Fatty Acid Oxidation Disorders

ACAD9

Acyl-CoA dehydrogenase 9 (ACAD9) is a member of the fatty acid acyl-CoA dehydrogenase (ACAD) protein family that for years had no clearly identified function. Like other members of the ACAD family, it resides within cells in the energy generating part called mitochondria and contributes to breaking down fats. It is found at high concentrations in certain organs like the liver and heart and in specific cell types in the lung and kidney. ACAD9 has a second important role in the assembly or stabilization of Complex 1 in the mitochondrial respiratory chain. The mitochondrial respiratory chain frees energy to do the body’s work, including that from the fat breakdown pathways(248, 249). The best guess at present is that ACAD9 is a dual function protein involved in essential functions for life.

Signs and symptoms

ACAD9 patients classically present with poor heart function due to an enlarged heart (hypertrophic cardiomyopathy), as early as the newborn period, but they can have a wide spectrum of presentations. Other common features include liver disease, large head (macrocephaly), and a progressive neurologic syndrome called Leigh’s (Robinson et al. 1998). Leigh’s syndrome is caused by the reduction of Complex 1 activity, making patients unable to generate sufficient energy to keep their cells healthy. The signs include poor suck; loss of head control and motor skills; loss of appetitevomiting; and seizures. As the condition progresses, symptoms may include weakness and lack of muscle tone; extreme muscle tightness (spasticity); movement disorders; specific inability to coordinate joints and even eyes (cerebellar ataxia); and loss of nerve function in feet and legs and even fingers (peripheral neuropathy). Because these patients always function with inadequate energy, even a mild illness can precipitate Leigh’s syndrome.

If the protein defect is located in the portion that is involved in fat breakdown, the patients tend to have more severe symptoms (250). Vitamin B2 (riboflavin) responsive mutations have been reported (250). One 36-year-old patient has been reported with a mild ACAD9 presentation. She had a lifetime history of exercise intolerance with lactic acidosis (clinical test) resulting in nausea and vomiting.

Diagnosis

Just as ACAD9 is a disorder with a varied presentation, there are no consistent specific biochemical markers in blood or urine of patients with ACAD9 deficiency. In some cases, especially those with a fatty acid oxidation defect-like presentation, the liver profile of the fat product acylcarnitine may be abnormal with an excess of unsaturated compared to saturated species (247). If the clinical presentation is more like that of a complex 1 defect, then the diagnosis becomes very difficult since there are over 100 genes that if defective can cause complex 1 dysfunction.  Complex 1 activity may be low or occasionally normal(ref). Unlike most of the fatty acid oxidation disorders, ACAD9 deficiency is not identified by newborn screening, and there is no test for protein activity, as with many other ACAD defects. Most recent patients have been identified through whole exome sequencing, a method to look for mistakes at the gene expression level.

Genetics:

ACAD9 deficiency occurs when an individual inherits one change (mutation) in the gene for ACAD9 from each parent (autosomal recessive). Because ACAD9 is difficult to diagnose, there is no information as to its incidence. Parents of patients are carriers of the disease and have no symptoms. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with ACAD9 deficiency. Many different mutations in ACAD9 have been reported (249), but there is no common mutation to date. There have been no reported cases of prenatal diagnosis.

Treatment

Treatment of ACAD9 deficiency should focus on the defect in complex 1 (258, 259). If low blood sugar (hypoglycemia) is present, it should be corrected, but care must be taken not to induce a secondary lactic acidosis due to excess pyruvate production. VitaminB2 (riboflavin) at 100 mg/kg/day should be provided due to reports of its stabilization of some mutant ACAD9 variants (250, 258, 259). Cardiomyopathy should be treated aggressively medically (259).

CACT Deficiency

Carnitine acylcarnitine translocase deficiency (CACT) is a rare inherited disorder that occurs when the protein that transfers fats into sac-like bodies called mitochondria is defective. Mitochondria are the site within cells where energy from fat is generated very efficiently. When the body has exhausted its stores of available sugars, it must turn to fats to produce energy. This change in energy source is particularly important during stress, illness and fasting and intense exercise. The entry of fats into mitochondria is highly regulated at the point where they cross the inner membrane of the mitochondria. In order to cross, free fats, known as fatty acids, are first linked to a molecule called carnitine. This fatty acylcarnitine next crosses the inner mitochondrial membrane to the inside of the mitochondria via a carnitine translocase protein (CACT). In the third step, using a protein called carnitine palmitoyltransferase 2 (CPT2), the carnitine molecule is detached and a replaced with coenzyme A. Then, the fatty acid can be broken down to generate energy.

Although few cases of CACT deficiency have been identified, at this point its presentation and diagnosis have paralleled that of the more abundant CPT2 defect. Similarly, its management parallels that of CPT2.

Signs and symptoms

CACT is a very rare disorder and the majority of those diagnosed have had the severe presentation with little or no active protein. It is possible that milder forms of the disease will be identified in the future. When stressed, infants with limited CACT may look listless (lethargy) and be irritable and be difficult to wake. They may have episodes of life threatening low blood sugar (hypoglycemia) which may lead to a coma or seizures within days or weeks after birth. Blood ammonia may also be high, and the liver may be noticeably enlarged (hepatomegaly), especially when they are sick. From ages two or three months to about two years, affected infants are at risk for many serious heart associated problems including a weakened heart muscle (cardiomyopathy), abnormal heart rhythms, and even total failure of the combined lung and heart function.,

Patients with severe CACT and similar diseases that interfere with the breakdown of fats have repeated episodes where they have a distinct form of low blood sugar called hypoketotic hypoglycemia. When healthy people fast or burn excessive calories in exercise, they burn fat to maximize calorie efficiency and to save glucose. At the end of this fat oxidation, some of its products are turned into protective molecules called ketones that provide energy for the brain. Since CACT patients have a limited ability to break down any fats, they lack the basic ingredients to make these ketones (thus are hypoketotic). This lack of ketones adds to the risk of damage to their brains from hypoglycemia.

Diagnosis

Next, clinical studies of blood and urine by tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis), respectively, will differentiate the patients with defective CACT or CPT2 from other fatty acid defects with similar signs and symptoms. Specifically, CACT and CPT2 deficiency have a characteristic blood pattern that includes increases in long chain fatty acids (16-18-carbon) that are complexed to carnitine (acylcarnitines) and low free carnitine levels. Organic acids are usually normal. Because both CACT and CPT2 have the same laboratory and symptom profile, the CACT defects can only be validated by showing reduced CACT activity in blood or skin cells or by positive genetic testing for CACT mutations. Fortunately, the treatments for CACT and CPT2 defects are identical, so that as soon as the newborn screening results are verified, treatment can begin, hopefully minimizing damage from the defect.

Genetics

CACT deficiency occurs when an individual inherits one change (mutation) in the gene for CACT (SLC25A20) from each parent (autosomal recessive). Although CACT deficiency is very rare, there is a specific mutation in Asian populations (). Parents of patients are carriers of the disease and have no symptoms. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with CACT deficiency. Genetic counseling will also be of benefit for affected individuals, as well as their families. Subsequent siblings of the index case should be tested for CACT defects, in addition, the family should be asked whether there have been episodes of sudden infant death (SID), which can be caused by previously unrecognized CACT.

