DIAMOND-BLACKFAN ANEMIA

Diamond-Blackfan anemia is a disorder of the bone marrow. The major function of bone marrow is to produce new blood cells. In Diamond-Blackfan anemia, the bone marrow malfunctions and fails to make enough red blood cells, which carry oxygen to the body's tissues. The resulting shortage of red blood cells (anemia) usually becomes apparent during the first year of life. Symptoms of anemia include fatigue, weakness, and an abnormally pale appearance (pallor). They may have an unusually small head size (microcephaly) and a low frontal hairline, along with distinctive facial features such as wide-set eyes (hypertelorism); droopy eyelids (ptosis); a broad, flat bridge of the nose; small, low-set ears; and a small lower jaw (micrognathia). Affected individuals may also have an opening in the roof of the mouth (cleft palate) with or without a split in the upper lip (cleft lip). They may have a short, webbed neck; shoulder blades which are smaller and higher than usual; and abnormalities of their hands, most commonly malformed or absent thumbs. About one-third of affected individuals have slow growth leading to short stature.

GENETIC FACTOR
Diamond-Blackfan anemia can be caused by mutations in the RPL5, RPL11, RPL35A, RPS7, RPS10,RPS17, RPS19, RPS24, and RPS26 genes. These genes provide instructions for making several of the approximately 80 different ribosomal proteins, which are components of cellular structures called ribosomes. Ribosomes process the cell's genetic instructions to create proteins. The specific functions of each ribosomal protein within these subunits are unclear. Some ribosomal proteins are involved in the assembly or stability of ribosomes. Others help carry out the ribosome's main function of building new proteins. Studies suggest that some ribosomal proteins may have other functions, such as participating in chemical signaling pathways within the cell, regulating cell division, and controlling the self-destruction of cells (apoptosis).

EPIDEMIOLOGY
Diamond-Blackfan anemia affects approximately 5 to 7 per million liveborn infants worldwide.

DIAGNOSTIC PROCEDURE
The diagnosis is based on the presence of: normochromic (usually macrocytic) anemia, reticulocytopenia, normal or slightly decreased leukocyte counts, normal or increased platelet counts, and normocellular bone marrow with selective deficiency of red cell precursors. Other genetic forms of anemia, such as Fanconi anemia, need to be considered and ruled out as appropriate. DBA has been associated with mutations in ten genes that encode ribosomal proteins and in GATA1. A mutation in one of these eleven genes is identified in approximately 55% of individuals with DBA. References:
http://ghr.nlm.nih.gov/condition/diamond-blackfan-anemia http://www.ncbi.nlm.nih.gov/books/NBK7047/ http://fiveminutehealthtip.com/wp-content/uploads/2012/12/diamond-blackfan-anemia.jpeg

Stargardt macular degeneration

Stargardt macular degeneration is a genetic eye disorder that causes progressive vision loss. This disorder affects the retina, the specialized light-sensitive tissue that lines the back of the eye. Specifically, Stargardt macular degeneration affects a small area near the center of the retina called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. In most people with Stargardt macular degeneration, a fatty yellow pigment (lipofuscin) builds up in cells underlying the macula. Over time, the abnormal accumulation of this substance can damage cells that are critical for clear central vision. In addition to central vision loss, people with Stargardt macular degeneration have problems with night vision that can make it difficult to navigate in low light. Some affected individuals also have impaired color vision.

GENETIC FACTOR
In most cases, Stargardt macular degeneration is caused by mutations in the ABCA4 gene. Less often, mutations in the ELOVL4 gene cause this condition. The ABCA4 and ELOVL4 genes provide instructions for making proteins that are found in light-sensing (photoreceptor) cells in the retina. The ELOVL4 protein plays a role in making a group of fats called very long-chain fatty acids. The ELOVL4 protein is primarily active (expressed) in the retina, but is also expressed in the brain and skin. The function of very long-chain fatty acids within the retina is unknown. Mutations in the ELOVL4 gene lead to the formation of ELOVL4 protein clumps (aggregates) that build up and may interfere with retinal cell functions, ultimately leading to cell death.

EPIDEMIOLOGY
Stargardt macular degeneration is the most common form of juvenile macular degeneration, the signs and symptoms of which begin in childhood. The estimated prevalence of Stargardt macular degeneration is 1 in 8,000 to 10,000 individuals.

