There are various types of FAOD diagnosis and deficiencies. Thanks to our partnership with the International Network for Fatty Acid Oxidation Research and Management (INFORM), below is an overview of the various FAODs, their diagnosis, treatments and symptoms.
ACAD9 Deficiency
Acyl-CoA dehydrogenase 9 (ACAD9) is a protein that contributes to breaking down fats in the mitochondria, the “powerhouses of the cell.” It is found at high concentrations in the liver and heart, as well as in specific cell types in the lung and kidney. Like other fatty acid oxidation disorders, or FAODs, ACAD9 deficiency prevents the body from generating sufficient energy during times of stress, illness, and fasting. It can have a serious impact on an infant’s heart and liver function.
Genetics
ACAD9 deficiency is an inherited disease that occurs when a genetic mutation is passed from each parent to the offspring. Parents who already have one child with this FAOD have a 25% chance with each pregnancy of having another child with this disease. While fatty acid oxidation research has found many different mutations in ACAD9, there is no common mutation to date
Signs and Symptoms of ACAD9 Deficiency
There are many symptoms of ACAD9 deficiency in babies. The most common symptoms are listed below:
- Poorly functioning enlarged heart (hypertrophic cardiomyopathy)
- Liver disease
- Large head (macrocephaly)
- Leigh’s syndrome (a neurological condition)
Some other symptoms include:
- Difficulty in suckling
- Loss of head control and motor skills
- Loss of appetite
- Vomiting
- Seizures
As the condition progresses, infants may exhibit other signs of the disease, including:
- Weakness and lack of muscle tone
- Extreme muscle tightness (spasticity)
- Movement disorders
- Inability to coordinate joints and even eyes (cerebellar ataxia)
- Loss of nerve function in feet, legs, and even fingers (peripheral neuropathy)
Milder cases of the disease may not be identified until adolescence or adulthood. Because ACAD9 deficiency is difficult to diagnose, its incidence in the U.S. population is not known.
How to Diagnose ACAD9 Deficiency
ACAD9 deficiency cannot be identified by prenatal diagnosis or by newborn screening. Unlike many other ACAD defects, there is no test for protein activity either. Instead, diagnosis may involve a search for biochemical markers in the blood or urine. The liver may also be tested for abnormal levels of the fat product acylcarnitine. Most ACAD9 deficiency cases today are identified through whole exome sequencing at the gene expression level.
Can You Treat ACAD9 Deficiency?
Management and treatment of ACAD9 deficiency focuses on preventing low blood sugar (hypoglycemia), but care must be taken not to induce a secondary problem called lactic acidosis. It may also be helpful to take VitaminB2 (riboflavin) at 100 mg/kg/day, because it may help to stabilize some ACAD9 variants. Cardiomyopathy or other serious heart or liver problems that may come with this fatty acid oxidation disease should receive appropriate medical treatment.
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Carnitine Transport Defect/CUD (Primary Carnitine Deficiency)
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Carnitine-Acylcarnitine Translocase (CACT) Deficiency
CACT deficiency is a rare form of FAODs.
What is CACT Deficiency?
Carnitine acylcarnitine translocase (CACT) deficiency is a rare inherited fatty acid oxidation disorder that occurs when the protein that transfers fats into the mitochondria is defective. Mitochondria are the site within cells where energy is generated. When the body has exhausted its stores of available sugars, especially during times of stress, illness, fasting or intense exercise, it must turn to fats to produce energy. People with CACT deficiency have trouble producing this energy because they lack the proper CACT proteins to efficiently transfer fatty acids into the mitochondria.
Genetics
CACT deficiency occurs from a genetic mutation in the CACT gene (SLC25A20) that patients inherit from both parents. Carriers of this FAOD have no symptoms. If both parents are carriers, they have a 25% chance of each child having the CACT deficiency. Inform Network suggests that if one child has CACT deficiency, all biological children should be tested. Fatty acid oxidation research suggests that a family history of sudden infant death (SID) may also be an indicator of previously undiagnosed CACT.
Signs and Symptoms of CACT Deficiency
Although few cases of CACT deficiency have been identified, it is similar to the more common CPT2 defect. Those with CACT deficiency tend to have severe presentation because they have little or none of the necessary protein. Milder forms of the disorder may be identified with future fatty acid oxidation research.
Signs and symptoms of CACT deficiency in infants include:
- Lethargy
- Irritability
- Difficulty waking
- High level of ammonia in the blood
- Enlarged liver (hepatomegaly)
From ages two or three months to about two years, affected infants are at risk for many serious heart-related problems, including:
- A Weakened heart muscle (cardiomyopathy)
- Abnormal heart rhythms
- Total failure of the combined lung and heart function
- Severe CACT deficiency and other similar fatty acid oxidation disorders can suffer from life-threatening low blood sugar (hypoglycemia), including specifically hypoketotic hypoglycemia. This can lead to:
- Coma
- Seizures
- Lack of ketones (hypoketotic)
- Increased risk of brain damage from lack of ketones
How to Diagnose CACT Deficiency
Those with CACT deficiency or CPT2 deficiency will require blood and urine tests with tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis) respectively to differentiate themselves from other fatty acid oxidation disorders. Both CACT deficiency and CPT2 deficiency have a characteristic blood pattern. CACT defects can only be validated by showing reduced CACT activity in blood or skin cells or by positive genetic testing for CACT mutations. Diagnosis of this FAOD can be determined with newborn screening.