Treatments

Because the treatment for both CACT and CPT2 is the same, treatment can begin as soon as the characteristic abnormality in acylcarnitines and carnitine are identified. Prevention of fasting is the mainstay of chronic therapy in CACT deficiency. Fasting in the first year of life can increase from 4 to 8 hours and should be limited to less than 10 hours after the age of 2 years. In the severe form, continuous feeding of carbohydrates directly into the stomach (intragastric) may be required to prevent low blood sugar. For most patients, time between feedings can increase as the child grows older. Additionally, your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil). Carnitine (Carnitor) supplementation does not usually improve severe disease but will be considered when free carnitine is extremely low, and the patient has some CACT protein activity.

Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation), as these are signs of dangerously low blood sugar. Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglycemia has occurred. At the medical facility, the hypoketotic hypoglycemia of CACT will be treated with intravenous glucose-containing fluids, usually at a rate of at least 8-10 mg/kg/min of glucose. The elevated blood ammonia usually reverses with correction of the low blood sugar. If it is not corrected, dialysis can be added to reduce the ammonia level.

Investigational Therapies

A Phase 3 clinical trial is currently being conducted on treatment of CACT 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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has coincidentally been shown to increase the amount of CACT protein in cells (Van.. Brain Dev 2014). However, Reneo Pharmaceuticals has developed a similar but more powerful potential drug that will soon be evaluated in clinical trials for CACT in the US.

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

References

Click here for a list of references in the scientific literature

Click here to ask an FAOD expert a question about VLCADD. Please note that specific questions about your individual child’s medical problems cannot be answered.

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CPT1a Deficiency

The breakdown of fats to provide energy occurs in segregated membrane-bound compartments of the cell known as mitochondria. Carnitine palmitoyltransferase 1a (CPT1a) is a protein that is the first in a three-protein unit that transfers fats across the inside mitochondrial membrane. It functions as a sentry at the outside entrance to mitochondria in certain tissues, especially the liver, where it regulates the amount of fat can enter the mitochondria to produce needed energy. Inside the cell, when fats are transported, they are attached to a molecule called coenzyme A. Fats can only cross the inner mitochondrial membrane if that coenzyme A group on the fatty acid is exchanged for a carnitine. If CPT1a is lost or reduced or if it functions poorly, the fatty acid stays in its coenzyme A form and cannot be picked up by the associated transport protein to cross the inner mitochondrial membrane. Shorter chain fatty acids containing 10 or fewer carbons can enter mitochondria without interacting with CPT1a. Unfortunately, these fatty acids are rare and provide much less energy than a typical long chain fatty acid. Most cases of CPT1a deficiency in the United States are identified during newborn screening of bloodspots taken in the first couple of days of life.

Signs and symptoms

The severe forms of CPT1a deficiency usually show up early in infancy and are episodic, usually appearing when an infant is stressed by fasting or illness. The most common symptom is low blood sugar (hypoglycemia) with low levels of fat-based energy preservation products known as ketones (hypoketotic) and may progress to coma and seizures. The build-up of unused fats in tissues can cause poor liver function and enlargement (hepatomegaly) and eventually failure of other organs. During acute episodes, infants may have high blood ammonia levels (hyperammonemia) and elevated creatine phosphokinase (CPK).

Many children with milder CPT1a defects have been identified by newborn screening as noted above. Some with mild defects may never become symptomatic. CPT1a deficiency differs in presentation from all other fat oxidation defects in that patients have no skeletal muscle involvement because a different protein performs this function in skeletal muscles.

Diagnosis

To make the clinical diagnosis, blood is analyzed by tandem mass spectrometry (acylcarnitine analysis) and urine by gas-chromatography mass spectrometry to differentiate CPT1a from other fatty acid defects with similar symptoms. Because these children cannot bind the fatty acid to carnitine, they will have normal to high levels of free carnitine with low levels of most fatty acid-carnitine complexes, when compared to normal children of the same age. Their urine organic acids will not show anything abnormal except for the absence of ketones. CPT1a defects are more difficult to diagnose by tandem mass spectrometry than some other fat oxidation disorders. For this reason, CPT1a activity assays in cells (fibroblasts, leukocytes from blood) or tissues are essential here. Some of those inheriting the milder variants may not express abnormal blood and urine profiles right after birth, but they will become abnormal when they are ill.

CPT1a is one of the fatty acid oxidation defects where the stress from carrying a CPT1a defective fetus in a mother with one mutation can cause her to have a life-threatening syndrome called HELLP (red blood cell breakdown (hemolysis), elevated liver enzymes, and low numbers of blood coagulation cells (platelets)). Fortunately, diagnosis can be made during pregnancy by CPT1a enzyme measurement of either cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus). If the mutations in a previously affected family member is known, direct mutation testing of prenatal samples is possible and more specific.

Genetics

CPT1a deficiency occurs when an individual inherits one change (mutation) in the gene for CPT1a from each parent (autosomal recessive). If parents have a child with CPT1a deficiency, in each succeeding pregnancy, they have a 25% or 1 in 4 chances of having another child with changes in both parental genes. The severe form of the CPT1a deficiency is very rare. However, a mild CPT1a defect is found frequently in the Inupiaq and Yu’pik and the Inuit nations in Alaska and Canada, respectively, and in Hutterite populations. In both cases, the altered CPT1a protein activity is usually identified through newborn screening. In the Inupiaq and Yu’pik nation in Alaska, around 50% of the population has two copies of the CPT1A gene with the so called “arctic variant”. Consequently, about 50% of the children born within this community will also have the arctic variant. Incidentally, this arctic variant would only be this abundant if it gives a survival advantage to the population in this extreme climate. For this reason, it is considered a variant rather than a defect. Even so, infants inheriting the variant can develop dangerously low blood sugar during illnesses as described above.

Treatment

As with most fatty acid oxidation defects, fasting should be avoided. As the child gets older, they will become more stable and can go longer between feedings, up to 6-8 hours from the initial 2-3 hours. Since prevention of fasting is the mainstay of therapy, in severe disease, continuous feeding by a stomach tube may be necessary, especially at night. Medium chain triglycerides (MCT oils), artificial fats, can also be fed as a supplement because they do not depend on CPT1a to enter the inner mitochondrial space.

Mildly ill children with low CPT1a should be given liquids that contain glucose or sugars frequently. Parents should call their health care provider immediately whenever these infants become excessively sleepy, are vomiting, have diarrhea, a fever, poor appetite, or an infection. These acute episodes of hypoketotic hypoglycemia can be rapidly reversed by giving intravenous glucose-containing fluids that provide at least 8-10 mg/kg/min of glucose along with normal body salts. The accompanying high blood ammonia (hyperammonemia) usually reverses with correction of the hypoglycemia. If it does not correct, dialysis may be required. These crises usually decrease in frequency with age and are rare after age 3 years.

Investigational

A Phase 3 clinical trial is currently being conducted on treatment of CPT1a 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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin.

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

Click here to ask an FAOD expert a question about VLCADD. Please note that specific questions about your individual child’s medical problems cannot be answered.

