Mitochondrial trifunctional protein (MTP) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are two related inherited disorders of fat metabolism. Patients with these disorders are not able to make enough energy for normal body functions during stress, illness and fasting. When the body has used up its stores of available sugars, it uses 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 beta-oxidation. MTP is a protein complex that performs the last three steps in the breakdown of fats using 3 separate enzyme functions. The second of these is LCHAD activity, (LCHAD is a part of MTP that acts on specifically sized fats, and the most commonly altered of the three). When MTP deficiency occurs, essentially no energy can be made from a fat molecule.
Signs and symptoms
Infants with any of the forms of MTP deficiency will often be sluggish (lethargic), irritable, feed poorly, and have low muscle tone. Patients who have lost all three MTP protein activities have serious symptoms, including heart malfunction/enlargement (cardiomyopathy), muscle breakdown (myopathy), and low blood sugar (hypoglycemia). Other signs include poor nerve function in the legs and hands (peripheral neuropathy) and reddish-brown urine (myoglobinuria). Infants who are deficient only in LCHAD activity (the second of the 3 enzymes), may have liver malfunction (hepatocellular dusease0, along with low blood sugar (hypoglycemia) and a specific type of vision loss called pigmentary retinopathy. The liver disease can become severe or life- threatening, causing blockage of bile flow and scarring
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.
If a fetus is affected with LCHAD deficiency, the mother may experience a life-threatening illness called HELLP syndrome, which includes hemolysis (red blood cell breakage, (elevated liver enzymes, and low number of platelets. See below for details.
Most MTP and LCHAD deficiency cases are diagnosed in the first three to four days of life through newborn screening of blood by tandem mass spectrometry. Identified babies are referred to a specialist who does enzyme activity testing of skin cells or white blood cells, Genetic testing is also done to determine the exact gene changes/mutations that are causing the disease. This is especially useful where there is an identified mutation in the family or where symptoms point to LCHAD with its common genetic change. Treatment is started as soon as the specific diagnosis is confirmed.
All brothers and sisters of the first identified patient in a family should be tested for MTP or LCHAD defects, in case a diagnosis was missed. In addition, the family should be asked whether any of their children have had sudden infant death (SIDs), which can be caused by previously unrecognized MTP or LCHAD deficiency.
For mothers potentially suffering from HELLP syndrome, LCHAD diagnosis of the fetus can be made during pregnancy by enzyme measurement of cells obtained from the amniotic fluid or during chorionic villus sampling (CVS).These can be used to detect an LCHAD gene defect or similar disorders in the fetus. Prenatal diagnosis during a pregnancy is also available if the genetic changes are known in the family.
MTP deficiency occurs when an individual inherits a change/mutation from each parent in one of two genes (HADHa or HADHb). The proteins made by these 2 genes work together to make MTP. The majority of individuals with HADHa mutations have a specific gene mutation that interferes with LCHAD function, the second fat oxidation step. Defects in HADHb usually alter the function of the entire MTP protein and occasionally HADHa mutations may affecte all 3 functions. With each pregnancy, the parents of a child who has either LCHAD deficiency of MTP deficiency have a 25% chance with each future pregnancy to have another child with the same condition (MTP or LCHAD deficiency, depending on what the first child had). Genetic counseling can benefit affected individuals, as well as their families.
Management of MTP and LCHAD deficiencies are focused primarily on preventing and controlling episodes of low blood sugar (hypoglycemia). Steps to prevent illness include avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding. Intervals between feedings should increase from 4 to 8 hours in the first years of life, increasing to 10 hours between feedings 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. Often, the specialty care provider will give the family an emergency letter that can be carried with them in case of emergency. This helps emergency room doctors quickly understand the urgent need for immediate treatment for these patients if ill.
Other treatments may include supplementation with docosahexaenoic acid, a fat that slows but does not stop or improve the retina changes (retinopathy) seen in LCHAD deficiency. A high protein diet and supplementation with MCT oil just prior to exercise may be beneficial.
A clinical trial is currently being done on treatment of MTP and LCHAD with triheptanoin (UX007, Ultragenyx Pharmaceuticals), an artificial fat that is substituted for MCT oil in the diet. Published clinical trial data shows fewer occurrences of low blood sugar and muscle breakdown (rhabdomyolysis) and fewer hospitalizations in patients treated with triheptanoin as compared to those treated with MCT oil. 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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