CACT Deficiency Treatment
CACT deficiency treatment is the same as CPT2 deficiency treatment. Chronic therapy of CACT deficiency involves regulating eating schedules. For example, infants should be fed every four hours. 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) for CACT deficiency treatment. Carnitine (Carnitor) supplementation does not usually help with severe cases but will be considered when free carnitine is extremely low, and the patient has some CACT protein activity. Home blood glucose monitoring is not helpful because symptomatic illness can begin before hypoglycemia has occurred.
In extreme cases, continuous feeding of carbohydrates directly into the stomach (intragastric) may be required to prevent low blood sugar. 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. Hypoketotic hypoglycemia from CACT will be treated with intravenous glucose-containing fluids. The elevated blood ammonia usually reverses with correction of the low blood sugar. If not, dialysis can be added.
Investigational Therapies and Fatty Acid Oxidation Research
Fatty acid oxidation research has shown new developments in the treatment of CACT deficiency.
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, 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). Reneo Pharmaceuticals has developed a similar but more powerful potential drug that will be evaluated in clinical trials for CACT in the US.
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Carnitine Palmitoy Transferase Ia Deficiency (CPT1a)
While rare, there are various fatty acid oxidation disorders (FAODs). CPT1a deficiency is just one form of the disorder that affects people around the world.
What is CPT1a Deficiency?
Several important proteins are involved when cells break down fats to provide energy for the body. This process happens inside the mitochondria, also known as the “powerhouses” of the cell. The mitochondria are small, enclosed organelles (little organs) in the cell. Carnitine palmitoyltransferase (CPT1a) control the amount of fat that can enter the mitochondria to produce needed energy. They are found in the liver and other tissues. If CPT1a is lost, reduced, or functions poorly (like in CPT1a deficiency), the fatty acid cannot produce this energy.
Genetics
CPT1a is a genetic fatty acid oxidation disorder. It occurs when a child inherits a mutation in the gene for CPT1a from each carrier parent. Like in other fatty acid oxidation disorders, a couple where both parents are carriers have a 25% chance of each of their children having this genetic disorder. While the severe form is rare, a mild CPT1a defect is found frequently in the Inupiaq, Yu’pik, and the Inuit populations in Alaska and Canada as well as in Hutterite populations. The gene change found in the Inupiaq and Yu’pik populations may be advantageous to people living in the arctic, so it is considered a variant rather than a mutation. Even so, infants inheriting the variant can develop dangerously low blood sugar during illnesses.
Signs and Symptoms of CPT1a Deficiency
While some children with milder forms of CPT1a may never develop dangerous symptoms, the most common signs of severe CPT1a deficiency usually show up early in infancy, especially if the infant is stressed, ill, or fasting. Some severe symptoms include:
- Low blood sugar (hypoglycemia)
- Low levels of ketones (hypoketosis)
- Coma and seizures from hypoglycemia and hypoketosis
- Poor liver function
- Enlarged liver (hepatomegaly)
- Liver failure
- Organ failure
Skeletal muscles are not affected by CPT1a.
How to Diagnose CPT1a
Most cases of CPT1a deficiency in the United States are identified through newborn screening of bloodspots collected in the first few days of life. If a newborn screen is suggestive of CPT1a deficiency, additional specialized testing will be needed to confirm the diagnosis. On rare occassions, diagnosis in a fetus can be made 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; a biopsy of the placenta) can be used to detect CPT1a or similar disorders in the fetus.
CPT1a Treatment
If you or someone you know receives a CPT1a diagnosis, there are CPT1a treatments to combat the effects. Regular feeding is the backbone of CPT1a therapy. Fasting should be avoided with regular feedings every two to three hours to start. In severe cases, continuous feeding by a stomach tube may be necessary, especially at night. As children grow older, they will typically become more stable and can usually go longer between feedings. Medium chain triglyceride (MCT) oil and artificial fats may be a helpful supplement. Children with low CPT1a should be given liquids that contain glucose or sugars frequently.
Parents should call their health care provider immediately if infants exhibit symptoms like excessive sleepiness, vomiting, diarrhea, a fever, poor appetite, or an infection. Once they are in the hospital, these children will be given sugar intravenously.
Carnitine Palmitoy Transferase 2 Deficiency (CPT2)
Carnitine palmitoyl transferase 2 deficiency, or CPT2, is the most common of the fatty acid oxidation disorders (FAODs) and occurs most often in a mild form.
