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104

Functional Assessment of Urinary Neuro-biogenic Amines—A COMPREHENSIVE GUIDE

thymic (neither manic nor depressed)

bipolar patients, and that the low plas-

ma levels persist even after treatment

or recovery. Other studies indicate that

plasma GABA levels were not correlat-

ed with severity of depression in the

study subjects; however additional re-

search indicates that association of low

GABA levels and mood disorder may be

familial. Low plasma GABA levels have

been associated with mood disorders in

children and adolescents. Low plasma

GABA levels have also been associated

with premenstrual dysphoric disorder.

GABA deficiency has not been directly

associated with epilepsy, but disorders of

GABA receptors have been.

Excess

urinary GABA may occur

due to nutritional deficiency or bacterial

overgrowth. GABA, and other amino ac-

ids that require B-6 dependent transam-

ination (leucine, isoleucine, valine) may

be elevated due to vitamin B-6 deficien-

cy. GABA may be artifactually elevated

during bacterial urinary tract infections

or, occasionally, due to gastrointestinal

infections (dysbiosis). GABA may be

produced or metabolized by gastroin-

testinal bacteria, including

Lactobacilli

and

Bifdobacteria

. The monoamine

oxidase inhibitor phenelzine may in-

crease GABA levels (animal study).

Hyperforin, one of the active ingredients

in Hypericum (St John’s wort) extract

may elevate GABA levels (animal stud-

ies). Magnetic resonance imaging studies

have measured elevated GABA levels in

the brain cortex of primary insomniacs.

The known genetic disorders of

GABA metabolism are succinic semial-

dehyde dehydrogenase (SSADH) defi-

ciency, GABA-transaminase deficiency,

and homocarnosinosis. All present ear-

ly in life with a variety of neurological

symptoms. GABA-transaminase defi-

ciency, and homocarnosinosis are ex-

tremely rare and require specialized

testing for diagnosis. The mutation caus-

ing SSADH deficiency is also rare, but

many single nucleotide polymorphisms

(SNPs) for this enzyme have been dis-

covered; research continues to deter-

mine what, if any, functional effects the

SNPs may have; SSADH may be inhib-

ited by oxidative stress. True SSADH

deficiency presents with elevated urine

gamma-hydroxybutyric acid (GHB) and

a constellation of neuropsychiatric signs,

including developmental delay, mental

retardation, language deficit, hypoto-

nia, cerebellar ataxia, hyporeflexia, sleep

disturbances, aggression, obsessive–

compulsive disorder, inattention and

hyperactivity. Epilepsy affects approxi-

mately half of these patients and is usu-

ally generalized. Taurine is considered a

GABA-A receptor agonist and has been

used (up to 3 grams daily) with success

in some patients with SSADH deficien-

cy, although the mechanism of action re-

mains unclear.

Synthesis and Metabolism:

Succinatesemi-aldehyde

Glutamine

Glutamate

{

AAT TCAcycle AAT

}

(mitochondria)

{

cellcytoplasm

}

GABA

GAD

PAG

GABA-T

GABA is synthesized from glutamate

by L-glutamate decarboxylase (GAD).

GAD is expressed in GABA-ergic neu-

rons in the CNS and requires a pyridox-

al-5’-phosphate (B6) cofactor. GAD has

two isoforms in the adult and two ad-