DIAGNOSTIC PROCEDURE

CABCA4-related Stargardt's Disease Methods: C Sequence analysis of the entire coding region Analytical Validity: 100% accurate. Lab: Ophthalmic Molecular Diagnostic Laboratory University of California-San Diego Directors: Radha Ayyagari, PhD, Lab Director CStargardt Disease, Cone-Rod Dystrophy Methods: C Sequence analysis of the entire coding region, T Targeted variant analysis Analytical Validity: APEX based test enables to detect up to 54-78% disease associated mutations. Lab: Asper Biotech Asper Biotech Ltd. Directors: Kairit Joost, PhD, MD, Lab Director CCNGB3-Related Stargardt Disease 1 Methods: C Sequence analysis of the entire coding region Analytical Validity: The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed. Lab: Labor-MVZ Westmecklenburg Laboratory for Molecular Diagnostics Directors: Hans-Otto Schmudlach, Lab Director CABCA4-Related Stargardt Disease 1 Methods: D Deletion/duplication analysis, C Sequence analysis of the entire coding region Analytical Validity: Analytical sensitivity is greater than 96%. Lab: Labor-MVZ Westmecklenburg Laboratory for Molecular Diagnostics Directors: Hans-Otto Schmudlach, Lab Director

References:
http://www.ncbi.nlm.nih.gov/gtr/tests/?term=C1855465[DISCUI]&test_type=Clinical&display_ string=Stargardt%20disease%201&condition=C1855465 http://ghr.nlm.nih.gov/condition/stargardt-macular-degeneration

Lafora progressive myoclonus epilepsy

Lafora progressive myoclonus epilepsy is a brain disorder characterized by recurrent seizures (epilepsy) and a decline in intellectual function. The signs and symptoms of the disorder usually appear in late childhood or adolescence and worsen with time. Myoclonus is a term used to describe episodes of sudden, involuntary muscle jerking or twitching that can affect part of the body or the entire body. Myoclonus can occur when an affected person is at rest, and it is made worse by motion, excitement, or flashing light (photic stimulation). In the later stages of Lafora progressive myoclonus epilepsy, myoclonus often occurs continuously and affects the entire body.

GENETIC FACTOR
Lafora progressive myoclonus epilepsy can be caused by mutations in either the EPM2A gene or theNHLRC1 gene. These genes provide instructions for making proteins called laforin and malin, respectively. Laforin and malin play a critical role in the survival of nerve cells (neurons) in the brain. Studies suggest that laforin and malin work together and may have several functions. One of these is to help regulate the production of a complex sugar called glycogen, which is a major source of stored energy in the body. The body stores this sugar in the liver and muscles, breaking it down when it is needed for fuel. Laforin and malin may prevent a potentially damaging buildup of glycogen in tissues that do not normally store this molecule, such as those of the nervous system.

EPIDEMIOLIOGY
The prevalence of Lafora progressive myoclonus epilepsy is unknown. Although the condition occurs worldwide, it appears to be most common in Mediterranean countries (including Spain, France, and Italy), parts of Central Asia, India, Pakistan, North Africa, and the Middle East.

DIAGNOSTIC PROCEDURE
The diagnosis of Lafora disease (LD) is suspected in a previously healthy older child or adolescent (usually in the early teens) who has the following:

Fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures Visual hallucinations (occipital seizures) Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia Slowing of background activity, loss of -rhythm and sleep features, and photosensitivity on early EEGs Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy Normal MRI of the brain at onset

Table 1. Clinical Evaluation of Lafora Disease

Evaluation Type General physical examination, including liver and spleen sizes Neurologic examination, including fundi and reflexes

At Onset

Later in Disease Course

Normal

Normal

Normal

Dysarthria, ataxia, spasticity; fundi remain normal

Mental state examination

Visual hallucinations (epileptic), depressed mood, cognitive deficits

Increased hallucinations, agitation, and dementia with predominantly frontal cognitive impairment affecting mainly performance ability and executive function

EEG

Normal or slow background, loss of rhythm and sleep features; photosensitivity is common

Slow background, paroxysms of generalized irregular spike-wave discharges with occipital predominance, and focal, especially occipital, abnormalities

Visual, somatosensory, and auditory brain stem evoked potentials

High-voltage visual and somatosensory evoked potentials

Amplitudes may return to normal size; prolongation of brain stem and central latencies