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CPT2 Deficiency

Carnitine palmitoyl transferase 2 deficiency (CPT2) is a rare inherited disorder that occurs when the last step in the entry of fats into sac-like bodies called mitochondria is blocked. Mitochondria are the site within cells where energy from fat is generated very efficiently. When the body has exhausted its stores of available sugars, it must turn to fats to produce energy. This change in energy source is particularly important during stress, illness and fasting and intense exercise. The entry of fats into mitochondria is highly regulated at the point where they cross the inner membrane of the mitochondria. In order to cross, free fats, known as fatty acids, must be linked to a molecule called carnitine. This fatty acylcarnitine next crosses the inner mitochondrial membrane via a carnitine translocase protein. In the last step of this transit, CPT2 returns this fatty acylcarnitine to its original fatty acyl-coenzyme A form that can enter the pathways to generate energy (fatty acid oxidation).

Signs and symptoms

Mild CPT2 deficiency is the most common fatty acid oxidation defect. Patients usually present in adolescence or early adulthood with brownish red urine (myoglobinuria) and muscle weakness or pain after prolonged exercise or other physical stress. During acute episodes, they will have elevated blood levels of creatine kinase (CPK), a marker for muscle injury (rhabdomyolysis) but they rarely will have low blood sugar (hypoglycemia).

More rarely, CPT2 defects occur in a severe newborn form. Overall, infants may look tired and listless (lethargy), be irritable, and not eat well. Affected children have life threatening low blood sugar (hypoglycemia) which may result in a coma or seizures within days or weeks after birth. Blood ammonia may also be high, and their liver may be noticeably enlarged (hepatomegaly), especially when they are sick.

From ages two or three months to about two years, affected infants are at risk for many serious heart problems including a weakened heart muscle (cardiomyopathy), abnormal heart rhythms, and even total failure of the combined lung and heart function.

Patients with severe CPT2 and similar diseases that interfere with the breakdown of fats have episodes where they have a distinct form of low blood sugar called hypoketotic hypoglycemia. When healthy people fast or burn excessive calories in exercise, they burn fat to maximize calorie efficiency and to save glucose. At the end of this fat oxidation, some of its products are turned into protective molecules called ketones that provide energy for the brain. Since CPT2 patients have a limited ability to break down any fats, they lack the basic ingredients to make these ketones (thus are hypoketotic). Consequently, they are at a greater risk for brain damage when they are hypoglycemic.

Diagnosis

CPT2 may be suspected when after a thorough clinical evaluation, the sick child has characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement). If the suspected patient is an older child or young adult, findings characteristic of muscle breakdown such as myoglobinuria, elevated CPK, and severe skeletal muscle pain will be validated. Next, clinical studies of blood and urine by tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis), respectively, differentiate CPT2 and its associated translocase defect from other fatty acid defects with similar characteristics. Specifically, CPT2 deficiency has a characteristic blood pattern that includes increases in long chain fatty acids (16-18-carbon), as well as their long chain dicarboxylic acids, all complexed to carnitine (acylcarnitines) and free carnitine levels are low. Organic acids are usually normal. Unfortunately, this laboratory profile is identical to that of the carnitine translocase (CACT) deficiency. To differentiate the two, the specific diagnosis must be

confirmed by genetic testing for CPT2 mutations or by measurement of CPT2 activity in blood or skin cells. For mild CPT2 deficiency, there is a common CPT2 mutation that can be used as a mutation analysis starting point. Patients with the common mild CPT2 deficiency can have a normal fatty acid carnitine pattern on newborn screening (222) if they are not stressed. Fortunately, the medical treatments of CACT and CPT2 defects are identical. Consequently, as soon as the newborn screening results are verified, treatment can begin, minimizing damage from the defect.

Prenatal diagnosis is available by CPT2 enzyme measurement of either cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus).) If the mutations in a previously affected family member are known, direct mutation testing of prenatal samples is possible

Genetics

CPT2 deficiency occurs when an individual inherits one change (mutation) in the gene for CPT2 from each parent (autosomal recessive). Parents of patients are carriers of the disease but have no symptoms. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with CPT2 deficiency. Genetic counseling will benefit affected individuals, as well as their families. Existing and subsequent siblings of the index case should be tested for CPT2 defects. For example, with the mild form of the disease, the children may not have been symptomatic during newborn screening or older children may not have been screened. With the severe form in particular, the family should be asked whether there have been episodes of sudden infant death (SID) or unexplained infant deaths, which may have been caused by previously unrecognized CPT2.

Treatments

Prevention of fasting is the mainstay of chronic therapy in CPT2 deficiency. Fasting in the first year of life can increase from 4 to 8 hours and should be limited to less than 10 hours after the age of 2 years. In the severe form, continuous feeding of carbohydrates directly into the stomach (intragastric) may be required to prevent low blood sugar. For most patients, time between feedings can increase as the child grows older. Additionally, your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil). Carnitine (Carnitor) supplementation does not usually improve severe disease but will be considered when free carnitine is extremely low, and the patient has some CPT2 protein activity.

Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation), as these are signs of dangerously low blood sugar. Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglycemia has occurred. At the medical facility, the hypoketotic hypoglycemia of CPT2 will be treated with high dose intravenous glucose-containing fluids, usually at a rate of at least 8-10 mg/kg/min of glucose. The elevated blood ammonia usually reverses with correction of the low blood sugar. If it is not corrected, dialysis can be added to reduce the ammonia level.

Investigational Therapies

A clinical trial is currently being conducted on treatment of CPT2 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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has coincidentally been shown to increase the amount of CPT2 protein in cells from mildly affected patients (Yao, 2011). Limited clinical studies using benzafibrate to treat CPT2 deficiency have been published, but no active clinical trials are in progress. However, Reneo Pharmaceuticals has developed a similar but more powerful potential drug that will soon be evaluated in clinical trials for CPT2 in the US.

Information on current clinical trials is posted on the Internet 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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Carnitine Uptake Defect (Primary Carnitine Deficiency)

Primary carnitine deficiency occurs when the protein OCTN2 is missing or contains errors that keep it from functioning normally. This protein, located within the cell membrane, transports a common molecule known as carnitine into cells. Carnitine is required to carry certain fats (long- chain fatty acids) into mitochondria, where the fats are used to produce energy. Fatty acids are a major source of energy for the heart and muscles (213, 218). During periods without food (fasting), fatty acids are also an important energy source for other tissues, especially the liver. OCTN2 not only transports carnitine into individual cells, but it also is essential for the whole body to take up carnitine and to maintain carnitine levels. In the gut, OCTN2 takes up carnitine from the diet, while in the kidney it also removes carnitine from the just filtered fluids, returning it to the blood. Without OCTN2, dietary carnitine cannot enter the blood and any carnitine made inside the body that enters the blood is lost through the kidney into urine, together resulting in a severe lack of circulating carnitine.