What is 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. 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, fasting, and intense exercise. The entry of fats into mitochondria is highly regulated at the point where they cross the inner membrane. 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). People with a CPT2 deficiency have problems which prevent them from efficiently completing this last step.
Genetics
Like other FAODs, the CPT2 deficiency is genetic. It occurs when an individual inherits a mutation in the gene for CPT2 from each parent making it autosomal recessive. The parents are carriers of the disorder but have no symptoms. When both parents are carriers, there is a 25% chance that any child they conceive will have the 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.
With the mild form of the disorder, the children may not have been symptomatic during newborn screening or older siblings 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.
Signs and Symptoms of CPT2 Deficiency
CPT2 deficiency can occur is both mild and severe forms. Patients usually present in adolescence or early adulthood. The first signs of CPT2 deficiency include brownish red urine (myoglobinuria) and muscle weakness or pain after prolonged exercise or other physical stress.
Patients with this fatty acid oxidation disorder may exhibit these common symptoms:
- High blood ammonia
- Enlarged liver (hepatomegaly), especially when sick
- Severe skeletal muscle weakness or pain
- Muscle breakdown such as myoglobinuria
- Heart enlargement
- A specific life-threatening low blood sugar (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 patients with a severe CPT2 deficiency and other fatty acid oxidation disorders have a limited ability to break down fats, this low blood sugar can lead to:
- Lack of ketones (hypoketotic)
- Coma or seizures (days or weeks after birth)
- Increased risk of brain damage from lack of ketones
When CPT2 defect present themselves in babies, infants will show signs of lethargy, irritability, and a poor appetite. 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
- Total failure of the combined lung and heart function
During acute episodes, patients will have elevated blood levels of creatine kinase (CPK), a marker for muscle injury (rhabdomyolysis), but they rarely will have low blood sugar (hypoglycemia).
How to Diagnose CPT2 Deficiency
If a thorough clinical evaluation reveals many of the symptoms previously mentioned, CPT2 deficiency is a likely suspect.
Older children or younger adults will have characteristics of muscle breakdown such as myoglobinuria, elevated CPK, and severe skeletal muscle pain. Once a FAOD is suspected, clinical studies of blood and urine by tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis), respectively, will be used to 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). Free carnitine levels are low, and 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.
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 cases continuous feeding by a stomach tube may be necessary, especially at night. Medium chain triglycerides (MCT oils) and artificial fats can be given as a supplement because they do not depend on CPT1a to enter the inner mitochondrial space. With more fatty acid oxidation research in the future, treatments may change.
Carnitine Uptake Defect (CUD)
A carnitine uptake defect (CUD) or primary carnitine transporter deficiency is a rare fatty acid oxidation disorder (FAOD). In the United States, it occurs in approximately 1 in 100,000 newborns. In Japan, this disorder is much more common affecting 1 in every 40,000 newborns.
What is a Carnitine Uptake Defect?
Carnitine is a common molecule that is required to carry certain fats into the mitochondria, the powerhouses of the cell, where the molecules are then converted into energy. Carnitine is transported into the cells by a protein called OCTN2. Essentially, this protein is used to maintain carnitine levels throughout the body. Fatty acid oxidation research shows that when OCTN2 is missing or fails to function normally, dietary carnitine cannot enter the blood, and any carnitine made by the body is filtered out by the kidney and lost through urine. When this problem occurs, the cells develop a condition called primary carnitine transporter deficiency.
Genetics
Children with the carnitine transporter deficiency inherit one defective SLC22A gene from each parent. With each pregnancy, the parents have a 25% chance that the child will inherit both of the SLC22A mutations and develop this FAOD as a result. Blood siblings of the affected person should be tested for SLC22A defects in case a diagnosis was missed at birth.
Signs and Symptoms of Carnitine Uptake Defect
Children commonly show symptoms of the OCTN2 deficiency between the ages of three months and two years, usually after a minor illness such as a stomach virus or an ear infection. The most common signs of primary carnitine transporter deficiency in children include:
- Lethargy and difficult to wake
- Irritability
- Refusal to eat
- Poor muscle tone
- Low blood sugar (hypoglycemia)
- Low ketones (hypoketotic)
- Enlarged or poorly functioning heart (dilated cardiomyopathy)
- Liver damage
Older children and adults will show other signs of the carnitine uptake defect including:
- Enlarged heart
- Progressive muscle weakness with fat deposits in muscle
- Mild increase in creatine kinase (a muscle damage indicator)
- Occasionally, primary carnitine deficiency in the fetus can cause a dangerous form of fluid accumulation called fetal hydrops.
How to Diagnose Carnitine Uptake Defect
Newborn screening by tandem mass spectrometry of blood spots is the most common method used to start the diagnostic process for primary carnitine transporter deficiency. While other fatty acid disorders have low carnitine levels, only infants with this condition have no dicarboxylic acids in their urine. If necessary, the carnitine defect can be analyzed in tissues such as cultured skin cells (fibroblasts) or white blood cells (lymphoblasts). Molecular testing of the OCTN2 gene (SLC22A5) is clinically available if necessary.
