GENETIC LIPID DISORDERS

Sitosterolemia is a rare inherited condition in which plant sterols accumulate in the blood and tissues. Plant sterols, including sitosterol, stigmasterol, and campesterol, are fatty substances found in vegetable oils and nuts. Individuals with sitosterolemia have extremely high levels of sitosterol (30 to 100 times higher than normal), along with mildly to moderately elevated levels of cholesterol in their blood. These plant sterols and cholesterol build up in the arteries, leading to premature thickening of the artery walls and early heart disease. Affected individuals may also develop small yellowish growths called xanthomas on or under the skin and in the tendons. Sitosterolemia is caused by mutations in the ABCG5 or ABCG8 gene. The condition is inherited in an autosomal recessive pattern. Treatment involves restricting foods that are high in plant and shellfish sterols, and taking medications that decrease the concentration of these products in the blood. Sitosterolemia is diagnosed by measuring the levels of plant sterols in the blood, including sitosterol, campesterol, and stigmasterol. Normal cholesterol studies will not diagnosed sitosterolemia because they cannot distinguish among the different sterols. DNA analysis of the ABCG5 and ABCG8 genes can be helpful in detecting mutations and confirming the diagnosis.

Chylomicronemia syndrome is a disorder in which the body does not break down fats (lipids) correctly. This causes fat particles called chylomicrons to build up in the blood. The disorder is passed down through families. Chylomicronemia syndrome can occur due to a rare genetic disorder in which a protein (enzyme) called lipoprotein lipase (LpL) is broken or missing. It can also be caused by the absence of second factor called apo C-II, which activates LpL. LpL is normally found in fat and muscle. It helps break down certain lipids. When LpL is missing or broken, fat particles called chylomicrons build up in the blood. This buildup is called chylomicronemia. Defects in apolipoprotein CII and apolipoprotein AV can cause the syndrome as well. It is more likely to occur when people who are predisposed to have high triglycerides (such as those who have familial combined hyperlipidemia or familial hypertriglyceridemia) develop diabetes, obesity or are exposed to certain medicines.

Familial hypertriglyceridemia (type IV familial dyslipidemia) is a disorder characterized by the overproduction of very-low-density lipoproteins (VLDL) from the liver. As a result, the patient will have an excessive number of triglycerides and VLDL on the lipid profile. This disorder typically follows an autosomal dominant inheritance pattern. Clinically, familial hypertriglyceridemia presents in patients with mild to moderate elevations in lab triglyceride concentration. Familial hypertriglyceridemia is typically accompanied by other co-morbidities: obesity, hyperglycemia, and hypertension. Patients with this disorder are often heterozygous for inactivating mutations of the lipoprotein lipase (LPL) gene. While this mutation can alone raise triglyceride levels significantly, the combination of other medications or pathology can further increase serum triglyceride levels to pathologic levels. Significant increases in triglycerides levels can lead to the development of clinical signs and acute pancreatitis.

Two triglyceride disorders, familial combined hyperlipidemia and familial hypertriglyceridemia, are genetically controlled, but the mechanisms are not clearly defined but are likely associated with overproduction and decreased of apo B–containing particles. Familial combined hyperlipidemia is an autosomal dominant disorder characterized by patients and their first-degree relatives who may have either isolated triglyceride or low-density lipoprotein (LDL) cholesterol elevations or both. Diagnosis of the disorder in a particular patient requires a family history of premature coronary artery disease (CAD) in 1 or more first-degree relatives and a family history for elevated triglycerides with or without elevated LDL cholesterol levels. The diagnosis is important for prognosis; 14% of patients with premature CAD have familial combined hyperlipidemia. Familial hypertriglyceridemia is also an autosomal dominant trait. These patients and their families have isolated triglyceride elevations and may have an increased risk of premature CAD.

Hyperlipoproteinemia type III is a genetic disorder that causes the body to breakdown (metabolize) fats (lipids) incorrectly. This results in the buildup of lipids in the body (hyperlipidemia) and can lead to the development of multiple small, yellow skin growths (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (atherosclerosis) blocking blood flow and potentially leading to heart attack or stroke. Hyperlipoproteinemia type III affects 1-5,000 to 1 in 10,000 people in the general population. Without treatment, affected individuals are 5-10 times more likely to develop cardiovascular disease.

Familial hypercholesterolemia (FH) is a genetic condition that causes high low-density lipoprotein (LDL) cholesterol (sometimes referred to as bad cholesterol) from birth. FH means high cholesterol that runs in a family. FH is caused by specific DNA changes that are passed on from parents to their children. It is not caused by lifestyle factors such as a high-fat diet or lack of exercise. There are 2 main types of FH, homozygous and heterozygous, that have different symptoms, risks, and treatments. FH is inherited and passed down through families. When one individual with FH is diagnosed, it is important that all family members are screened for FH. Treatment should begin early. Although lifestyle and diet are important factors to staying heart healthy, for individuals with FH, that is not enough. Like many other genetic conditions, FH is inherited. Each child of a person with FH has a 50% chance of inheriting the disorder so it is essential to screen parents, siblings and children of a person diagnosed with FH to find others who may have inherited the genes. At present, most people with FH have variants in one of three genes: LDLR gene, APOB gene, and PCSK9 gene. To date, there are over 2,000 known variants for FH. How many mutations you inherit affects the type of FH you may have. One Inherited Mutation – Called Heterozygous Familial Hypercholesterolemia (HeFH), one abnormal mutation is passed down to a child, typically from one parent. Two Inherited Mutations - When the mutation for HeFH is passed on from both parents to their children this can result in Homozygous Familial Hypercholesterolemia (HoFH), the more rare and severe form of FH.