Signs and symptoms

Symptoms of OCTN2 deficiency appear periodically whenever the body needs fat for energy. This usually happens when the patient is not eating (fasting) for a long period. Alternatively, they also may appear when more than the normal amount of energy is required, as when someone is sick or exercising intensely. Patients commonly show symptoms between the ages of three months and two years. Usually after a minor illness such as a stomach virus or an ear infection, infants become extremely sleepy and difficult to wake (lethargy), are irritable, refuse to eat, and have poor muscle tone.  Clinically, they have low blood sugar (hypoglycemia) with low ketones (hypoketotic) and an enlarged poorly functioning heart (dilated cardiomyopathy) (213, 218), Their livers become damaged causing release of their liver enzymes into the blood. At later ages, they may have an enlarged heart (hypertrophic cardiomyopathy), progressive muscle weakness with fat deposits in muscle, accompanied by a mild increase in a muscle damage indicator (creatine kinase). While much of this damage occurs because of inadequate energy for normal bodily functions, some results from the excessive accumulation of fats in cells. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children recovering from viral infections such as chicken pox or flu.

There are milder forms of OCTN2 deficiency. For example, several mothers without noticeable symptoms have been identified only during newborn screening of their infants (see below) (219). Occasionally, this disorder in the fetus can cause a dangerous form of fluid accumulation in utero called fetal hydrops (220, 221).

Diagnosis

Newborn screening by tandem mass spectrometry of blood spots is the most common method for starting the diagnosis of primary carnitine transporter deficiency. Blood spots from these newborns have very low amounts of all carnitine containing molecules including free carnitine (222). There are other fatty acid disorders where carnitine levels can be low, but only this group has no dicarboxylic acids in their urine. The diagnosis can be complicated by the fact that during pregnancy the mother provides carnitine to the fetus. If the blood for the newborn screening is taken too soon, an affected infant may have enough left-over carnitine from the mother to pass the test (Longo, 2016). On the other hand, this same maternal situation has led to the diagnosis of several mothers with the defect, some who had undiagnosed symptoms and some without symptoms. For this reason, the carnitine status of the mother is an essential part of the diagnosis whenever low carnitine is found on newborn screening.

If necessary, the carnitine defect can be directly observed by testing for carnitine uptake by tissues such as cultured skin cells (fibroblasts) or white blood cells (lymphoblasts). Molecular testing of the OCTN2 gene (SLC22A5) is clinically available. Testing can also be performed on tissues or cultured cells (amniocytes) from a fetus, if a defect is suspected (218, 225).

Genetics

The OCTN2 protein defective in primary carnitine transporter deficiency is coded for by the SLC22A5 gene. Mistakes (mutations) in this gene can either make a low functioning protein or an unstable protein or no protein. More than 60 different mutations in the SLC22A5 gene have been found (222, 223). Everyone has two copies of the SLC22A gene. Patients with carnitine transporter deficiency inherit one defective SLC22A gene from each parent (autosomal recessive inheritance).

Parents of these patients are carriers of the disease. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with the same SLC22A mutations. Siblings of the affected person should be tested for SLC22A defects, in case a diagnosis was missed. Primary carnitine deficiency is rare in the United States, occurring in approximately 1 in 100,000 newborns. In Japan, this disorder is more frequent and affects 1 in every 40,000 newborns.

Treatment    

Primary carnitine transporter deficiency is treated by giving large pharmaceutical quantities of L-carnitine to the patient. Their response is dramatic and life-saving. In emergency situations, it can be given intravenously, followed by larger oral doses for the rest of the patient’s life (218). If the patient has progressed to symptomatic cardiomyopathy, treatment for the cardiac symptoms may be necessary until it has resolved. If the patient receiving these large L-carnitine doses develops a fishy odor, they can be given metronidazole orally to reduce this odor.

Multiple Acyl-CoA Dehydrogenase Deficiency/Glutaric Acidemia Type II

Introduction

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an inherited disorder where the body has a reduced ability to obtain energy from most proteins and fats. It is also called glutaric acidemia Type II because these patients excrete glutaric acid in their urine. For routine body maintenance, the body uses carbohydrates and their sugar products, but this energy pool is limited. Whenever this pool of carbohydrates has been exhausted by either lack of food ingestion (fasting) or from increased demand from illness, trauma or exercise, the body turns to fatty acids and amino acids, both highly efficient energy sources. Amino acids come from and are the building blocks of proteins and fatty acids are the core component of fats. Most amino acids and all fatty acids are broken down into energy in subunits of every cell known as mitochondria. Patients with MADD cannot process the energy taken from fats and amino acids because either of two proteins, electron transfer flavaproten (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) is defective. Without these proteins, not only is there an inability to generate energy for the cell’s work, but the unused fats and amino acids accumulate in quantities that are toxic. Riboflavin, also called Vitamin B2, is an essential partner of both proteins that can malfunction in MADD.

Clinical

MADD can be a very severe or a mild defect. It varies from being apparent at birth and incompatible with life to only appearing as a mild disease in adolescence or young adulthood.  Symptoms also vary by age of presentation. The most severely affected, who present as newborns, visually are very limp (hypotonic), have abnormal features of both face and body, may have a large liver, and may have a characteristic smell like sweaty feet. Upon closer observation, they may have brain abnormalities, weak and enlarged hearts (dilated cardiomyopathy), and kidneys with fluid filled sacs (cystic).  Routine laboratory studies in blood show low sugar (hypoglycemia), lack of the fatty acid products known as ketones (hypoketotic), elevated blood ammonia (hyperammonemia), and lactic acid accumulation.  Infants and children with milder forms of the disease are common and usually only present at their first episode of mild stress such as an ear infection or gastrointestinal distress. At that time, they can be difficult to awaken (lethargic), limp, irritable, or vomiting.  Laboratory studies will show hypoketotic hypoglycemia, and/or intermittent lactic acidosis. (311,312).  The mildest patients may only show muscle pain and weakness and may only present in adolescence or young adulthood.

Diagnosis

MADD blocks the mitochondrial breakdown of many different sources of energy and these many unused products form the basis of its diagnosis. The two major diagnostic tests are organic acid analysis in urine and tandem mass spectrometry analysis of blood. The organic acid analysis usually shows both increased amino acid products (ethylmalonic, glutaric, 2-hydroxyglutaric, and 3-hydroxyisovaleric acids and isovalerylglycine), together with increased fatty acid products (6-, 8-, and 10-carbon dicarboxylic acids).  Tandem mass spectrometry in blood shows accumulation of both amino acid products (glutarylcarnitine and isovalerylcarnitine) and fatty acid products (4-, 8-, 10-, 10:1-, and 12-carbon acylcarnitines) (266, 319). Blood carnitine is usually low. There is also increased serum sarcosine apparent even in patients with mild disease. Fortunately, today most MADD patients are identified in early infancy through expanded newborn screening with tandem mass spectrometry.

If necessary, further studies can determine whether the defect is in ETF or ETFDH. Both can be identified by analysis of either activity or its presence or absence in cells (immunoblot analyses). ETF is formed from two proteins that assemble together called ETFA and ETFB. Either component can be defective. ETFDH has only one component. Since a specific DNA sequence codes for each of the three proteins, molecular testing for their defect is another approach and is usually more available than protein diagnostics.