Testing can also be performed on tissues or cultured cells (amniocytes) from a fetus, if a defect is suspected before the child is born. This diagnosis can be more complicated because the mother provides carnitine to the fetus during pregnancy. Also, if the blood for a newborn screening is taken too soon, an affected infant may have a supply of leftover carnitine from the mother causing a false negative. On the other hand, newborn screenings have identified several mothers with a mild form of the defect, including 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.
Treatment of Primary Carnitine Deficiency
Primary carnitine transporter deficiency is treated by giving large doses of L-carnitine to the patient. In emergency situations, the fluids can be given intravenously. Larger oral doses for the rest of the patient’s life will follow. If the patient develops a fishy odor, oral metronidazole can be added to the regimen. A patient with cardiomyopathy or other heart problems as a result of this fatty acid oxidation disorder will need specialized cardiac treatment separately.
Glutaric Acidemia Type II / Multiple Acyl-CoA Dehydrogenase Deficiency (GA2/MADD)
Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase Deficiency or GA2/MADD is a rare but serious fatty acid oxidation disorder (FAOD).
What is GA2/MADD Deficiency?
GA2/MADD is an inherited disorder that reduces the body’s ability to obtain energy from most proteins and fats. The mitochondria, known as “powerhouses of the cell,” cannot process the energy from fats and amino acids because of a defect in electron transfer flavoproten (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH). Without these proteins, a patient with GA2/MADD may have a range of symptoms from lethargy to life-threatening organ failure, since the unused fats and amino acids can grow to toxic levels in the body.
Genetics
Like other FAODs, Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase Deficiency is a genetic disorder. Specifically, GA2/MADD occurs where there are genetic defects in any of three genes: ETFa, ETFB, or ETFDH. When a child inherits a mutation for one of these genes from each carrier parent, they will have this fatty acid oxidation disorder. When both parents are carriers, there is a 25% chance that every child they bear together could have this genetic disorder.
Signs and Symptoms of GA2/MADD Deficiency
GA2/MADD can be apparent as a serious condition at birth or as a mild disease in adolescence or young adulthood. Symptoms also vary by age and severity. Fatty acid oxidation research suggests that in newborns, the most common symptoms include:
- Low muscle tone (hypotonic)
- Abnormal facial and body features
- A large liver
- Characteristic smell like sweaty feet
- Brain abnormalities
- Weak and enlarged hearts (cardiomyopathy)
- Kidneys with fluid filled sacs (cystic)
Infants and children with milder forms of the disease may only show symptoms after an ear infection, gastrointestinal distress, or another relatively minor health problem. At that time, a child may exhibit signs of GA2/MADD like:
- Difficulty waking (lethargy)
- Vomiting
- Limpness
- Irritability
The mildest cases of GA2/MADD may only become evident in adolescence or young adulthood as muscle pain and weakness.
Diagnosis
Like other fatty acid oxidation disorders, newborn screening is one way to diagnose this problem. Newborn screening by tandem mass spectrometry of blood spots can identify the most severe cases of GA2/MADD in early infancy. An organic acid analysis of urine samples is also used for diagnostic purposes. If necessary, further studies on the analysis of cellular activity can determine whether the defect is in the ETF or ETFDH protein. Molecular testing for these defects is usually more readily available than protein diagnostics.
Severe forms of GA2/MADD can be diagnosed before birth by using organic acid analysis to identify increased glutaric acid in amniotic fluid. In some cases, an ultrasound examination of the fetus will show cysts in the kidneys.
Treatment
Without immediate treatment, infants with the most severe GA2/MADD defects often die during the first weeks of life, usually from heart-associated problems. Fortunately, most newborns who receive early treatment can survive well into adulthood. Like other fatty acid oxidation disorders, the primary form of treatment is frequent feedings. Patients must eat every 2-3 hours to start to avoid going without food (fasting). In some cases, continuous feeding of carbohydrates through a stomach tube may be necessary to prevent low blood sugar, especially at night. A riboflavin supplement may help some patients by stabilizing the defective protein. Pharmacologic doses of carnitine (50-100 mg/kg/day) are given as well 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 show signs of lethargy, vomiting, diarrhea, fever, poor appetite, or an infection. Once in the hospital, these children will be given sugar intravenously to provide energy and correct the issues.
Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
Medium-chain acyl-CoA dehydrogenase deficiency, or MCAD deficiency, is a more common fatty acid oxidation disorder (FAOD).
What is MCAD Deficiency?
Medium chain acyl-CoA dehydrogenase deficiency is an inherited disorder involving fat metabolism. The deficiency prevents the body from making enough energy when a person is stressed, ill, or fasting. When the body has used up all of the sugars its stores from food, it turns to fats to make energy. In each cell in the body, energy is made as fats are broken down in the mitochondria, the “powerhouses of the cell.” For someone who has a medium-chain acyl-CoA dehydrogenase deficiency, one of the steps in the breakdown of fats is missing or reduced.
