Carnitine/Acylcarnitine Translocase (CACT) Deficiency
Carnitine/Acylcarnitine Translocase (CACT) Deficiency is a disorder of fatty acid oxidation. Fatty acid oxidation generates ATP in the mitochondria and provides acetyl-CoA for gluconeogenesis. CACT normally acts to transport long-chain acylcarnitine across the inner mitochondrial membrane into the mitochondrial matrix where ß-oxidation occurs. CACT also facilitates the export of free carnitine out of the mitochondria where it can be utilized for formation of acylcarnitines. Deficiency of this transport protein results in impaired long-chain fatty acid oxidation and causes the accumulation of long-chain acylcarnitines outside the mitochondria and in plasma. Short- and medium-chain (C8 and less) fatty acids do not require CACT for entry into the mitochondria and are therefore available for energy metabolism.

The severe form has neonatal onset of acute cardiorespiratory symptoms in the first days of life. If the patients survive the initial illness, they suffer from chronic muscle weakness, cardiac hypertrophy, hypoglycemia and hyperammonemia. Plasma carnitine is low. Death may occur due to cardiomyopathy complications.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Hydroxy Long Chain Acyl-CoA Dehydrogenase Deficiency (LCHAD)
Long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. LCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), which acts on shorter-chain substrates. LCHAD activity resides on the Mitochondrial Trifunctional Protein, which acts to catalyze 3 sequential steps in ß-oxidation. LCHAD deficiency occurs as an isolated defect (described here) or together with deficiency of the other 2 enzymes in Mitochondrial Trifunctional Protein deficiency. LCHAD deficiency impairs oxidation of dietary and endogenous fatty acids of long-chain length (16 carbons and longer).

LCHAD deficiency patients presents with symptoms of cardiomyopathy, may lead to death. Several cardiac problems have been described, including cardiomegaly, left ventricular hypertrophy, and poor contractility. Onset may be acute or chronic. A second group of patients presents, usually following fasting, with non-ketotic hypoglycemia, vomiting, hypotonia, and hepatomegaly. Rhabdomyolysis may occur. Both presentations are highly variable and may have overlapping features. Symptoms may be initiated by a seemingly innocuous illness (a cold or otitis media), leading to prolonged fasting. Symptoms often precede onset of hypoglycemia.

This disorder follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Medium Chain Acyl-CoA Dehydrogenase Deficiency
Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is a disorder of fatty acid ß-oxidation, occurring in at least 1 in 20,000 live births. The enzyme deficiency is medium-chain acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation of fatty acids. MCAD deficiency results in an impaired ability to oxidize dietary and endogenous fatty acids of medium-chain length (6 – 12 carbons).

MCAD deficiency generally presents between the second month and the second year of life, although onset as early as two days and as late as adulthood has been reported. Clinical presentation is often triggered by a seemingly innocuous illness like otitis media or a viral syndrome. The initiating event is probably prolonged fasting, which increases lipolysis and the need for fatty acid oxidation. Symptoms include vomiting, lethargy, apnea, coma, cardiopulmonary arrest, or sudden unexplained death. Initial symptoms often precede the onset of profound hypoglycemia, and are probably related to high free fatty acid levels.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Multiple Acyl-CoA Dehydrogenase Deficiency
Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is also known as Glutaric Acidemia Type II (GA-II). It is associated with deficiency of several mitochondrial dehydrogenase enzymes that utilize Flavin Adenine Dinucleotide (FAD) as cofactor, at least 9 of which are known. These include the acyl-CoA dehydrogenases of fatty acid ß-oxidation, and enzymes that degrade glutaric acid, isovaleric acid, and sarcosine (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contributes its electrons to the oxidized form of Electron Transfer Flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF- ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins.

Three clinical presentations are reported for MADD. Two newborn presentations are seen – one with congenital anomalies, and one without. Those with congenital anomalies are often premature, and develop symptoms in the first 24–48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low. Those patients with no congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat. The third cohort of patients has a mild and/or later onset with variable symptoms including lipid storage myopathy.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Neonatal Carnitine Palmitoyl Transferase Deficiency-Type II (CPT-II)
Carnitine Palmitoyl Transferase II (CPT II) Deficiency is a disorder of mitochondrial fatty acid oxidation. Fatty acid oxidation normally generates ATP inside the mitochondria and provides acetyl-CoA for gluconeogenesis. Long-chain fatty acids require carnitine for transport into the mitochondria as long-chain acyl-carnitine esters (i.e. carnitine esterified to a fatty acid). CPT II is located on the inner mitochondrial membrane and acts to convert long-chain acyl-carnitine substrates that are transported across the outer mitochondrial membrane to acyl-CoAs for subsequent ß-oxidation. Deficiency of CPT II results in the accumulation of long-chain acylcarnitines inside the mitochondria and in the plasma. Medium- and short-chain (C8 and shorter) fatty acids do not require CPT II and are metabolized normally. Muscle is particularly dependent on fatty acid oxidation for energy production.

There are three clinical presentations of CPT II Deficiency. The classic form has adult onset of exercise-induced muscle weakness, often with rhabdomyolysis and myoglobinuria that can be associated with acute renal failure. CK levels are found to be elevated only during a symptomatic period. Carnitine levels are normal.

A second phenotype is often fatal in the period from 3 to 18 months of age. Presentation can be onset of seizures with hepatomegaly, non-ketotic hypoglycemia, cardiomyopathy, hypotonia, and muscle weakness. Plasma free carnitine levels are low and acyl-carnitine high.

