Lynch Syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is characterised by a risk of colorectal cancer and other cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. HNPCC is subdivided into Lynch Syndrome I (familial colon cancer) and Lynch Syndrome II (other cancer of the gastrointestinal system or the reproductive system). The increased risk for these cancers is due to inherited mutations that degrade the self-repair capability of DNA.

Colon Cancer


Genes are related to Lynch syndrome

Variations in the MLH1, MSH2, MSH6, and PMS2 genes increase the risk of developing Lynch syndrome. All of these genes are involved in the repair of mistakes made when DNA is copied (DNA replication) in preparation for cell division. Mutations in any of these genes prevent the proper repair of DNA replication mistakes. As the abnormal cells continue to divide, the accumulated mistakes can lead to uncontrolled cell growth and possibly cancer. Although mutations in these genes predispose individuals to cancer, not all people who carry these mutations develop cancerous tumors.

Lynch syndrome cancer risk is inherited in an autosomal dominant pattern, which means one inherited copy of the altered gene in each cell is sufficient to increase cancer risk. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop cancer.

Mitochondrial Trifunctional Protein Deficiency

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food . People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to break down (metabolize) fats and convert them to energy. People with mitochondrial trifunctional protein deficiency have inadequate levels of an enzyme required for three steps that metabolize a group of fats called long-chain fatty acids.Onset of mitochondrial trifunctional protein deficiency may begin during infancy or later in life. Signs and symptoms that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), muscle weakness (hypotonia), and liver problems. Infants with this disorder are also at high risk for complications such as life-threatening heart and breathing problems, coma, and sudden unexpected death. Characteristic features of mitochondrial trifunctional protein deficiency that begins after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and abnormalities in the nervous system that affect arms and legs (peripheral neuropathy).

Genes related to Definency

Mutations in the HADHA and HADHB genes cause mitochondrial trifunctional protein deficiency.

Mutations can lead to inadequate levels of an enzyme complex known as mitochondrial trifunctional protein. Long-chain fatty acids from food and body fat cannot be metabolized and processed without sufficient levels of this enzyme complex. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.

LCHAD Deficiency

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to break down (metabolize) fats and convert them to energy. People with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme required for a step that metabolizes a group of fats called long-chain fatty acids.

Typically, initial signs and symptoms of this disorder occur during infancy or early childhood and can include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), muscle weakness (hypotonia), liver problems, and abnormalities in the part of the eye that detects light and color (the retina). Muscle pain, breakdown of muscle tissue, and abnormalities in the nervous system that affect arms and legs (peripheral neuropathy) may occur later in childhood. Individuals with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are also at risk for complications such as life-threatening heart and breathing problems, coma, and sudden unexpected death.

Problems related to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop 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.


Causes

Mutations in the HADHA gene cause long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

Mutations in the HADHA gene lead to inadequate levels of an enzyme called long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase, which is part of a protein complex known as mitochondrial trifunctional protein. Long-chain fatty acids from food and body fat cannot be metabolized and processed without sufficient levels of this enzyme. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, retina, and muscles, causing more serious complications.

Alport Syndrome

Alport syndrome is a genetic disorder characterized by glomerulonephritis, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes. The presence of blood in the urine (hematuria) is almost always found in this condition.

Symptoms

The disorder damages the tiny blood vessels in the kidneys, called glomeruli, that filter wastes.

At first, there are no symptoms. Then the progressive destruction of the glomeruli leads to blood in the urine and decreases the effectiveness of the kidney's filtering system. There is a progressive loss of kidney function and a build-up of fluids and wastes in the body.

In women, the disorder is usually mild, with minimal or no symptoms. In men, the symptoms are more severe and get worse faster.

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen bio synthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, and eye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein into the urine. The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a progressive disorder characterized by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Hypertension occurs when most of the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, pressure increases in the pulmonary artery and in the heart chamber that pumps blood into the pulmonary artery (the right ventricle).

Signs and symptoms of pulmonary arterial hypertension occur when increased pressure cannot fully overcome the elevated resistance and blood flow to the body is insufficient. Shortness of breath (dyspnea) during exertion and fainting spells are the most common symptoms of pulmonary arterial hypertension. People with this disorder may experience additional symptoms, particularly as the condition worsens. Other symptoms include dizziness, swelling (edema) of the ankles or legs, chest pain, and a racing pulse.

Genes are related to Pulmonary Arterial Hypertension

Mutations in the BMPR2 gene cause pulmonary arterial hypertension.The BMPR2 gene plays a role in regulating the number of cells in certain tissues. Researchers suggest that a mutation in this gene promotes cell division or prevents cell death, resulting in an overgrowth of cells in small arteries throughout the lungs. As a result, these arteries narrow in diameter, which increases the resistance to blood flow. Blood pressure in the pulmonary artery and the right ventricle of the heart increases to overcome the increased resistance to blood flow.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive disease that affects motor neurons, which are specialized nerve cells in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons are important for controlling muscle movement and strength. Most people with amyotrophic lateral sclerosis have a form of the condition that is described as sporadic or noninherited. The cause of sporadic amyotrophic lateral sclerosis is largely unknown but probably involves a combination of genetic and environmental factors. About 10 percent of people with amyotrophic lateral sclerosis have a familial form of the condition, which is caused by an inherited genetic mutation.

The first signs and symptoms of amyotrophic lateral sclerosis may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Speech may become slurred, and later there is difficulty chewing or swallowing. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue is lost (atrophies). Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with amyotrophic lateral sclerosis die from respiratory failure.