Severe forms of MADD can be diagnosed before birth by using organic acid analysis to identify increased glutaric acid in amniotic fluid. In addition, sometimes ultrasound examination of the fetus will show cysts in their kidneys (320-322).

Treatment

Patients with the most severe MADD defects often die during the first weeks of life, usually from heart associated problems. Many of those with less severe defects will be identified first by newborn screening. This early identification allows them early treatment so that most can survive well into adult life. The first rule of treatment is the avoidance of going without food (fasting). Feedings are closely spaced, every 2-3 hours, to start. In some cases, continuous feeding of carbohydrates through a stomach tube may be necessary to prevent low blood sugar, especially at night. A riboflavin (100-400 mg/kg/day) supplement is usually given and may help some patients by stabilizing the defective protein. Pharmacologic doses of carnitine (50-100 mg/kg/day) are given to help remove unused fats and amino acids.

Mildly ill children with MADD should be given liquids that contain glucose or sugars frequently. Parents should call their health care provider immediately whenever these infants become excessively sleepy, are vomiting, have diarrhea, a fever, poor appetite, or an infection. In hospital, these children will be given sugar by vein to provide energy.

Genetics

MADD is a genetic disorder that can result from defects in any of three genes: ETFa, ETFB, and ETFDH. It occurs when a child inherits a mutation in the gene for one of the ETFs or ETFDH from each carrier parent. A couple in which both parents are carriers for MADD have a 25% chance with each pregnancy of having another child with this genetic disorder.  One common a-ETF gene mutation has been described (266). MADD is a rare disorder and its frequency is unknown.

MCAD Deficiency

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of a group of inherited disorders of fat metabolism that makes the body unable to generate 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 a special sac-like bodies called mitochondria. Inside mitochondria energy is generated efficiently from the breakdown of fats, as well as from some protein components (in a process known overall as mitochondrial b-oxidation). In MCAD, an intermediate step in the breakdown of fats is missing or reduced. Today in the United States, the majority of MCAD patients are identified right after birth because of the expanded newborn screening program. For most infants in the United States, a blood spot for MCAD testing is obtained from the infant’s heel before they go home from the birthing facility.

Signs and symptoms

Before newborn screening, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common of the fatty acid oxidation disorders, usually presented during the first 2 years of life with episodes of vomiting, enlarged liver (hepatomegaly), a special form of low blood sugar (hypoketotic hypoglycemia), and extreme tiredness (lethargy) progressing to coma and seizures after seemingly mild illnesses such as a viral illness or ear infection (261). During these acute episodes, ammonia, uric acid, liver transaminases, and creatine phosphokinase (CPK) were elevated in the blood, and their liver was often fatty (262, 263). This initial episode was fatal in about 25% of cases, some of which were grouped into Sudden Infant Death Syndrome. Today, most cases are diagnosed in the first three to four days of life through newborn screening of a blood spot rather than from clinical presentation. Usually, patients are well when identified, though at high risk for low blood sugar (hypoglycemia) with even simple illnesses, and deaths are rare (243). A few enzyme-deficient individuals born before newborn screening first still present with symptoms in adolescence or adult life and some have even never had an acute episode (264, 265).

The hypoketotic hypoglycemia found in MCAD is a special form of low blood sugar. When healthy people fast or use excessive calories in exercise, they start to burn fat to maximize calorie efficiency and to save glucose. At the end of this fat oxidation, some of its products are turned into protective molecules called ketones that provide energy for the brain when glucose is limited (216). Since MCAD patients have a limited ability to break down any fats, they lack the basic ingredients to make these ketones (thus are hypoketotic). Unfortunately, this lack of ketones increases the risk for brain damage during hypoglycemic episodes.

Diagnosis

The majority of patients with MCAD defects are diagnosed through newborn screening of an infant’s blood spot by tandem mass spectrometry and are not ill at diagnosis. As soon as the abnormal result is validated, infants are referred to a physician for immediate intervention.

Whether MCAD patients are sick or healthy, their blood nearly always has increased amounts of specific fats called acylcarnitines.  MCAD patients uniquely accumulate fats of a medium carbon chain length, usually 8 or 10 carbons long (266). They occur in the blood in their carnitine form because they are transported there to help dispose of them. These are the same fats identified in newborn screening of MCAD patients. At the same time, free carnitine in blood is usually low. During episodes of acute illness, urine from MCAD patients also have high levels of several types of medium chain fat derivatives. If an ill child has not been screened for MCAD as a newborn, the presence of these medium chain species is suggestive that an MCAD workup is in order. Enzyme can be measured in fibroblasts or leukocytes, but molecular diagnosis is more readily available and often faster because of the presence of one very common mutation (see common mutation below under Genetics).

Because of the prevalence of the common mutation, prenatal diagnosis is usually done most rapidly by analysis for the common mutation from DNA obtained from the amniotic fluid or chorionic villus sampling (CVS). MCAD enzyme measurement can also be performed, but it takes a much longer to get results. In amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus).

Genetics

MCAD deficiency occurs when an individual inherits one change (mutation) in the gene for MCAD (ACADM) from each parent (autosomal recessive). The vast majority of patients have a single common mutation (985A>G) that causes one change in the protein chain (270). In MCAD, 90% of the patients inherit this common mutation from at least one parent, while approximately 70% of patients inherit the same mutation from both parents. Thus, few MCAD patients do not have at least one 985A>G allele. The unusually high frequency of a single common mutation has made molecular diagnosis especially valuable in MCAD deficiency. Patients with the common mutation accumulate the highest levels of metabolites in the newborn period and are probably at risk for more severe disease than are many other mutations (271)

Treatment

Day-to-day management of MCAD consists of avoiding excessive fasting that can lead to coma. Overnight fasting in MCAD infants should be limited to no more than 8 hours. In children over 1 year of age, 12-18 hours without food is probably safe (268). Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglycemia has occurred. Although it is reasonable to modestly reduce dietary fat because this fuel cannot be used efficiently in MCAD deficiency, patients appear to tolerate normal diets. Formulas containing medium-chain triglyceride oil should be avoided. Although MCAD patients tend to have low blood levels of carnitine, the use of carnitine supplementation is controversial (269). Some investigators suggest 50 to 100 mg/day of oral carnitine, but its usefulness is unproven.

Treatment of acute episodes in MCAD deficiency is primarily supportive and aimed at quickly stopping the body from depending on fat breakdown for energy (252). Low blood sugar (hypoglycemia) should be corrected with administration of intravenous dextrose (glucose) at a rate that maintains plasma glucose levels at, or slightly above, the normal range. Specific therapy for the mild hyperammonemia that may be present during acute illness is not usually required. Rarely, there is acute brain injury in the form of coma. The sensitivity of the brain in MCAD may not be entirely due to the hypoglycemia but it may also be affected by the fatty acid intermediates that accumulate (ref 4,7 chapter). Recovery is usually complete within 12 to 24 hours except where serious injury to the brain has occurred.

Investigational

The combination of chronic fasting avoidance and rapid glucose intervention in acute low blood sugar episodes usually allows MCAD children to thrive. As they age, children usually become less prone to these episodes.

Currently there are no active programs to develop additional specific interventions for MCAD. However, other potential interventions may appear as products that are effective on the entire class of fatty acid oxidation disorders are developed.