Genetics
MCAD deficiency occurs when an individual inherits one change (mutation) in the MCAD gene called ACADM from each parent. MCAD deficiency is unusual in that most affected people carry at least one copy of a specific common mutation that causes a change in the protein chain. In fact, 90% of those who inherit two ACADM mutations share one copy of this common mutation, and in approximately 70% of cases, those with MCAD deficiency have inherited this same common mutation from both parents. Genetic counseling can benefit affected individuals as well as their families.
Signs and Symptoms of MCAD Deficiency
In the United State today, this fatty oxidation disorder is typically identified in the first few days of life through newborn screening. This involves the collection of a blood spot from the infant’s heel that is used for special testing. Before newborn screening, children with this deficiency usually showed signs and symptoms of the condition, sometimes multiple times, during the first two years of life.
These symptoms include:
- Vomiting
- Enlarged liver (hepatomegaly)
- Low blood sugar
- Low ketones (hypoketotic hypoglycemia)
- Lethargy (lack of sleep)
In some cases, these episodes worsened over time, leading to coma or seizures after seemingly mild illnesses, such as a viral illness or ear infection. As they get older, children usually become less prone to serious episodes. A few individuals with MCAD deficiency who were born before newborn screening may have mild symptoms of the disorder in adolescence or adulthood.
How to Diagnose MCAD Deficiency
As noted, most medium-chain acyl-CoA dehydrogenase deficiency patients are identified through newborn screening. Infants suspected of having this fatty acid oxidation disorder are immediately referred to a physician who specializes in the care of patients who have metabolic disorders, including FAODs. They have testing to confirm the diagnosis, and then immediately start treatment. This testing may include biochemical testing called an acylcarnitine profile, and DNA testing to look for the genetic changes that caused the condition. Before newborn screening, about 25% of first episodes were fatal, and were often grouped into Sudden Infant Death Syndrome.
If there is a family history of this deficiency or if the parents are known to carry genetic changes that cause the MCAD deficiency, prenatal diagnosis can be done during pregnancy using cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). If an ill child has not been screened for MCAD as a newborn, diagnostic testing may involve analysis of specific fats called acylcarnitine, the levels of free carnitine in the blood, and the medium carbon-chain-length fats in the urine.
Treatment Options
Day-to-day management of this disorder consists of avoiding excessive fasting, as it could lead to a coma. How long infants should only go without food will depend on their age, but it’s typically only a few hours. Overnight fasts of 8 hours are allowed after 6 months of age. Children over one year of age can usually safely go without food for 12 to 18 hours. Home blood glucose monitoring is not useful, because an episode can begin before hypoglycemia (low blood glucose) has occurred.
Patients appear to tolerate normal diets, but it is reasonable to modestly reduce dietary fat to < 30% of daily calories because this fuel cannot be used efficiently in MCAD deficiency. Formulas containing medium-chain triglyceride oil should be avoided. MCAD patients tend to have low blood levels of carnitine, but the use of carnitine supplementation is controversial. Some fatty acid oxidation research suggests a supplement of 50 to 100 mg/day of oral carnitine, but its usefulness is not proven.
Medical treatment should be sought immediately if an infant or child cannot keep down formula or food, or if the child experiences loss of consciousness or severe confusion. These are all signs of dangerously low blood sugar (hypoglycemia). At the medical facility, intravenous glucose-containing fluids will be given to address the hypoglycemia. Specific therapy for the mild hyperammonemia that may be present during acute illness is not usually required, but a recent study has used an ammonia-reducing medication in MCAD deficient patients. Recovery is usually complete within 12 to 24 hours, except where serious injury to the brain has occurred.
Investigational Therapies and Fatty Acid Oxidation Research
Currently, there are no active programs to develop additional specific treatments or management for MCAD, but new approaches may appear as products that are effective in treatment of the entire class of fatty oxidation disorders are developed.
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MCHAD/SCHAD Deficiency
M/SCHAD is a rare inherited disorder of fat metabolism, also known as a type of fatty acid oxidation disorder (FAOD).
What is M/SCHAD Deficiency?
Like other FAODs, medium/short chain L-3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency prevents the body from making enough energy during times of stress, illness, and fasting. When the body has used up its stores of sugars, it must turn to fats to make energy in a four-step process known as beta-oxidation. In each cell in the body, this breakdown of fats is done in the mitochondria known as the “powerhouses of the cell.” M/SCHAD is a member of a protein family that performs the third step in the process. It also has a different role inside the mitochondria as a part of the control of insulin secretion. Without M/SCHAD, too much insulin goes into the blood. This increased insulin causes low blood sugar levels. Loss of normal control of insulin levels is the most dangerous aspect of this deficiency.