Nerve conduction studies MRI of the brain

Normal

Normal Normal or atrophy 1 Reduced NAA/creatine ratio in frontal and occipital cortex, basal ganglia, and cerebellum; reduced NAA/myoinositol ratio in frontal grey and white matter; reduced NAA/choline ratio in cerebellum 2 Defective short intracortical inhibition(SICI): inhibition at ISI 6 ms and ISI 10 ms; Defective long interval cortical inhibition (LICI)

Normal

Proton MR spectroscopy of the brain

Data not available

Transcranial magnetic Not applicable stimulation (TMS)

1. No significant correlation observed with disease evolution 2. At least two years after onset of symptoms References: http://www.ncbi.nlm.nih.gov/books/NBK1389/ http://www.ncbi.nlm.nih.gov/gtr/conditions/C0751783/

Weissenbacher-Zweymller syndrome
Weissenbacher-Zweymller syndrome is a condition that affects bone growth. It is characterized by skeletal abnormalities, hearing loss, and distinctive facial features. This condition has features that are similar to those of another skeletal disorder, otospondylomegaepiphyseal dysplasia (OSMED). Infants born with WeissenbacherZweymller syndrome are smaller than average because the bones in their arms and legs are unusually short. The thigh and upper arm bones are shaped like dumbbells, and the bones of the spine (vertebrae) may also be abnormally shaped. High-tone hearing loss occurs in some cases. Distinctive facial features include wide-set protruding eyes, a small, upturned nose with a flat bridge, and a small lower jaw. Some affected infants are born with an opening in the roof of the mouth (a cleft palate).

GENETIC FACTOR
Mutations in the COL11A2 gene cause Weissenbacher-Zweymller syndrome. The COL11A2 gene is one of several genes that provide instructions for the production of type XI collagen. This type of collagen is important for the normal development of bones and other connective tissues that form the body's supportive framework. At least one mutation in the COL11A2 gene is known to cause Weissenbacher-Zweymller syndrome. This mutation disrupts the assembly of type XI collagen molecules, resulting in delayed bone development and the other features of this disorder.

EPIDEMIOLOGY
Weissenbacher-Zweymller syndrome is very rare; only a few families with the disorder have been reported worldwide.

DIAGNOSTIC PROCEDURE
Diagnosis of Weissenbacher-Zweymuller syndrome is usually made from physical examination by a medical geneticist and x rays of the legs, arms, and back. Careful charts of growth and development over time also help with diagnosis. Most characteristic of WZS is the gradual improvement in bone size, growth, and shape. Prenatal diagnosis of WZS is difficult, but can sometimes be made through a level II ultrasound examination of bone growth in the late second to third trimester of pregnancy. Genetic testing may be available through an amniocentesis procedure if the exact

mutations running in the family are known. In 2001, genetic testing is done on a research basis in most cases. One of the most important aspects in the diagnosis of WZS is ruling out other diagnoses. Conditions can be eliminated based on features that are not seen in WZS or are missing in other syndromes. For example, other conditions that look like WZS usually have progressively worsening symptoms instead of WZS's characteristic catch-up growth. Additionally, most conditions resembling WZS are inherited in an autosomal dominant pattern through the family. In an autosomal dominant condition, only one copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50/50 chance for each child to have the same or similar condition. References: http://health.yahoo.net/galecontent/weissenbacher-zweymuller-syndrome/2 http://ghr.nlm.nih.gov/condition/weissenbacher-zweymuller-syndrome

Sialidosis
Sialidosis is a severe inherited disorder that affects many organs and tissues, including the nervous system. This disorder is divided into two types, which are distinguished by the age at which symptoms appear and the severity of features. Sialidosis type I, also referred to as cherryred spot myoclonus syndrome, is the less severe form of this condition. People with type I develop signs and symptoms of sialidosis in their teens or twenties. Initially, affected individuals experience problems walking (gait disturbance) and/or a loss of sharp vision (reduced visual acuity). Individuals with sialidosis type I also experience muscle twitches (myoclonus), difficulty coordinating movements (ataxia), leg tremors, and seizures. The myoclonus worsens over time, causing difficulty sitting, standing, or walking. People with sialidosis type I eventually require wheelchair assistance. Affected individuals have progressive vision problems, including impaired color vision or night blindness. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Sialidosis type I does not affect intelligence or life expectancy. Sialidosis type II, the more severe type of the disorder, is further divided into congenital, infantile, and juvenile forms. The features of congenital sialidosis type II can develop before birth. This form of sialidosis is associated with an abnormal buildup of fluid in the abdominal cavity (ascites) or widespread swelling before birth caused by fluid accumulation (hydrops fetalis). Affected infants may also have an enlarged liver and spleen (hepatosplenomegaly), abnormal bone development (dysostosis multiplex), and distinctive facial features that are often described as "coarse." As a result of these serious health problems, individuals with congenital sialidosis type II usually are stillborn or die soon after birth. Infantile sialidosis type II shares some features with the congenital form, although the signs and symptoms are slightly less severe and begin within the first year of life. Features of the infantile form include hepatosplenomegaly, dysostosis multiplex, "coarse" facial features, short stature, and intellectual disability. As children with infantile sialidosis type II get older, they may develop myoclonus and cherry-red spots. Other signs and symptoms include hearing loss, overgrowth of the gums (gingival hyperplasia), and widely spaced teeth. Affected individuals may survive into childhood or adolescence.