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

References

Click here to ask an FAOD expert a question about VLCADD. Please note that specific questions about your individual child’s medical problems cannot be answered.

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Short Chain L-3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Medium/short chain L-3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) is a complicated inherited disorder of fat metabolism.  When the body has used up its stores of available sugars for energy, it must turn to fats. In each cell in the body, this breakdown of fats takes place very efficiently in special membrane defined bodies called mitochondria, by a four-step process known as b-oxidation. M/SCHAD is a member of a protein family that performs the third step, with each member designed to work on fats of different lengths. In addition, M/SCHAD has a second completely different role inside the mitochondria where it is a component in the regulation of insulin secretion. Without M/SCHAD, too much insulin goes into the blood, making the sugar levels in the blood too low.  Loss of that insulin control is the most dangerous aspect of the M/SCHAD defect (306).  Because of the expanded newborn screening program, today many potential M/SCHAD patients are identified right after birth, before they can show symptoms.

Signs and symptoms

The symptoms of M/SCHAD deficiency include extreme sleepiness, irritability, poor appetite, and mood changes. If they do not get treated medically, they can have fever, diarrhea, vomiting, and low blood sugar which can progress to seizures and coma.  These symptoms usually appear the first time the child gets an illness where they stop eating regularly. Without regular feedings, SCHAD deficient infants develop a type of low blood sugar called hypoketotic hypoglycemia. It occurs because SCHAD patients secrete too much insulin into the blood. The insulin causes the blood levels of glucose to drop, leaving too little glucose to provide energy in even minor stresses like an ear infection or diarrhea. In addition, while most people can save their blood glucose by switching to fats for energy during illnesses or other stresses, these infants cannot make this switch normally. This combination of dysfunctions leaves the patients with blocks in two different means to provide energy from glucose (303-305). Infants with M/SCHAD may also have liver disease (MJ Bennett).

Diagnosis

M/SCHAD deficiency is very rare and difficult to diagnose. Most patients have symptoms in early infancy. Today, the first suspicion of M/SCHAD defects is usually the detection of high levels of the fat products 3-hydroxy-C4-carnitine and 3-hydroxy-C6-carnitine in blood spots during expanded newborn screening (Stanley C 2011).  After the newborn screen results are validated, infants will be sent to their physician to look for the combination of low blood sugar with high levels of insulin (hyperinsulinemic hypoglycemia), and their urine will be taken to search for elevation of another fat product, 3-hydroxyglutarate (stanley). (303-305).  Skin cells from infants with the defect may have reduced M/SCHAD activity. The final diagnosis depends on the identification of mutations in the gene for M/SCHAD.  Gene mutations have only been found in patients who have abnormal fats as described above and excess insulin. In several patients, abnormal metabolites or enzymatic studies suggestive of M/SCHAD deficiency with a normal M/SCHAD gene sequence have been reported. In these cases, he underlying disorder remains unclear.

Genetics

Everyone has two genes that make the M/SCHAD protein and, to make it confusing, this same gene has two names (HADHSC or HADH). In children with M/SCHAD, both genes contain mistakes (mutations) that result in either no protein or protein that does not work well. The disorder is inherited in an autosomal recessive manner with one mutated gene for M/SCHAD coming from each parent. Parents of children with M/SCHAD only occasionally carry two mutant genes. Rather, each parent usually carries a single bad gene, while the other gene is normal. For them, the one good HADHSC gene makes enough protein to keep the parents healthy. When both parents are carry a mutation (are carriers), there is a 25% chance in each pregnancy for the child to have M/SCHADD. There is a 50% chance for the child to be a carrier, just like the parents, and, there is a 25% chance for the child to inherit two healthy genes.

Treatment

The goal of treating SCHAD deficiency is to avoid low blood sugar (hypoglycemia). Because SCHAD defects can lower blood sugar by two different mechanisms, it is treated with two different approaches. First, to reduce the circulating insulin levels. the drug diazoxide is given (306). Second, since SCHAD patients have limited abilities to use fats, avoid excessively relying on fat for energy by avoiding fasting and making certain that plenty of carbohydrates and sugars are given. If the SCHAD patient is sick and will not take in sugars by eating or drinking them, they may need to be given intravenous (IV) fluids with glucose solutions to prevent the blood sugar level from dropping.

Medium Chain 3-Ketoacyl-CoA Thiolase Deficiency

Medium chain 3-ketoacyl-CoA thiolase deficiency (MCKAT) is the rarest of the many possible defects in the pathway for breaking down fats. When the body has exhausted its stores of available sugars during stress, illness, and fasting, it must turn to fats to make energy. In each cell in the body, this efficient breakdown of fats takes place in a special sac-like bodies called mitochondria. Generating energy from fats is both a multi-step and multi-round process. In MCKAT defects, the last step in the final round of the breakdown of fats is missing or reduced. Surprisingly, recent laboratory studies have shown that this step is an important controller of the rate of fat entry into the fat breakdown pathways (Plos, 2017).

Signs and symptoms

Because less a handful of cases of MCKAT have been identified to date, there is limited knowledge about the symptoms of this disorder. In the first reported case, an infant presented at 2 days of age with vomiting, dehydration, acidic blood (metabolic acidosis), liver disease, and severe muscle breakdown (rhabdomyolysis) resulting in reddish-brown urine (myoglobinuria) (307). Later patients presented with low blood sugar (hypoglycemia), vomiting, floppiness (poor muscle tone), and even coma whenever time between feedings are too long (fasting intolerance).  Others have had heart malfunctions (cardiomyopathy), and, in one case, the first presentation was with sudden death (SIDS) (308, 309).

Diagnosis

The only extensive diagnostic reports are from the first MCKAT case. Organic acid analysis of urine revealed elevated lactic acids, ketones and significantly increased 6- to 12-carbon dicarboxylic acids, with strikingly elevated 10- and 12-carbon species. In skin cells, 8-carbon fats made little energy and there was little medium-chain 3-ketoacyl-CoA thiolase (MCKAT) activity and reduced MCKAT protein. Unfortunately, no additional functional or molecular information is available.

Treatment

Nothing is available because of the limited patient experience.

Trifunctional Protein And Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Mitochondrial trifunctional protein (MTP) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are two related inherited disorders of fat metabolism. Their loss makes the body unable to generate enough energy during stress, illness and fasting. When the body has exhausted its stores of available sugars, it turns to fats to make energy. In each cell in the body, there are mitochondria, sac-like units that specialize in efficiently extracting energy from fats. MTP is a protein complex that is made up of two different types of protein. The assembled protein performs the last three enzymatic steps in mitochondrial b-oxidation of fats. The second of those three steps are the LCHAD activity and its loss is the most common of the MTP defects. LCHAD only acts on fatty acid intermediates called 3-hydroxyacyl-CoAs that are more than 8 carbons long (240). Without this activity, essentially no energy can be obtained from a fat molecule because MTP is required for the very first round of energy generation.