Genetics
Everyone has two genes that make up the M/SCHAD protein; this gene has two names –HADHSC or HADH. In children with M/SCHAD deficiency, both copies of the gene have changes or mutations. This causes either no protein to be made or protein to be made that does not work efficiently. The disorder is inherited with one altered gene for M/SCHAD coming from each parent. Occasionally, parents may carry two altered or mutant genes. In the parents, the one good HADHSC gene makes enough protein to keep them healthy. When both parents carry the mutation, there is a 25% chance that any child they bear together will have M/SCHAD. There is also a 50% chance that the child will be a carrier with one bad gene, just like the parents, and there is a 25% chance that the child will inherit two healthy genes.
Signs and Symptoms of M/SCHAD Deficiency
The most common symptoms of this fatty acid oxidation disorder include
- extreme sleepiness
- irritability
- poor appetite
- mood changes
Without appropriate treatment, patients may develop further symptoms such as
- fever
- diarrhea
- vomiting
- low blood sugar
Fatty acid oxidation research shows that low blood sugar could worsen to cause seizures and coma, and infants with M/SCHAD may also develop liver disease. These symptoms usually appear the first time the child gets an illness and stops eating regularly. Without regular feedings, M/SCHAD deficient infants have too little blood sugar (glucose) to use for energy when facing minor stresses like an ear infection or diarrhea. Because they have too much insulin in their blood that further lowers their blood sugar and they cannot use fat to make energy, they have two reasons to develop the symptoms listed above.
How To Diagnose M/SCHAD Deficiency
While M/SCHAD deficiency is very rare and difficult to diagnose, many children are identified right after birth through newborn screening before they even show symptoms. Once identified by newborn screening, infants will be sent to a physician to look for the combination of low blood sugar and high levels of insulin. Urine will be tested for the presence of specific fats, and skin cell samples will be examined for reduced M/SCHAD activity. The final diagnosis depends on the identification of mutations in the gene for M/SCHAD.
Treatment Options
The goal of treating this fatty oxidation disorder is to avoid low blood sugar (hypoglycemia). Because M/SCHAD defects can lower blood sugar in two different ways, treatment can take two different approaches. First, the drug diazoxide is given to reduce insulin levels in the blood. Second, patients should avoid fasting and receive plenty of carbohydrates and sugars since their cells can’t use fats for energy. If a M/SCHAD patient is sick, intravenous (IV) fluids with glucose solutions may be given to prevent blood sugar levels from dropping.
Medium Chain 3-Ketoacyl-CoA Thiolase Deficiency (MCKAT)
Medium chain 3-ketoacyl-CoA thiolase deficiency (MCKAT) is the rarest of the fatty acid oxidation disorders (FAODs). If you know someone who is diagnosed with this disorder, it can be overwhelming, and you may feel lost.
What is MCKAT Deficiency?
Medium chain 3-ketoacyl-CoA thiolase deficiency (MCKAT), the rarest of the many fatty acid oxidation disorders, is a defect in the cellular pathway for breaking down fats. The breakdown of fats takes place in the mitochondria that act as the “powerhouses of the cells.” When there are MCKAT defects, the last step in the final round of the breakdown of fats is reduced or missing completely. Recent fatty acid oxidation research has shown that this step is an important controller of the rate of fat entry into the fat breakdown pathways.
Signs and Symptoms
Because only a few cases of MCKAT have been identified to date, there is limited knowledge about the signs and symptoms of this disorder. In the first reported case, a 2-day-old infant showed signs of:
- Vomiting
- Dehydration
- Acidic blood (metabolic acidosis)
- Liver disease
- Severe muscle breakdown (rhabdomyolysis)
- Reddish-brown urine (myoglobinuria)
Later patients have shown other symptoms, including:
- Low blood sugar (hypoglycemia)
- Vomiting
- Floppiness (poor muscle tone)
- Coma if the time between feedings is too long (fasting intolerance)
- Heart malfunctions (cardiomyopathy)
In one extreme case, the first presentation was sudden death (SIDS).
How to Diagnose MCKAT Deficiency
The only extensive diagnostic reports on MCKAT were taken from the first case of the 2-day old infant. Organic acid analysis of urine revealed elevated lactic acids, ketones, and significantly increased dicarboxylic acids. In skin cells, certain fats made little energy. There was also little medium-chain 3-ketoacyl-CoA thiolase (MCKAT) activity and reduced MCKAT protein. No additional diagnostic information is available at this time.
Treatment
Unfortunately, there are no treatments available because of the limited patient experience; however, individuals with symptoms such as dehydration, low blood sugar, and heart malfunctions should be treated with the appropriate therapies immediately. They could be suffering from one of the many fatty oxidation disorders.
Mitochondrial Trifunctional Protein Deficiency (MTP) and Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHAD)
Mitochondrial trifunctional protein (MTP) deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are two related inherited disorders of fat metabolism.
What Is MTP/LCHAD Deficiency?
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 three 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.
Genetics
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 two 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. Occasionally HADHa mutations may affect all three functions. When one child has the MTP/LCHAD deficiency, the parent has a 25% chance of each future pregnancy resulting in a child with the same condition as the first afflicted child. Genetic counseling can benefit affected individuals, as well as their families.
