PEDBASE.org - The Pediatric Database - Detailed information of GLUTARIC ACIDEMIA I

GLUTARIC ACIDEMIA I

DEFINITION:

A disorder of amino acid metabolism characterized by the build-up of glutaric acid resulting in progressive neurological manifestations and acute metabolic manifestations.

EPIDEMIOLOGY:

incidence: over 300 cases reported worldwide
age of onset:
- first two years of life
risk factors:
- familial - autosomal recessive
  - chrom.#: ?19p
  - gene: glutaryl-CoA dehydrogenase
- M = F
- Sweden, Pennsylvania Amish,

PATHOGENESIS:

1. Background

glutaryl-CoA dehydrogenase is a mitochondrial FAD-dependent enzyme found in the liver and kidney
glutaryl CoA is an intermediate in the catabolism of the amino acids lysine, hydroxylysine, and tryptophan and is converted to glutaconyl CoA by glutaryl-CoA dehydrogenase
a deficiency of glutaryl-CoA dehydrogenase results in a build-up of glutaric acid
also called Glutaric Aciduria Type 1

2. Genetic Defect

genetic defect -> defective expression of glutaryl-CoA dehydrogenase -> build-up of glutaric acid in body fluids (blood, urine, CSF) -> neurologic and metabolic manifestations
45 different mutations have been identified in the glutaryl-CoA dehydrogenase gene

CLINICAL FEATURES:

1. Classical Form

patients may present normally for the first 2 years of life and then present with progressive neurologic manifestations and acute metabolic manifestations
acute episodes my be triggered by stress such as infections or surgery

1. Neurological Manifestations

movement abnormalities
- progressive dystonia and dyskinesia (choreoathetosis)
- hyptonia progressing to rigidity, spasticity, and/or opisthotonis
acute episodes of:
- seizures
- lethargy -> coma

2. Metabolic Manifestations

acute episodes of:
- vomiting +/- dehydration
- metabolic acidosis

INVESTIGATIONS:

1. Diagnostic

deficiency of glutaryl-CoA dehydrogenase activity in leukocytes or cultured skin fibroblasts
perinatal
- deficiency of glutaryl-CoA dehydrogenase activity in cultured chorionic villi or amniocytes
- may be elevated glutaric acid levels in the amniotic fluid

2. Serum

serum organic acids
- elevated glutaric acid (may be massive after lysine loading)
others (during an acute episode)
- hypoglycemia
- hyperammonemia
- elevated serum transaminases
- metabolic acidosis
- serum amino acids are usually normal

3. Urine

urine organic acids
- elevated glutaric acid (may be in excess of 1 gm/day)
- elevated 3-hydroxyglutaric acid

4. Imaging Studies

1. CT (Head)

? atrophy of the putamen and caudate

MANAGEMENT:

1. Diagnosis

1. Clinical - History, Physical

2. Laboratory - enzyme deficiency on assay

2. Goals of Therapy

avoidance of and symptomatic control of acute episodes
not curative

3. Management Strategies

1. Acute Episodes

correct dehydration, electrolyte disturbances, and metabolic acidosis
removal of blood ammonia if significantly elevated

2. Chronic Management

1. Counselling

a chronic long-term disorder where the patient may decompensate when stressed and is at risk for sudden death
plan for acute episodes
- aggressively treat infections
- guidelines on when to contact the physician

2. Diet

dietary consultation
diet restricted in protein to reduce intake of lysine and tryptophan
riboflavin supplements (200-300 mg/day)
carnitine supplements (50-100 mg/kg/day)

4. Prognosis

early diagnosis (newborn screening) and correct treatment may prevent the progressive neurological manifestations of the disorder
many become progressively disabled by the movement disorder if correct therapy is not initiated early
intelligence ranges from normal to impaired in untreated patients
death may occur during an acute episode

ADDITIONAL REFERENCES:

1. Rudolph A.M.; Rudolph's Pediatrics. 19th Edition; p. 357-358; 1991).

Pediatric Database - GLUTARIC ACIDEMIA 1

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