GENETIC FACTOR Mutations in the NEU1 gene cause sialidosis. This gene provides instructions for making an enzyme called neuraminidase 1 (NEU1), which is found in lysosomes. Lysosomes are compartments within the cell that use enzymes to digest and recycle materials. The NEU1 enzyme helps break down large sugar molecules attached to certain proteins by removing a substance known as sialic acid. Mutations in the NEU1 gene lead to a shortage (deficiency) of the NEU1 enzyme. When this enzyme is lacking, sialic acid-containing compounds accumulate inside lysosomes. Conditions such as sialidosis that cause molecules to build up inside lysosomes are called lysosomal storage disorders. People with sialidosis type II have mutations that severely reduce or eliminate NEU1 enzyme activity. Individuals with sialidosis type I have mutations that result in some functional NEU1 enzyme. It is unclear exactly how the accumulation of large molecules within lysosomes leads to the signs and symptoms of sialidosis.

EPIDEMIOLOGY
The overall prevalence of sialidosis is unknown. Sialidosis type I appears to be more common in people with Italian ancestry. GENETIC FACTOR Mutations in the NEU1 gene cause sialidosis. This gene provides instructions for making an enzyme called neuraminidase 1 (NEU1), which is found in lysosomes. Lysosomes are compartments within the cell that use enzymes to digest and recycle materials. The NEU1 enzyme helps break down large sugar molecules attached to certain proteins by removing a substance known as sialic acid. Mutations in the NEU1 gene lead to a shortage (deficiency) of the NEU1 enzyme. When this enzyme is lacking, sialic acid-containing compounds accumulate inside lysosomes. Conditions such as sialidosis that cause molecules to build up inside lysosomes are called lysosomal storage disorders. People with sialidosis type II have mutations that severely reduce or eliminate NEU1 enzyme activity. Individuals with sialidosis type I have mutations that result in some functional NEU1 enzyme. It is unclear exactly how the accumulation of large molecules within lysosomes leads to the signs and symptoms of sialidosis.

DIAGNOSTIC PROCEDURE

I-Cell Disease (Mucolipidosis Type II) Mucopolysaccharidosis Type IH Reference:

http://www.ncbi.nlm.nih.gov/gtr/conditions/C1850510/ http://ghr.nlm.nih.gov/condition/sialidosis http://emedicine.medscape.com/article/948704-differential

Idiopathic inflammatory myopathy

Idiopathic inflammatory myopathy is a group of disorders characterized by inflammation of the muscles used for movement (skeletal muscles). Idiopathic inflammatory myopathy usually appears in adults between ages 40 and 60 or in children between ages 5 and 15, though it can occur at any age. The primary symptom of idiopathic inflammatory myopathy is muscle weakness, which develops gradually over a period of weeks to months or even years. Other symptoms include joint pain and general tiredness (fatigue).

GENETIC FACTOR
Researchers have identified variations in several genes that may influence the risk of developing idiopathic inflammatory myopathy. The most commonly associated genes belong to a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. Specific variations of several HLA genes seem to affect the risk of developing idiopathic inflammatory myopathy. Researchers are studying variations in other genes related to the body's immune function to understand how they contribute to the risk of developing idiopathic inflammatory myopathy.

EPIDEMIOLOGY
The incidence of idiopathic inflammatory myopathy is approximately 2 to 8 cases per million people each year. For unknown reasons, polymyositis and dermatomyositis are about twice as common in women as in men, while sporadic inclusion body myositis is more common in men.

