PEDBASE.org - The Pediatric Database - Detailed information of LCAD DEFICIENCY

LCAD DEFICIENCY

DEFINITION:

A disorder of lipid metabolism characterized by a defect in the oxidation of long-chain fatty acids resulting in recurrent episodes of hypoglycemia, vomiting, and coma when stressed.

EPIDEMIOLOGY:

incidence: rare (about 14 cases reported)
age of onset:
- newborn -> childhood (18 months)
risk factors:
- familial - autosomal recessive
  - chrom.#: 2q34-35
  - gene: long-chain acyl-CoA dehydrogenase (LCAD)

PATHOGENESIS:

1. Background

LCAD is one of four ezymes in the mitochondria responsible for the breakdown of long-chain (C12-C18) fatty acids to 2-carbon fragments (acetyl-CoA) in the beta oxidation pathway
there are 3 straight-chain acyl-CoA dehydrogenases to deal with long, medium, and short chain fatty acids
LCAD, MCAD, and SCAD are all homotetramers
Hale et al., Peds. Res. 19:666 (1985) were the first to describe LCAD Deficiency in 3 infants

2. Genetic Background

genetic defect -> deficiency of LCAD activity -> homozygous patients are unable to mobilize large fat stores and are thus at risk for becoming hypoglycemic when stressed (i.e., during infection or fasting) during which time the medium and short acyl-CoA dehydrogenases are unable to compensate for the lack of LCAD
LCAD Deficiency tends to be more severe with an earlier age of onset than MCAD Deficiency and have skeletal and cardiac muscle involvement
may present as recurrent episodes of hypoglycemic coma with long-chain dicarboxylicaciduria, impaired ketogenesis (hypoketotic), and low plasma & tissue carnitine levels
characterized by an intolerance to prolonged fasting
the accumulation of long-chain acyl-CoA intermediates within the mitochondria during acute episodes is toxic to other metabolic pathways (glycogenolysis, gluconeogenesis, ureagenesis) in the mitochrondria and thus impairs energy production during periods of stress

CLINICAL FEATURES:

1. Episodic Manifestations

the first episode occurs by 18 months of age after a 12-16 hour period of stress

1. Neurological Manifestations

lethargy -> coma
seizures

2. Gastrointestinal Manifestations

persistent vomiting (+/- dehydration)
hepatomegaly

2. Other Manifestations

1. Hypertrophic Cardiomyopathy

+/- congestive heart failure/arrest

2. Skeletal Muscle Weakness

hypotonia +/- persistent muscle weakness
gross motor developmental delay
poor exercise tolerance

INVESTIGATIONS:

1. Serum

wide anion gap metabolic acidosis (anion = dicarboxylic acid)
hypoketotic hypoglycemia
secondary hyperammonemia
elevated urea, uric acid, transaminases, CPK
prolonged PT, PTT
secondary carnitine deficiency

2. Urine

1. Organic Acids

low ketones
elevated long- and medium-chain dicarboxylic acids

3. Diagnosis

deficiency of LCAD activity in leukocytes and cultured skin fibroblasts
prenatal
- deficiency of LCAD activity in cultured chorionic villi or amniocytes

4. Pathology

1. Liver

fatty infiltration; portal and perilobular fibrosis

5. Imaging Studies

1. Chest X-Ray

cardiomegaly

MANAGEMENT:

1. Supportive

a chronic disease with a life-long risk of episodes of hypoketotic hypoglycemia and thus must:
- provide long-term follow-up
- moniter serum glucose (for hypoglycemia)
- coordinate a multidisciplinary approach:
  - Paediatrics, Neurology, Cardiology, Dietary, Genetics,
  - Metabolics
- plan for acute episodes
- provide a medic alert bracelet

2. Goals of Therapy

symptomatic control of and avoidance of acute episodes (stress)
not curative

3. Diet

1. Acute Episodes

glucose monitering with carbohydrate and high caloric supplements during acute illness
MTC oil and frequent feeding may also be used
IV D10W (to suppress lipolysis) if hospitalized

2. Chronic Management

ensure patients never fast for more than 10-12 hours
dietary fat restriction (low fat)

4. Carnitine Therapy

100 mg/kg/day po
due to secondary carnitine deficiency

Pediatric Database - LCAD DEFICIENCY

Pediatric Organization - Pedbase [at] Gmail.com