A severe form presents in the newborn period with non-ketotic hypoglycemia, cardiomyopathy, muscle weakness, and renal dysgenesis in some patients. All of these patients have expired within days of birth.

These different clinical presentations appear to be correlated with residual CPT II enzyme activity. Adult onset patients are found to have approximately 25% of normal activity while the other clinical groups have less than 15%.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Carnitine Palmitoyl Trtansferase Deficiency Type 1
Carnitine palmitoyltransferase I deficiency is a condition that prevents the body from converting certain fats called long-chain fatty acids into energy, particularly during periods without food (fasting). Carnitine, a natural substance acquired mostly through the diet, is required by cells to process fats and produce energy. People with this disorder have a faulty enzyme that disrupts carnitine's role in processing long-chain fatty acids.

One of the main signs of this disorder is a low level of ketones, which are products of fat breakdown that are used for energy. Low blood sugar (hypoglycemia) is another major feature. Together these signs are called hypoketotic hypoglycemia, which can result in a loss of consciousness or seizures. People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, nervous system damage, and elevated levels of carnitine in the blood.

This condition is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections

This condition is rare; there are fewer than 50 individuals identified with this disorder. This disorder may be more common in the Hutterite populations of the northern United States and Canada, and in the Inuit populations of northern Canada, Alaska, and Greenland.


Short Chain Acyl-CoA Dehydronase Deficiency (SCAD)
Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency is a disorder of fatty acid ß-oxidation. The defect involves short-chain (butyryl) acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation cycle. SCAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons).

SCAD deficiency usually has clinical onset between the second month and second year of life, although presentations as early as two days and as late as adulthood have been reported. Clinical presentation is highly variable with patients having constant symptoms marked by episodic deterioration. Patients have hypotonia, progressive muscle weakness, developmental delay and, possibly seizures. Failure to thrive, vomiting, and hypoglycemia may be seen. Symptoms may be worsened by a seemingly innocuous illness (a cold or otitis media) that is associated with prolonged fasting, which may lead to lethargy, coma, apnea, cardiopulmonary arrest, or sudden unexplained death. Physical examination of the acutely ill child may reveal mild to moderate hepatomegaly. Symptoms often precede the onset of hypoglycemia, which occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production - proteolysis. Cerebral edema and fatty liver and muscle are noted at autopsy, often leading to a misdiagnosis of Reye’s Syndrome or Sudden Infant Death Syndrome (SIDS). SCAD deficiency accounts for about one of every 100 SIDS deaths. Older patients who present chiefly with progressive muscle involvement may respond to riboflavin (Vitamin B2) supplementation and have a generalized multiple acyl-CoA dehydrogenase deficiency. SCAD enzyme is the most vulnerable dehydrogenase to low riboflavin levels.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Short Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (SCHAD)
Short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. SCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), which acts on longer-chain substrates. SCHAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons and shorter). The gene for SCHAD has been cloned and mutations identified in several patients.

SCHAD deficiency has been reported in only a few patients and the true spectrum of the disease remains to be defined. Most patients have hypoglycemia as the major symptom with seizures, neurologic sequela or even death as the outcome. Several patients have presented in the first days or months of life with hypoglycemic seizures secondary to hyperinsulinism. Other patients have presented after one year of age with acute onset of vomiting, lethargy and hyponatremic seizures. One patient has presented at 16 years of age with recurrent episodes of hypoketotic hypoglycemia, myoglobinuria, encephalopathy and cardiomyopathy.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Trifunctional Protein Deficiency
Mitochondrial Trifunctional Protein (TFP) Deficiency is a defect in mitochondrial fatty acid ß-oxidation. Three enzyme activities that act sequentially in the oxidation of fatty acids reside together on the TFP enzyme complex located on the inner mitochondrial membrane. The enzymes are Long-Chain-2-Enoyl-CoA Hydratase, Long-Chain HydroxyAcyl-CoA Dehydrogenase (LCHAD), and ß-KetoAcyl-CoA Thiolase. The TFP complex consists of two different protein subunits (a and ß) coded for by two nuclear genes. The TFP complex has specificity toward fatty acids of ten carbons (C10) or longer.

Diverse clinical presentations have been reported in patients having TFP Deficiency. The usual presentation is in infancy and follows a period of fasting associated with a minor illness. Patients develop non-ketotic hypoglycemia, hypotonia, and lactic acidemia. Areflexia and cardiomyopathy is often found on physical exam, and sudden death can occur. Patients may have elevated CK levels and even rhabdomyolysis, and a few have had hyperammonemia. Low carnitine levels have been measured in serum and muscle. Hepatic steatosis is found at biopsy. Many of these patients succumb to severe muscular hypotonia with respiratory distress.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) is a disorder of ß-oxidation of fatty acids. The enzymatic deficiency is one of four mitochondrial acyl-CoA dehydrogenases that carries out the initial dehydrogenation step in the ß-oxidation of fatty acids. VLCAD deficiency impairs oxidation of dietary and endogenous fatty acids of long chain length (16 carbons and longer). The buildup of the long chain fatty acid acyl-CoA intermediates results in toxic effects to normal metabolism. The gene is on chromosome 17 and encodes a protein that functions on the inner mitochondrial membrane.

Two general presentations have been reported with VLCAD deficiency, although both can vary considerably. Infants can present with severe, sepsis-like symptoms resembling a Reye-like syndrome, which is often lethal. The patient may be hypoglycemic with fasting and have metabolic acidosis, elevated liver enzymes with hepatomegaly (due to steatosis), cholestasis, hypertrophic cardiomyopathy, proteinuria, and hematuria. A second presentation has later onset and exhibits lethargy and coma with fasting. These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.