Disorders We Support

Patient resource website: https://creatineinfo.org/ccds-overview/

VLCADD Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is transmitted in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. In the past, the name long-chain acyl-CoA dehydrogenase deficiency (LCADD) was applied to one such disease, but today it is clear that all cases once thought to be LCADD are actually VLCADD.

The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined structures that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation).

Classically, two forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, can lead to extreme weakness of the heart muscles (cardiomyopathy) and be life-threatening, and a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia). In reality, patients can present with a combination of symptoms and the disease is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected neonatal period.

MCADD
Medium chain acyl-coA dehydrogenase deficiency (MCADD) is a genetic disorder caused by a lower than normal level of the medium chain acyl-coenzyme A dehydrogenase enzyme. This enzyme is involved in breaking down fat stores in the body to be used for energy. Symptoms of this disorder generally develop between 1 and 24 months of age, although they can sometimes first appear in adulthood. Individuals with MCADD experience symptoms of metabolic crisis due to low blood sugar (hypoglycemia) after periods of prolonged fasting or in response to a common illness. These may include weakness, vomiting, and seizures. Rarely, coma or sudden death may occur. MCADD is inherited as autosomal recessive genetic condition.

MCADD is usually diagnosed through newborn screening. An early diagnosis of this disorder is important in order to be able to prevent symptoms from occurring. Treatment involves avoiding long periods of fasting and restricting fat intake. MCADD is a known cause of sudden infant death syndrome (SIDS).

SCADD
Short chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive genetic defect in fatty acid catabolism belonging to a group of diseases known as fatty acid oxidation disorders (FOD). It occurs because of a deficiency of the short-chain acyl-CoA dehydrogenase (SCAD) enzyme.

Although SCADD was initially thought to produce severe problems including progressive muscle weakness, hypotonia, acidemia, developmental delay, and even early death, it is now believed that this deficiency has no clinical relevance. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, many more SCADD infants are being detected, all of whom are asymptomatic. When symptoms are present, additional diagnostic testing for another condition should be performed as the association is likely coincidental rather than causative.

• Glutaric Acidemia Type II (GA-II)
• Carnitine Uptake Deficiency (CUD)

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Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert galactose (a sugar contained in milk, including human mother’s milk) to glucose (a different type of sugar). The disorder is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process. Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health problems unless treatment is started shortly after birth. A biochemical variant form of galactosemia termed Duarte is not thought to cause clinical disease due to lactose consumption.

• Disorders of Fructose Metabolism
• Congenital Sucrase-Isomaltase Deficiency

Glutaric aciduria type I (GA1) is a rare hereditary metabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). It is in the group of disorders known as cerebral organic acidemias. Individuals with this condition have deficiency or absence of GCDH enzyme that is involved in the lysine metabolism. GCDH deficiency results in increased concentrations of potentially neurotoxic metabolites, glutaric acid (GA), 3-hydroxy glutaric acid (3-OH-GA) and glutaconic acid within body tissues, especially within the brain. Two arbitrary biochemical subtypes have been defined, high (HE) and low excretors (LE), depending on the amount of GA in the urine. Newborns may show unspecific clinical signs like enlarged head circumference (macrocephaly) or decreased muscle tone (hypotonia). Without treatment, most affected children develop an acute encephalopathic crisis following febrile illness episodes or other catabolic conditions resulting in bilateral striatal injury and consequently, dystonic movement disorder. Cognitive outcome has not been systematically studied, but severe cognitive dysfunction is rarely seen. Sometimes babies with GA1 have been mistaken to have been abused because they present with subdural and/or retinal hemorrhages. GA1 is included in the newborn screening panel in a growing number of countries which is essential for early intervention. Importantly, patients with the low excreting phenotype may be missed by newborn screening.

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Glycogen storage disease type I (also known as GSDI or von Gierke disease) is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body’s cells. The accumulation of glycogen in certain organs and tissues, especially the liver, kidneys, and small intestines, impairs their ability to function normally. Signs and symptoms of this condition typically appear around the age of 3 or 4 months, when babies start to sleep through the night and do not eat as frequently as newborns. Affected infants may have low blood sugar (hypoglycemia), which can lead to seizures. They can also have a buildup of lactic acid in the body (lactic acidosis), high blood levels of a waste product called uric acid (hyperuricemia), and excess amounts of fats in the blood (hyperlipidemia). As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin (xanthomas). People with GSDI may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals may have thinning of the bones (osteoporosis), a form of arthritis resulting from uric acid crystals in the joints (gout), kidney disease, and high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension). Females with this condition may also have abnormal development of the ovaries (polycystic ovaries). In affected teens and adults, tumors called adenomas may form in the liver. Adenomas are usually noncancerous (benign), but occasionally these tumors can become cancerous (malignant). Researchers have described two types of GSDI, which differ in their signs and symptoms and genetic cause. These types are known as glycogen storage disease type Ia (GSDIa) and glycogen storage disease type Ib (GSDIb). Two other forms of GSDI have been described, and they were originally named types Ic and Id. However, these types are now known to be variations of GSDIb; for this reason, GSDIb is sometimes called GSD type I non-a. Many people with GSDIb have a shortage of white blood cells (neutropenia), which can make them prone to recurrent bacterial infections. Neutropenia is usually apparent by age 1. Many affected individuals also have inflammation of the intestinal walls (inflammatory bowel disease). People with GSDIb may have oral problems including cavities, inflammation of the gums (gingivitis), chronic gum (periodontal) disease, abnormal tooth development, and open sores (ulcers) in the mouth. The neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa.

Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems. Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The signs and symptoms of homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.

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Isovaleric acidemia (IVA) is a type of organic acid disorder in which affected individuals have problems breaking down an amino acid called leucine from the food they eat. Signs and symptoms may range from very mild to life-threatening. In severe cases, symptoms begin within a few days of birth and include poor feeding, vomiting, seizures, and lack of energy (lethargy); these may progress to more serious medical problems including seizures, coma, and possibly death. In other cases, signs and symptoms appear during childhood and may come and go over time. A characteristic sign of IVA is a distinctive odor of sweaty feet during acute illness. Other features may include failure to thrive or delayed development. IVA is caused by mutations in the IVD gene and is inherited in an autosomal recessive manner. Treatment involves moderate restriction of proteins in the diet and oral administration of glycine and L-carnitine which helps to rid the body of excess isovaleric acid.

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Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is required to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all three BCAAs, along with a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life. The presentation starts with non-specific symptoms of increasing neurological dysfunction and include lethargy, irritability and poor feeding, soon followed by focal neurological signs such as abnormal movements, increasing spasticity, and shortly thereafter, by seizures and deepening coma. If untreated, progressive brain damage is inevitable and death occurs usually within weeks or months. The only specific finding that is unique to MSUD is the development of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched-chain ketoacids (BCKAs). The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled. However, even with treatment, patients of any age with MSUD remain at high risk for developing acute metabolic decompensation (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden rise in amino acid levels necessitating immediate medical intervention. There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset. All forms are inherited in an autosomal recessive pattern.

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Methylmalonic acidemia is an inherited condition in which the body is unable to process certain proteins and fats properly. Signs and symptoms usually appear in early infancy and vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, lethargy, hepatomegaly, and failure to thrive. Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and pancreatitis. Without treatment, this condition can lead to coma and death in some cases. Mutations in the MUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. It is inherited in an autosomal recessive fashion. Methylmalonic acidemia is treated with a low-protein, high-calorie diet, certain medications, antibiotics and, in some cases, organ transplantation.

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• 3-Methylcrotonyl CoA Carboxylase (3-MCC) Deficiency
• Beta-Ketothiolase Deficiency

Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life via routine newborn screening. PKU is characterized by absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH), responsible for processing the amino acid phenylalanine. Amino acids are the chemical building blocks of proteins, and are essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic to the brain. Without treatment, most people with PKU would develop severe intellectual disability. To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life. Tetrahydrobiopterin (BH4) Deficiency is another cause of hyperphenylalaninemia.

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Propionic acidemia is a rare metabolic disorder affecting from 1/20,000 to 1/250,000 individuals in various regions of the world. It is characterized by deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical “building blocks” (amino acids) of proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), dehydration and seizures. Without appropriate treatment, coma and death may result. Rarely, the condition may become apparent later in life and may be associated with less severe symptoms and findings. Propionic acidemia is inherited in an autosomal recessive pattern. Individuals with this condition have to follow a specific diet including a low protein intake and specific food formulas (medical foods). Liver transplant is a surgical option that can help decrease the frequency of acute metabolic episodes (decompensation).

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Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocarcinoma if left untreated. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed.

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Tyrosinemia type 2 is a genetic disorder in which individuals have elevated blood levels of the amino acid tyrosine, a building block of most proteins. This condition can affect the eyes, skin, and intellectual development. Symptoms of tyrosinemia type 2 often begin in early childhood and include excessive tearing, abnormal sensitivity to light (photophobia), eye pain and redness, and painful skin lesions on the palms and soles (palmoplantar hyperkeratosis). About 50 percent of individuals with this condition have an intellectual disability. Tyrosinemia type 2 is caused by a deficiency of the enzyme tyrosine aminotransferase, one of the enzymes required for the multi-step process that breaks down tyrosine. This enzyme shortage is caused by mutations in the TAT gene. This condition is inherited in an autosomal recessive manner. There is no cure for this condition; however, some of the symptoms may be managed with a diet that limits certain amino acids, such as phenylalanine and tyrosine. A medication called NTBC may also be used to help control the amount of tyrosine in the body.

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Tyrosinemia type 3 is a genetic disorder characterized by elevated blood levels of the amino acid tyrosine, a building block of most proteins. This condition is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase, one of the enzymes required for the multi-step process that breaks down tyrosine. This enzyme shortage is caused by mutations in the HPD gene. Characteristic features include intellectual disability, seizures, and periodic loss of balance and coordination (intermittent ataxia). Tyrosinemia type 3 is inherited in an autosomal recessive manner.

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A urea cycle disorder is a genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is changed to a compound called urea and removed from the blood. Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death. The onset and severity of urea cycle disorders is highly variable. The severity correlates with the amount of urea cycle enzyme function.

• Citrin Deficiency (also called Citrullinemia type II)

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