LCHAD

LCHAD : long-chain 3- hydroxyacyl-coenzyme A dehydrogenase ) deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food ( fasting ). Normally through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to brakdown ( metabolize ) fats and convert them to energy. People with LCHAD have inadequate levels of an enzyme required for a step that metabolizes a group of fats called long-chain fatty acids.
Catalyzes the third step of mitochondrial oxidation of long chain fatty acids, converting long chain 3-hydroxyacyl0-CoA enters into the corresponding 3-ketoacyl-CoA esters. The LCHAD enzyme is part of the mitochondrial trifunctional protein ( MTP), which also narbors long-chain enoy-CoA hydratase and the long chain thiolase activity.
Diagnosis of LCHAD deficiency is suggested by demonstrating increased secretion of 3-hydroxydicarboxylic acids in urine by gas chromatography mass spectrometry, or by demonstrating accumulation of 3-hydroxyacyl carnitines as measured by tandem-mass-spectrometry in plasma. Confirmation of the diagnosis is possible by measuring LCHAD activity in lymphocytes, fibroblasts, muscle or liver biopsies, and by mutational analysis.

MEDICAL CARE

• If the patient present with acute hypoketotic hypoglycemia encephalophaty, the main goal is to secure sufficient energy intake by infusions of iv glucose.
• The management of affected patients is directed at the avoidance of fasting. Most patients also are provided with uncooked cornstarch and medium chain triglycerida ( MCT ) oil supplementation to further decrease exposure to fasting. Consider carnitine supplementation if any hypocarnitinemia is present, however, carnitine should not be used during acute decompensation.

LAB STUDIES

- Blood sugar and urine ketones

The hallmark biochemical feature is acute hypoketotic hypoglycemia. Collect urine ketones in the acute episode.

- Creatinine phosphokinase, ammonia, uric acid, liver enzymes, lactic acid.Durimg acute episodes, elevated levels of creatinine phosphokinase are observed.Hyperammonemia maybe observed in acute episodes. Elevation of liver trans inase also is observed. A high incidence of lactic acidemia accompanies the metabolic decompensation or acute episode.

- Plasma carnitine levels and acylcarnitine profile.Plasma carnitine levels are low

VERY LONG - CHAIN ACYL - COA DEHIDROGENASE DEFICIENCY ( VLCADD )

LCHAD: Long chain 3 -hydroxy acyl-co.euzyme A dehydrogenase deficiency.

Classification : Fatty acid oxidation disorder

Genetic information:

Inheritance : Autosomal recessive

Autosomal recessive : a genetic condition that appears only in individuals who have received two copies of an autosomal gene, one copy from each parent. The gene is on an autosome, a non sex chromosome. The parents are carries who have only one copy of the gene and do not exhibit the trait because the gene is recessive to its normal counterpart gene.If both parents are carrier, there is a 25% chance of the child inheriting both normal genes.

Population incidence : Unknow

Ethnic Incidence : no known population at increased risk.

DISEASE INFORMATION

Symptom onset : Variable depending on the phenotype, ranging from neonatal to adult onset.

Symptoms : Approximately 50 percent present as infants with nonketotic hypoglycemia, hepatic dysfunction andcardiomyopathy, and this has been generally lethal.

Thirty-tree percent present in late infancy or child hood with episodes of nonketotic hypoglycemia and hepatic dysfunction but no cardiac involvement. There is generally a mildly increased ammonia, lactate, and creatinine kinase.

Approximately 20 percent present as adolescents or adults with symptoms limited to muscle fatique, rhabdomyolysis and myoglobinuria triggered bye exercise or fasting. There is no hypoglycemia or cardiac involvement.

PRESENTING SIGNS AND SYMPTOMS OF VLCADD :

• Low blood sugar ( hypoglycemia ),lack of energy ( lethargy ), muscle weakness.
• neurological examination:
• 1.The acute episode of hypoketotic hypoglycemic encephalopathy may begin with a seizure.
• 2.Most patient are hypotonic, at least in infancy
• 3.Examination may reveal profound weakness, decreased movements, and a frog-leg position.
• Cardiac : examination of the heart may reveal cardiomegaly, poor heart sounds and gallop rhythm.
• Abdomen: 1. most patient have hepatomegaly. 2. Jaundice may develop in infancy along with elevation of the transaminase.
• Ophthalmological exam :
• 1. In the youngest patients, fundus may be pale. Thereafter, aggregation og pigment has been detected in the posterior, aggregation of pigment has been detected in the posterior pole and macular region.
• 2.progressive atrophy of the retinal pigment epithelium, choroid, neural retina and retina vessels follow initial pigment abnormalities. This may lead to a completely bare scelera in the central fundus.
• posterior staphylomas and delicate lens opacities also maybe observed.

Physical findings : No particular dysmorphims. Cardiomyopathy in infants.

Treatment : The mainstay of traetmen is a high carbohidrate, low fat diet supplemented with MCT oil and strict avoidance of fasting and prolonged exercised. Aggressive support with calories and fluid is needed for intercurrent illness. Carnitine use is controversial.

Natural history without treatment : Patients with the infantile form of the disease usually die in the first year of life. The late infantile hepatic presentation children will die without treatment. The adult form can progress to renal failure if the myoglubinuria is not addressed.

Natural history with treatment : The infantile form is generally fatal, although there are reports of survivors and complete resolution of cardiomyopathy with early diagnosis and treatment. The later onset patients can survive if treated appropriately. In general the outcome is believed to be good for patents who are identified oresymptomatically.

METABOLIC INFORMATION

Missing enzyme & location : defect in palmitoyl - COA dehydrogenase. Responsible for reducing Acyl - COA's of chain lengths C14 - C20. This is the first and rate - limiting step in the beta- oxidation of fatty acids by the mitochondria for energy metabolism.

MS/MS profile : C14:1 ( tetradecenoyl Carnitine )- elevated

C14 : 1 / C12 :1 ratio - elevated.

Prenatal testing : prenatal testing : prenatal diagnosis is possible in families with a previously affected child.

Miscellasneous information : in the mouse model , there have been arrythmias and death even in older mice.Confirmatory and diagnostic metabolic testing may be normal even in patiens with a known VLCAD mutation.