Apo A1 (FHA, Milano) Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels ABCA1 (Tangier’s Disease) Tangier disease is a rare inherited disorder characterized by significantly reduced levels of high-density lipoproteins (HDL) in the blood. HDL-cholesterol (HDL-C) is often referred to as the “good cholesterol” as it can facilitate the removal of cholesterol out of the walls of arteries, particularly the coronary (heart) arteries. Classic features of Tangier disease include fatty accumulations that present as enlarged and yellow- or orange-colored tonsils, or enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes. Tangier disease may also be associated with an increased risk of cardiovascular disease, moderate elevation in triglycerides (hypertriglyceridemia), nerve disturbances (neuropathy), and rarely an opaqueness in the covering of the eye (corneal clouding). This disorder was originally named after the location in which it was first discovered - Tangier Island in the Chesapeake Bay. Later, the disease was further characterized as more individuals were found to have the disease in other areas of the United States and around the globe. LCAT Deficiency and Fish Eye Disease Familial LCAT deficiency is a genetic disorder that affects the body's ability to process (metabolize) cholesterol. It is characterized by cloudiness of the clear front surface of the eye (corneal opacities), a shortage of red blood cells (hemolytic anemia), and kidney failure. Symptoms usually appear in adulthood and may also include enlargement of the liver (hepatomegaly), spleen (splenomegaly), and lymph nodes (lymphadenopathy), as well as an accumulation of fat in the artery walls (atherosclerosis). Familial LCAT deficiency is one of two types of LCAT deficiency; the other type of LCAT deficiency is fish-eye disease. Both types of LCAT deficiency are caused by mutations in the LCAT gene and are inherited in an autosomal recessive manner. Although there is no specific treatment or cure for familial LCAT deficiency, there may be ways to manage the symptoms. A team of specialists is often needed to figure out the treatment options for each person.

CTEP Deficiency This asymptomatic, hereditary syndrome is caused by low CETP levels. Decreased CETP activity slows the transport of cholesteryl esters from HDL to apo B–containing lipoproteins. The condition is frequently observed in Japanese Americans. Clinical features include marked elevations of plasma HDL cholesterol in homozygotes (usually >100 mg/dL) and probably lower rates of CHD. In heterozygotes, the HDL levels are only moderately elevated. CETP deficiency has not yet been demonstrated to be associated with a decreased risk for atherosclerotic cardiovascular disease, and some experts do not consider this condition protective against cardiovascular disease.

Familial hypobetalipoproteinemia (FHBL) is a disorder that impairs the body's ability to absorb and transport fats. This condition is characterized by low levels of cholesterol The severity of signs and symptoms experienced by people with FHBL vary widely. The most mildly affected individuals have few problems with absorbing fats from the diet and no related signs and symptoms. Many individuals with FHBL develop an abnormal buildup of fats in the liver called hepatic steatosis or fatty liver. In more severely affected individuals, fatty liver may progress to chronic liver disease (cirrhosis). Individuals with severe FHBL have greater difficulty absorbing fats as well as fat-soluble vitamins such as vitamin E and vitamin A. This difficulty in fat absorption leads to excess fat in the feces (steatorrhea). In childhood, these digestive problems can result in an inability to grow or gain weight at the expected rate (failure to thrive).

Abetalipoproteinemia is a rare inherited disorder affecting fat absorption by the intestine and mobilization by the liver. Inability to absorb fat results in deficiencies of lipids and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking, and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited as an autosomal recessive trait and is caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene.

Elevated serum lipoprotein(a), also referred to as Lp(a), is a risk factor for atherosclerotic cardiovascular disease (ASCVD). There is a causal relationship between Lp(a) excess and the development of ASCVD and aortic valve stenosis. Serum Lp(a) levels are genetically determined. In families of European descent without familial hypercholesterolemia, greater than 90 percent of the variability in Lp(a) levels can be explained by polymorphisms at the apo(a) gene locus (isoforms), also referred to as the LPA gene (Online Mendelian Inheritance in Man [OMIM] 152200). One important LPA polymorphism is the kringle IV type 2 size polymorphism, which results in a large number of differently sized isoforms of apo(a). There is a strong inverse relationship between the size of the apo(a) isoforms and the Lp(a) concentrations. A significant proportion (30 to 60 percent) of the population variation in Lp(a) levels is determined by this polymorphism. The distribution of serum Lp(a) concentrations is highly skewed toward lower values among most racial/ethnic groups; however, Black Americans, Africans, and Asian Indians have a more normal distribution, centered at a higher mean Lp(a) level.