Signs and symptoms

Typically, infants with any form of MTP dysfunction will be sluggish (lethargic), feed poorly, be irritable and have poor muscle tone. Depending on which protein activities they have lost, patients with low MTP function can present with either of two patterns of systemic involvement. Those with loss of all three protein activities present primarily with symptoms of heart malfunction (cardiomyopathy), muscle breakdown (myopathy), and low blood sugar (hypoglycemia). Poor nerve function in the legs and hands (peripheral neuropathy) and reddish brown urine (myoglobinuria) can also occur (284-288). In contrast, the second more common group, deficient only in LCHAD activity, has liver malfunction (hepatocellular disease), low blood sugar (hypoglycemia) and a specific type of vision loss (pigmentary retinopathy) (289, 290). The liver dysfunction can become severe or life-threatening, causing blockage of bile outflow (cholestasis) and replacement of liver cells by scar tissue (fibrosis) (291). A few patients have symptoms that overlap between these two groups. LCHAD deficiency has also been found in patients originally believed to have recurrent Reye syndrome or in sudden infant death(SID) (290). Some milder cases of MTP deficiency do not appear until adolescence. Their main symptoms are repeated episodes of severe skeletal muscle pain from muscle breakdown (rhabdomyolysis), especially after vigorous exercise. The muscle loss is followed clinically as increased creatine kinase in the blood and a reddish brown breakdown product in the urine (myoglobinuria) (284).

The LCHAD defect in a fetus can also cause life threatening disease in its own mother. In this case, the stress from carrying a fetus that accumulates fats can cause the mother to have a syndrome called HELLP (red blood cell breakdown (hemolysis), elevated liver enzymes, and low numbers of blood coagulation cells (platelets)) (292). HELLP syndrome is especially associated with the common LCHAD gene defect (see below).

Diagnosis

Today, MTP or LCHAD defects are usually identified by newborn screening of a blood spot taken before the infant leaves the birthing facility. The blood spots are promptly analyzed by tandem mass spectrometry for accumulation of specific fat products called acylcarnitines. Infants with LCHAD and MTP nearly always have increased amounts of all types of 16- and 18-carbon 3-hydroxyacylcarnitines in blood (266). The positive newborn test is then repeated to make certain it was correct, and the physician is notified to contact the parents as soon as possible. If urinary organic acids are analyzed, they often show increased 6- to14-carbon 3-hydroxydicarboxylic acids. Unfortunately, because these same abnormalities have been reported in urine from patients with other defects, organic acid results from urine are not sufficient. For final diagnosis, usually cells, either skin cells (fibroblasts) or white blood cells from blood or, for prenatal diagnosis, amniocytes are tested for functional (enzyme) activity. Alternately, gene testing will also yield a final diagnosis and is especially useful where there is an identified mutation or, where symptoms point to LCHAD with its common defect (mutation).

For mothers potentially suffering from HELLP syndrome, LCHAD diagnosis of the fetus can be made during pregnancy by enzyme measurement of either cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus). If the mutations in a previously affected family member are known, direct mutation testing of prenatal samples is possible and more specific.

Genetics

MTP deficiency occurs when an individual inherits from each parent one change (mutation) in one of the two genes (HADHa or HADHb) whose products associate to make MTP (autosomal recessive). (256, 257). Multiple disease-causing mutations have been identified and most are located in HADHa (298, 299). Within the group of MTP patients, the majority with HADHa defects have a specific gene mutation called G1528C that interferes with only the second fat reduction step, named LCHAD. Among patients with isolated LCHAD deficiency, this mutation is inherited from both parents (homozygosity) in 65% and from one parent (heterozygosity) in the remaining 35% of those of European extraction (300).  Defects in the b subunit (protein product of HADHb) usually interferes with the stability of the entire MTP protein, resulting in reduction of all three of the fat breakdown enzymatic steps (MTP deficiency) (286, 301, 302). Rarely, certain HADHa defects can also cause reduction in all three enzyme activities.

Parents of patients are carriers of the disease and have no symptoms. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with the same MTP or LCHAD deficiency. Genetic counseling will be of benefit for affected individuals, as well as their families. All siblings of the first identified patient should be tested for MTP or LCHAD defects, in case a diagnosis was missed. In addition, the family should be asked whether any their children have had sudden infant death (SID), which can be caused by previously unrecognized MTP or LCHAD deficiency.

Standard therapies

The management and treatment of MTP and LCHAD deficiency are focused primarily on preventing and controlling acute episodes of low blood sugar (hypoglycemia). Preventive measures include avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding (i.e. to keep periods of fasting to a minimum). Fasting in the first year of life can increase from 4 to 8 hours and should be limited to less than 10 hours after the age of 2 years. In some cases, continuous intragastrie feeding with a tube may be necessary to avoid hypoglycemia, especially overnight.  Additionally, your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil). They may also advise carnitine (Carnitor) supplements. (293-295).

Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation). If hospitalized for an acute episode, treatment requires the prompt administration of high volume intravenous glucose (10% dextrose) containing appropriate bodily salts and additional supportive measures as required. An emergency regimen should be available for each patient to use when they cannot tolerate their prescribed diet.

Other treatments that have been used include supplementation with docosahexaenoic acid, a polyunsaturated 22-carbon acid. It slows but does not stop or improve the retinopathy seen in LCHAD deficiency (294), but it does not alter the progression of neuropathy in complete TFP deficiency. A high protein diet and supplementation with MCT oil just prior to exercise may be beneficial (296, 297).

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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved (256, 257).

SCAD

Short chain acyl-CoA dehydrogenase (SCAD) deficiency is one of a group of inherited protein alterations that affect the body’s ability to make energy from fats 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 efficient breakdown of fats takes place in a special sac-like bodies called mitochondria. Generating energy from fats is a multi-round process. In SCAD defects, the first step in the final round of the breakdown of fats is missing or reduced. Fortunately, this loss of function at the very last round means this defect usually has less impact than those in earlier rounds. Today in the United States, the majority of SCAD patients are identified right after birth by the expanded newborn screening program. For most infants in the United States, a blood spot for this newborn screening is obtained from the infant’s heel before they go home from the birthing facility.

Signs and symptoms

By following infants with defective SCAD proteins, as identified from newborn screening, it was shown that most people with SCAD mutations never will show any specific symptoms. Earlier reported clinical findings have included episodes of intermittent metabolic acidosis, coma from elevated blood ammonia (hyperammonemic coma), neonatal acidosis with elevated muscle tone (hyperreflexia), multicore muscle breakdown (myopathy), and muscle fat storage with failure to thrive, and poor muscle tone (hypotonia) (276, 277). In contrast to other fat oxidation defects, SCAD deficiency does not cause low blood sugar (hypoglycemia) or low ketones (hypoketosis).

Diagnosis

The majority of SCAD defects are identified initially through newborn screening of an infant’s blood spot by tandem mass spectrometry. Because they cannot perform the last round of chain-shortening of fats, these infants will accumulate two specific four- carbon fat products known as butrylcarnitine and ethylmalonic acid in blood and urine. The majority of these infants are not ill at diagnosis. Because pure SCAD alterations are considered benign (274-277, 281) many newborn screening programs no longer report infants with butrylcarnitine elevations, especially those with lesser changes.