Signs and Symptoms of MTP/LCHAD Deficiency
These fatty acid oxidation disorders can have a variety of symptoms depending on various factors including the exact issue and the severity.
Infants with any of the forms of MTP deficiency will often exhibit signs like:
- Acting sluggish (lethargic)
- Irritability
- Feed poorly
- Low muscle tone
Patients who have lost all three MTP protein activities have serious symptoms including:
- Heart malfunction/enlargement (cardiomyopathy)
- Muscle breakdown (myopathy)
- Low blood sugar (hypoglycemia)
- Poor nerve function in the legs and hands (peripheral neuropathy)
- Reddish-brown urine (myoglobinuria)
Infants who are deficient only in LCHAD activity (the second of the 3 enzymes), may have
- Low blood sugar (hypoglycemia)
- A specific type of vision loss called pigmentary retinopathy
- Liver malfunction (hepatocellular disease) that 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 red blood cell breakage (hemolysis), elevated liver enzymes, and low number of platelets.
How to Diagnose MTP/LCHAD Deficiency
Most MTP/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 FAOD. 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 tests 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.
Treatment Options
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. This time can increase to 10 hours between feedings after age 2. Your doctor may recommend special nutritional supplements such as medium-chain triglycerides (e.g., MCT oil) or carnitine (Carnitor) supplements.
Medical treatment should be sought immediately if your child loses consciousness or is severely confused. If hospitalized for an acute episode, your 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 a letter that can be carried with them in case of emergency. This letter helps emergency room doctors quickly understand the 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 also be beneficial.
Investigational Therapies and Fatty Acid Oxidation Research
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) as well as fewer hospitalizations in patients treated with triheptanoin as compared to those treated with MCT oil. Heart function may also be improved.
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Short Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)
Short chain acyl-CoA dehydrogenase (SCAD) deficiency is one type of fatty acid oxidation disorder (FAOD). If you or your loved one is diagnosed with this disorder, you are probably looking for answers.
What Is SCAD Deficiency?
Short chain acyl-CoA dehydrogenase deficiency is one of a group of inherited protein alterations that affects the mitochondria’s ability to generate cellular energy from fats during times of stress, illness, and fasting. In children, the first step in the final round of breaking down fats is reduced or missing. Fortunately, this loss of function toward the end of the process means that the SCAD defect usually has less impact than other fatty acid oxidation disorders that occur earlier in the process.
Genetics
This fatty acid disorder occurs when an individual inherits one mutation in the gene for SCAD (ACADS) from each parent. There are two common SCAD alterations that change the active protein but still leave it with sufficient activity to function without causing illness. Some rare mutations cause a greater loss of protein function and a higher accumulation of butrylcarnitine and ethylmalonic acid, but still rarely cause illness. There is one rare mutation inherited with one of the common alterations that usually results in an intermediate loss of activity.
Signs and Symptoms of MTP/LCHAD Deficiency
Most children and adults with SCAD mutations do not show any specific symptoms. Earlier reported clinical findings of fatty acid oxidation research 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
- Poor muscle tone (hypotonia)
Unlike other fat oxidation disorders, SCAD deficiency does not cause low blood sugar (hypoglycemia) or low ketones (hypoketosis).
How to Diagnose MTP/LCHAD Deficiency
Today, the majority of SCAD patients in the U.S. are identified right after birth by the expanded newborn screening program. A blood spot is obtained from the infant’s heel and sent to a laboratory for screening before the infant goes home from the birthing facility. The diagnosis involves an analysis of two fat products, butrylcarnitine and ethylmalonic acid, that tend to accumulate in the blood and urine of infants with this deficiency. Because pure SCAD alterations are considered benign, many newborn screening programs no longer report infants with butrylcarnitine elevations, especially those with lesser changes. Because butrylcarnitine and ethylmalonic acid can accumulate in other metabolic defects besides SCAD, infants or children with symptoms of FAODs, along with increased levels of these two metabolites may be referred for further study to rule out other metabolic syndromes.
Treatment
At present, this deficiency is considered a benign condition with no characteristic symptoms that need to be treated.
Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)
VLCAD deficiency is one example of a fatty acid oxidation disorder (FAOD). At the International Network for Fatty Acid Oxidation Research and Management (INFORM), we want to educate the general public on these disorders.
What is VLCAD Deficiency?
Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency) is a rare inherited disorder of fat metabolism that prevents the body from making enough energy during stress, illness, and fasting. After 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 happens in the mitochondria, or the “powerhouses of the cell.” For someone with a VLCAD deficiency, the first step in the breakdown of fats is missing or reduced.
Genetics
VLCAD deficiency occurs when an individual inherits one disease-causing change in the ACADVL gene from each parent. With each subsequent pregnancy, there is a 25% chance that the child will have the VLCAD deficiency. In addition, pregnant women have an increased risk for pregnancy complications if they are carrying an affected baby (HELLP syndrome). Genetic counseling can benefit affected individuals, as well as their families. Blood-related siblings of those diagnosed with this disorder should be tested for VLCAD in case a diagnosis was missed.