Different types of familial amyotrophic lateral sclerosis are distinguished by genetic cause, age when symptoms begin, and disease progression. Researchers have identified genetic mutations that cause amyotrophic lateral sclerosis types 1, 2, 4, and 8. Onset of symptoms in adulthood is characteristic of types 1 and 8. Symptoms of type 1 usually begin between ages 40 and 60. Depending on the genetic mutation involved, the condition may progress slowly or rapidly. Symptoms of type 8 amyotrophic lateral sclerosis begin earlier than type 1 (usually between ages 25 and 44) but progress slowly over several years to several decades. Early onset of symptoms is characteristic of amyotrophic lateral sclerosis types 2 and 4. Type 2 symptoms usually begin in early childhood or adolescence and slowly worsen for 10 to 15 years. Symptoms of type 4 amyotrophic lateral sclerosis typically begin before age 25 and slowly progress over several decades.

Genes related to Amyotrophic lateral sclerosis

Mutations in the ALS2, SETX, SOD1, and VAPB genes cause amyotrophic lateral sclerosis.Variations of the ANG, DCTN1, NEFH, PRPH, SMN1, and SMN2 genes increase the risk of developing amyotrophic lateral sclerosis.

Each type of familial amyotrophic lateral sclerosis is caused by mutations in a specific gene. Type 1 is caused by mutations in the SOD1 gene, type 2 by ALS2 mutations, type 4 by mutations in the SETX gene, and type 8 by VAPB mutations. It is unclear how mutations in these genes contribute to the death of motor neurons, which leads to muscle weakness and atrophy. Research findings suggest that these mutations lead to the production of toxic substances or clumps (aggregates) of misshapen proteins that accumulate and damage motor neurons. Another possible effect is the altered development of axons, the specialized extensions of nerve cells (such as motor neurons) that transmit nerve impulses. The altered axons may impair transmission of impulses from nerves to muscles, which leads to muscle weakness and atrophy. Other genes are thought to cause familial amyotrophic lateral sclerosis, but they have not been identified or fully characterized.

Mutations in the ANG, DCTN1, NEFH, or PRPH gene appear to increase the risk of developing amyotrophic lateral sclerosis. Research findings also suggest that a decrease in the number of SMN1 or SMN2 genes may lead to an increased chance of developing this disorder. It is unclear how variations in these genes lead to increased susceptibility.

About 90 percent of amyotrophic lateral sclerosis cases are sporadic and are not inherited.

Among the estimated 10 percent of familial cases of this disorder, the pattern of inheritance varies with the type of amyotrophic lateral sclerosis. Type 2 amyotrophic lateral sclerosis is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Amyotrophic lateral sclerosis types 1, 4, and 8 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Studies in Sweden and Finland revealed a small number of type 1 cases that are inherited in an autosomal recessive pattern.

Alstrom Syndrome

Alström syndrome is a rare condition that affects many body systems. Many of the signs and symptoms of this condition begin in infancy or early childhood, although some appear later in life.

Alström syndrome is characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), obesity, type 2 diabetes mellitus (the most common form of diabetes), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs. Some individuals with Alström syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick, dark, and velvety. The signs and symptoms of Alström syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder.

This condition is very rare; about 500 affected people have been reported worldwide.

Genes Related to Disorder

Mutations in the ALMS1 gene cause Alström syndrome. The ALMS1 gene provides instructions for making a protein whose function is unknown. Mutations in this gene probably lead to the production of an abnormally short, nonfunctional version of the ALMS1 protein. This protein is normally present at low levels in most tissues, so a loss of the protein's normal function may help explain why the signs and symptoms of Alström syndrome affect many parts of the body.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Primary Hyperoxaluria

Primary hyperoxaluria is a rare condition characterized by the overproduction of a substance called oxalate (also called oxalic acid). In the kidneys, the excess oxalate combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney stones. Deposits of calcium oxalate can lead to kidney damage, kidney failure, and injury to other organs.

Primary hyperoxaluria is caused by the shortage (deficiency) of an enzyme that normally prevents the buildup of oxalate. There are two types of primary hyperoxaluria, distinguished by the enzyme that is deficient. People with type 1 primary hyperoxaluria have a shortage of a liver enzyme called alanine-glyoxylate aminotransferase (AGXT). Type 2 primary hyperoxaluria is characterized by a shortage of an enzyme called glyoxylate reductase/hydroxypyruvate reductase (GRHPR).

Type 1 primary hyperoxaluria is estimated to occur in 1 to 3 per million people; it is more common in some Mediterranean countries, such as Tunisia. Although the incidence of type 2 primary hyperoxaluria is unknown, it is less common than type 1.

Genes Related to Disorder

Mutations in the AGXT and GRHPR genes cause primary hyperoxaluria.The breakdown and processing of certain sugars and protein building blocks (amino acids) produces a substance called glyoxylate. Normally, glyoxylate is converted to the amino acid glycine or to a compound called glycolate through the action of two enzymes, alanine-glyoxylate aminotransferase and glyoxylate reductase/hydroxypyruvate reductase, respectively. Mutations in the AGXT or GRHPR gene cause a shortage of these enzymes, which prevents the conversion of glyoxylate to glycine or glycolate. As levels of glyoxylate build up, it is converted to oxalate. Oxalate combines with calcium to form calcium oxalate deposits, which can damage the kidneys and other organs.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.