Disorders of γ-amino butyric acid (GABA) metabolism

The inherited disorders of γ-amino butyric acid (GABA) metabolism

Overview:
- Two primary disorders affect GABA catabolism:
  - GABA transaminase deficiency
  - Succinic semialdehyde dehydrogenase (SSADH) deficiency (also known as 4-hydroxybutyric aciduria)

Extremely rare; only two families reported
Clinical features:
- Axial hypotonia
- Spasticity
- Severe convulsions
- Feeding difficulties requiring tube feeding
- Accelerated growth and increased growth hormone (reported in one family)
MRI findings: Diffusion restriction in internal and external capsule and subcortical white matter
Biochemical findings:
- Elevated free GABA in cerebrospinal fluid (CSF)
- Elevated homocarnosine and β-alanine
Diagnostic tools:
- Elevated GABA detectable via magnetic resonance spectroscopy (MRS)
- Enzyme deficiency confirmed in liver and lymphocytes
- Mutations identified in ABAT gene

Also known as 4-hydroxybutyric aciduria
Caused by accumulation of succinic semialdehyde, which is converted into 4-hydroxybutyric acid and excreted in urine
Presentation:
- Usually presents in the first 2 years of life
- 26% present neonatally; 26% have normal early development
Neurological features (static course):
- Developmental delay
- Intellectual disability
- Expressive language deficits
- Motor delay
- Hypotonia
- Nonprogressive ataxia
Neuropsychiatric features:
- Hyperactivity
- Inattention
- Anxiety
Sleep disturbances:
- Excessive daytime sleepiness
- Prolonged REM latency
- Reduced REM sleep
Seizures:
- Present in 48% of patients
- Mostly generalized tonic-clonic and atypical absence seizures
- Myoclonic seizures in a minority
- EEG abnormalities in 26% of cases
Degenerative features (in ~10% of patients):
- Myoclonus
- Chorea
- Dystonia
Neuroimaging findings:
- Increased T2 signal in:
  - Globus pallidus
  - Cerebellar dentate nucleus
  - Brainstem
  - Subcortical white matter
- Cerebellar and cerebral atrophy may be present
MRS findings:
- Usually normal unless specialized sequences are used
- Special MRS shows elevated GABA and GABA metabolites

Lecture Notes