LCHAD Deficiency

Introduction

Mitochondrial trifunctional protein (MTP) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are two related inherited disorders of fat metabolism that prevent the body from generating sufficient energy during stress, illness and fasting. When the body has exhausted its stores of available sugars, it must turn to fats to make energy. In each cell in the body, this breakdown of fats takes place in the mitochondria, the “powerhouses of the cell,” in a four-step process known as b-oxidation.  MTP is a protein complex that performs the last three steps in the oxidation of fats, including LCHAD activity, the second of those steps. When this deficiency occurs, essentially no energy can be obtained from a fat molecule.

Signs and symptoms

Typically, infants with any form of MTP problem will be lethargic, irritable, feed poorly, and have poor muscle tone.  Young children who have lost of all three protein activities also have serious symptoms, including of heart malfunction (cardiomyopathy), muscle breakdown (myopathy), and low blood sugar (hypoglycemia). Other signs include poor nerve function in the legs and hands and reddish-brown urine. Infants who are deficient only in LCHAD activity, may have a life-threatening liver malfunction, along with low blood sugar and a specific type of vision loss  called pigmentary retinopathy.

Some milder cases of MTP deficiency do not appear until adolescence. The main symptoms include repeated episodes of severe skeletal muscle pain from muscle breakdown (rhabdomyolysis), especially after vigorous exercise and reddish-brown urine.

Diagnosis

Most MCAD deficiency cases are diagnosed in the first three to four days of life through newborn screening of blood by tandem mass spectrometry. For final diagnosis, usually skin cells (fibroblasts) or white blood cells from blood are tested for functional enzyme activity. Genetic testing may also be done to determine the exact mutation.  As soon as the abnormal result is validated, these infants are referred to a physician for immediate intervention.

Prenatal diagnosis can be done during pregnancy if the mother experiences a life-threatening syndrome called HELLP syndrome (this includes red blood cell breakdown, abnormal liver function and decreased blood clotting). Cells obtained from the amniotic fluid or during chorionic villus sampling (CVS) can be used to detect an LCHAD gene defect or similar disorders in the fetus.

Genetics

MTP deficiency occurs when an individual inherits a mutation in one of the two genes (HADHa or HADHb) whose products associate to make MTP.  The majority of individuals with HADHa defects have a specific gene mutation that interferes with LCHAD, the second fat oxidation step. Defects in HADHb usually interferes with the stability of the entire MTP protein. With each pregnancy, the parents have a 25% risk chance to have another child with the same MTP or LCHAD deficiency. Genetic counseling can benefit affected individuals, as well as their families.

Treatment

Management of MTP and LCHAD deficiency is focused primarily on preventing and controlling acute episodes of low blood sugar. Preventive measures include avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding.  Intervals between feeding should be between 4 to 8 hours in the first two years, increasing to 10 hours after age two. Your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil) or carnitine (Carnitor) supplements. (293-295).

Medical treatment should be sought immediately if your child loses consciousness or is severely confused. If hospitalized for an acute episode, you child should receive high-volume intravenous glucose (10% dextrose) containing appropriate bodily salts and additional supportive measures as required. An emergency regimen should be available for children when they cannot tolerate their prescribed diet.

Other treatments include supplementation with docosahexaenoic acid, which slows but does not stop or improve the retinopathy seen in LCHAD deficiency. A high protein diet and supplementation with MCT oil just prior to exercise may be beneficial.

 Investigational Therapies

A clinical trial is currently being conducted on treatment of MTP and LCHAD with triheptanoin (UX007, Ultragenyx Pharmaceuticals), an artificial fat that is substituted for MCT oil in the diet. Published phase 2 studies indicate fewer episodes of low blood sugar and muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

Information on current clinical trials is posted at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

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