Both butrylcarnitine and ethylmalonic acid can accumulate in other metabolic defects besides SCAD. As a result, infants or children who have symptoms similar to those of fat oxidation disorders, along with increased levels of these two metabolites and other accumulating metabolites may be referred for further study to rule out other metabolic syndromes.

Genetics

SCAD deficiency occurs when an individual inherits one change (mutation) in the gene for SCAD (ACADS) from each parent (autosomal recessive). There are two common SCAD alterations (625 G>A and 511 C>T) that change the active protein but leave it with sufficient activity to function without causing illness (278-280). Other rarer mutations usually cause more loss of protein function and more accumulation of butrylcarnitine and ethylmalonic acid, but still rarely cause illness. One rare mutation inherited with one of the common alterations usually results in an intermediate loss of activity.

Treatment

At present, SCAD deficiency by itself is considered a benign condition with no characteristic symptoms that need to be treated.

References

Click here for a list of references in the scientific literature

Click here to ask an FAOD expert a question about VLCADD. Please note that specific questions about your individual child’s medical problems cannot be answered.

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Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)

A rare inherited disorder of fat metabolism that makes the body unable to generate 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 a special sac-like bodies called mitochondria. Inside mitochondria energy is generated efficiently from the breakdown of fats, as well as from some protein components (in a process known overall as mitochondrial b-oxidation). In VLCADD, the first committed step in the breakdown of fats is missing or reduced. Today in the United States, the majority of VLCADD patients are identified right after birth because of the expanded newborn screening program. For most infants in the United States, a blood spot for VLCADD testing is obtained from the infant’s heel before they go home from the birthing facility. VLCADD affected individuals may also be identified later in life, either because they were either not screened or not screened properly at birth or because they have a milder form of the deficiency that did not show up until later.

Signs & Symptoms

VLCADD can present at any age from birth to adolescence and occasionally presents in early adulthood.  The disorder varies from mild to life threatening and is associated with different symptoms in the same patient as they age. In the severe infantile presentation, children have life threatening low blood sugar (hypoglycemia) which may result in a coma within days or weeks after birth. Blood ammonia may also be high. From ages two or three months to about two years, affected infants are at risk for many serious heart associated problems including a weakened heart muscle (cardiomyopathy), abnormal heart rhythms, and even total failure of the combined lung and heart function. Overall infants may look tired and listless (lethargy), be irritable, and the liver may be noticeably enlarged (hepatomegaly) when they are sick. During later childhood and early adulthood, low blood sugar episodes associated with life threatening comas and cardiac episodes become less common. Instead patients start to have periodic attacks of severe muscle pain caused by skeletal muscle breakdown (rhabdomyolysis) with their urine showing a brownish red color (myoglobinuria). This muscle loss may occur chronically at low levels but is increased by illness, stress, cold/heat or exercise. Unchecked severe rhabdomyolysis is serious and must be treated promptly. The mildest patients typically only show symptoms for the first time as severe muscle pain (rhabdomyolysis) after a severe illness or intense exercise using during adolescence or young adulthood.

Patients with VLCADD and similar diseases that interfere with the breakdown of fats all have a distinct form of low blood sugar called hypoketotic hypoglycemia. When healthy people fast or expend excessive calories in exercise, they burn fat to maximize calorie efficiency. At the end of the b-oxidation of fat, some of its products are turned into protective molecules called ketones that provide energy for the brain. In disorders like VLCADD, few ketones are found in the blood or urine after stress because formation of ketones requires a component that comes from the b-oxidation of fats.  Since VLCADD patients cannot even begin to oxidize fat, their hypoglycemia comes without ketones (hypoketotic hypoglycemia), a paired finding that is unique to fatty acid b-oxidation disorders.

In between acute episodes, some individuals with VLCADD deficiency may be well, but others may have poor muscle tone (hypotonia) and/or chronic cardiomyopathy. Cardiomyopathy leads to weakening in the force of heart contractions, decreased efficiency in the circulation of blood through the lungs and to the rest of the body (heart failure), and various associated symptoms that may depend upon the nature and severity of the condition, patient age, and other factors. Abnormalities of heart rhythm can occur at any age and may be life threatening.

Diagnosis

VLCADD may be suspected when after a thorough clinical evaluation, the sick child or adult has characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement). Next, clinical studies of blood and urine by tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis), respectively, are done to differentiate VLCADD from other fatty acid defects with similar presentations. Specifically, VLCADD has a characteristic pattern that includes increases in several fatty acid species called acylcarnitines in the blood and several organic acid species in the urine. The specific diagnosis will be confirmed by genetic testing for mutations or by measurement of VLCAD activity in blood or skin cells.

Prenatal diagnosis is available by VLCAD enzyme measurement of either cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus).) If the mutations in a previously affected family member are known, direct mutation testing of prenatal samples is possible

Genetics

VLCAD deficiency occurs when an individual inherits one change (mutation) in the gene for VLCAD (ACADVL) from each parent (autosomal recessive). The incidence of VLCADD in the general population is ~1:40,000 births and it can usually be identified by newborn screening in babies before they get sick. Parents of patients are carriers of the disease and have no symptoms. With each pregnancy, the parents have a 25% risk (1 in 4) chance to have another child with VLCAD deficiency. In addition, pregnant women have an increased risk for pregnancy complications if they are carrying an affected baby (HELLP syndrome). Genetic counseling will also be of benefit for affected individuals, as well as their families. Existing and subsequent siblings of the index case should be tested for VLCAD, in case a diagnosis was missed. In addition, the family should be asked whether there have been episodes of sudden infant death (SID), which can be caused by previously unrecognized VLCADD. Initially, VLCAD deficiency was mistakenly called LCAD deficiency, but all previously published cases of LCAD deficiency were, in fact, VLCAD deficiency.

Treatment

The management and treatment of VLCADD are focused primarily on preventing and controlling acute episodes of low blood sugar (hypoglycemia). Preventive measures include avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Fasting in the first year of life can increase from 4 to 8 hours and should be limited to less than 10 hours after the age of 2 years. In some cases, continuous intragastric feeding with a tube may be necessary to avoid hypoglycemia, especially overnight.

Additionally, your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil). They may also advise carnitine (Carnitor) and/or riboflavin (Vitamin B2) supplements. Those with the milder disease forms may find that limiting exercise and cold/heat exposure and avoiding fasting will be sufficient to control the symptoms.

Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation). If hospitalized for an acute episode, treatment requires the prompt administration of high volume intravenous glucose (10% dextrose) containing appropriate bodily salts and additional supportive measures as needed. An emergency regimen should be available or each patient to use when they cannot tolerate their prescribed diet.

Investigational Therapies

A clinical trial is currently being conducted on treatment of VLCADD 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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has coincidentally been shown to increase the amount of VLCAD protein in cells. Limited clinical studies using benzafibrate to treat VLCAD deficiency have been published, but no active clinical trials are in progress. However, Reneo Pharmaceuticals has developed a similar but more powerful potential drug that will soon be evaluated in clinical trials for VLCADD in the US.

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

References

Click here for a list of references in the scientific literature

Click here to ask an FAOD expert a question about VLCADD. Please note that specific questions about your individual child’s medical problems cannot be answered.