instructions for making the GABA-transaminase enzyme. This enzyme helps break down a brain chemical (neurotransmitter) called GABA when it is not needed. GABA normally helps slow down (inhibit) brain cell activity when necessary, to prevent the brain from being overloaded with too many signals. For this reason, GABA is called an inhibitory neurotransmitter.

Mutations in the ABAT gene lead to a shortage (deficiency) of functional GABA-transaminase enzyme. As a result, GABA is not properly broken down, so this neurotransmitter and another molecule called beta-alanine accumulate abnormally in brain cells. This accumulation alters the balance between the brain's neurotransmitters, leading to the neurological problems characteristic of GABA-transaminase deficiency. Excess GABA also leads to abnormal release of a protein that is necessary for growth of the body's bones and tissues (growth hormone), resulting in the accelerated linear growth that sometimes occurs in this disorder.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

GABA-transaminase deficiency is a very rare disorder. Only a small number of affected individuals have been described in the medical literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Cerebral dysmyelination · Very frequent (99-80%)

Defective structure and function of myelin sheaths of the white matter of the brain.

EEG abnormality · Very frequent (99-80%)

Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.

Elevated circulating gamma-aminobutyric acid concentration · Very frequent (99-80%)

The concentration of gamma-aminobutyric acid in the blood circulation is above the upper limit of normal.

Epileptic encephalopathy · Obligate (100%)

A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.

Hypotonia · Very frequent (99-80%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Increased level of gamma-aminobutyric acid in urine · Very frequent (99-80%)

Elevated concentration of gamma-aminobutyric acid in the urine.

Severe global developmental delay · Very frequent (99-80%)

A severe delay in the achievement of motor or mental milestones in the domains of development of a child.

Elevated CSF gamma-aminobutyric acid concentration · Very frequent (99-80%)

Cerebral atrophy · Frequent (79-30%)

Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.

Choreoathetosis · Frequent (79-30%)

Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).

Elevated circulating growth hormone concentration · Frequent (79-30%)

Acromegaly is a condition resulting from overproduction of growth hormone by the pituitary gland in persons with closed epiphyses, and consists chiefly in the enlargement of the distal parts of the body. The circumference of the skull increases, the nose becomes broad, the tongue becomes enlarged, the facial features become coarsened, the mandible grows excessively, and the teeth become separated. The fingers and toes grow chiefly in thickness.

Failure to thrive · Frequent (79-30%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Feeding difficulties in infancy · Frequent (79-30%)

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

High-pitched cry · Frequent (79-30%)

A type of crying in an abnormally high-pitched voice.

Other findings in the same source

From: Orphanet

Additional reported features include Hyperreflexia (Frequent (79-30%)); Seizure (Frequent (79-30%)); Tall stature (Frequent (79-30%)); Hypersomnia (Frequent (79-30%)); Progressive psychomotor deterioration (Frequent (79-30%)); Abnormal corpus callosum morphology (Occasional (29-5%)); Cerebellar atrophy (Occasional (29-5%)); Lethargy (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing GABA-transaminase deficiency is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for GABA-transaminase deficiency. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.