Signs and Symptoms of VLCAD Deficiency
Today in the United States, the majority of fatty acid oxidation disorder patients are identified right after birth because of a newborn screening program that involves taking a blood spot from the infant’s heel. Although VLCAD is usually detected from newborn screening as well, the signs of VLCAD deficiency can occur at any age, from birth to early adulthood. The disorder varies from mild to life-threatening, with different symptoms in the same patient as he or she ages.
Patients with VLCAD deficiency all have a specific form of low blood sugar called hypoketotic hypoglycemia. When healthy people fast or expend extra calories in exercise they burn fat. At the end of the fat-burning, some of its products are turned into protective molecules called ketones, that provide energy for the brain. In disorders like VLCAD deficiency, few ketones are found in the blood or urine after stress because a product from the burning of fat (beta-oxidation) is required to make ketones. Since VLCAD patients cannot even begin to oxidize fat, their hypoglycemia comes without ketones (hypoketotic hypoglycemia). This specific type of low blood sugar is only seen in FAODs.
Infants who are symptomatic early may experience symptoms like:
- Life-threatening low blood sugar (hypoglycemia)
- High blood ammonia
- Coma within days or weeks after birth from low blood sugar
From about two months to two years of age, affected infants will experience various symptoms and are at risk for many serious problems. They may suffer from:
- Lethargy (looking tired and listless)
- Irritability
- Noticeably enlarged liver (hepatomegaly) when they are sick
- A weakened heart muscle (cardiomyopathy)
- Abnormal heart rhythms
- Total failure of the combined lung and heart function
During later childhood and early adulthood, low blood sugar episodes associated with life-threatening comas and heart problems become less common. Instead, patients may experience:
- Periodic severe muscle pain caused by skeletal muscle breakdown (rhabdomyolysis)
- Urine that is a brownish red color (myoglobinuria).
This muscle breakdown is increased by illness, stress, cold/heat or exercise. Unchecked severe rhabdomyolysis is serious and must be treated promptly. Patients with a milder form may only have episodes of muscle pain after a severe illness or intense exercise.
Between acute episodes, some individuals with VLCAD deficiency are well, but others may have:
- Poor muscle tone (hypotonia)
- Chronic heart problems like cardiomyopathy or heart failure
These problems depend on the nature and severity of the condition, the patient’s age, and other factors. Abnormalities of heart rhythm can occur at any age and may be life threatening.
How to Diagnose VLCAD Deficiency
Most VLCAD deficiency cases are identified in the first three to four days of life through newborn screening of blood by tandem mass spectrometry. These infants are referred to a physician for immediate diagnosis and intervention. Clinical studies of blood and urine are done to differentiate a VLCAD deficiency from other fatty acid defects with similar signs and symptoms. Each of these conditions has specific blood and urine findings that help confirm the exact diagnosis. VLCAD deficiency can also be confirmed by genetic testing for disease-causing changes in the ACADVL gene or by measurement of VLCAD enzyme activity in blood or skin cells.
Prenatal diagnosis can be done during pregnancy using cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). If an ill child has not been screened for VLCAD as a newborn, diagnostic testing may involve analysis of specific fats called acylcarnitines, levels of free carnitine in the blood, and very long chain fat derivatives in the urine.
In some cases, VLCAD deficiency-affected individuals may also be identified later in life, either because they were not screened properly at birth or not screened at all. It is also possible that they have a milder form of the deficiency that did not show up in infancy.
Treatment
Management of VLCAD deficiency is focused primarily on preventing acute episodes of low blood sugar (hypoglycemia). This process includes avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding. 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 severe cases, continuous feeding with a tube may be necessary to avoid hypoglycemia, especially overnight.
A doctor may recommend special nutritional treatments such as medium-chain triglycerides like MCT oil), carnitine (Carnitor), and/or riboflavin (Vitamin B2) supplements. Limiting exercise, avoiding cold/heat exposure, and not fasting may be sufficient enough to control the symptoms in mild cases.
Medical treatment should be sought immediately if there is a loss of consciousness or severe confusion as these are signs of dangerously low blood sugar. At the medical facility, intravenous glucose-containing fluids are given to address the hypoglycemia. All patients should carry an emergency letter that details their prescribed treatment to manage severe episodes.
Investigational Therapies and Fatty Acid Oxidation Research
A clinical trial is currently being conducted on treatment of VLCAD deficiency with triheptanoin (UX007, Ultragenyx Pharmaceuticals), an artificial fat that is used instead of MCT oil in the diet. Published clinical trial data indicate fewer episodes of low blood sugar and muscle breakdown (rhabdomyolysis) as well as hospitalizations in patients treated with triheptanoin. Heart function may also be improved.
Other fatty acid oxidation research has looked at the use of Bezafibrate. Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has also 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. A similar but more powerful potential drug will soon be evaluated in clinical trials for VLCAD deficiency in the U.S.
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