DIAGNOSTIC PROCEDURE
As with other muscle diseases, a doctor diagnoses an inflammatory myopathy by considering the patients history, family medical history, and the results of a careful physical examination. This may be followed by some lab tests, perhaps of the electrical activity inside the muscles, and usually a muscle biopsy.After a careful history and physical exam to document the pattern of weakness inthe patients muscles, a doctor who suspects myositis likely will order a blood test to check the level of creatine kinase (CK), an enzyme that leaks out of muscle fibers when the fibers are being damaged. In PM and DM, the CK level is usually very high. In IBM, it may be only mildly elevated, or even normal.In some cases, the doctor may ask for a blood test for

specific antibodies, proteins produced by the immune system in myositis and other autoimmune diseases.

References: http://ghr.nlm.nih.gov/condition/idiopathic-inflammatory-myopathy http://mda.org/sites/default/files/publications/Facts_Inflamm_Myopathies_P-199.pdf

Methylmalonic academia
Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to lifethreatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate (failure to thrive). Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases.

GENETIC FACTOR
Mutations in the MUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. The long term effects of methylmalonic acidemia depend on which gene is mutated and the severity of the mutation. About 60 percent of methylmalonic acidemia cases are caused by mutations in the MUT gene. This gene provides instructions for making an enzyme called methylmalonyl CoA mutase. This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain lipids, and cholesterol. Mutations in the MUT gene alter the enzyme's structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. As a result, a substance called methylmalonyl CoA and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia. Mutations in the MUT gene that prevent the production of any functional enzyme result in a form of the condition designated mut0. Mut0 is the most severe form of methylmalonic acidemia and has the poorest outcome. Mutations that change the structure of methylmalonyl CoA mutase but do not eliminate its activity cause a form of the condition designated mut-. The mut- form is typically less severe, with more variable symptoms than the mut0 form.

EPIDEMIOLOGY
This condition occurs in an estimated 1 in 50,000 to 100,000 people.

DIAGNOSTIC PROCEDURE
Definitive diagnosis of isolated methylmalonic acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the

specific enzymatic subtype of methylmalonic acidemia requires studies on vitamin B12 responsiveness, 14C propionate incorporation assays, complementation analysis, and cobalamin distribution assays. As an alternative or complement to the cellular biochemical studies, the finding of two distinct mutations in one of the genes associated with methylmalonic acidemia, with confirmation of carrier status in the parents, can definitely establish the diagnosis. MUT, MMAA, MMAB, MCEE, and MMADHC are the genes known to be associated with isolated methylmalonic acidemia. References: http://www.ncbi.nlm.nih.gov/books/NBK1231/ http://ghr.nlm.nih.gov/condition/hemochromatosis

Hemochromatosis
Hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hemochromatosis is also called an iron overload disorder. Hemochromatosis is classified by type depending on the age of onset and other factors such as genetic cause and mode of inheritance. Hemochromatosis type 1, the most common form of the disorder, and type 4 (also called ferroportin disease) are adult-onset disorders. Men with type 1 or type 4 hemochromatosis typically develop symptoms between the ages of 40 and 60, and women usually develop symptoms after menopause. Type 2 hemochromatosis is a juvenile-onset disorder. Iron accumulation begins early in life, and symptoms may begin to appear in childhood. By age 20, decreased or absent secretion of sex hormones is evident. Females usually begin menstruation in a normal manner, but menses stop after a few years. Males may experience delayed puberty or sex hormone deficiency symptoms such as impotence. If the disorder is untreated, heart disease is evident by age 30. Onset of type 3 hemochromatosis is usually intermediate between types 1 and 2. Symptoms of type 3 hemochromatosis generally begin before age 30.

GENETIC FACTOR
Mutations in the HAMP, HFE, HFE2, SLC40A1, and TFR2 genes cause hemochromatosis. The HAMP, HFE, HFE2, SLC40A1, and TFR2 genes play an important role in regulating the absorption, transport, and storage of iron. Mutations in these genes impair the control of iron absorption during digestion and alter the distribution of iron to other parts of the body. As a result, iron accumulates in tissues and organs, which can disrupt their normal functions. Each type of hemochromatosis is caused by mutations in a specific gene. Type 1 hemochromatosis is caused by mutations in the HFE gene, and type 2 hemochromatosis is caused by mutations in either theHFE2 or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in theSLC40A1 gene cause type 4 hemochromatosis. The cause of neonatal hemochromatosis is unknown.

EPIDEMIOLOGY
Type 1 hemochromatosis is one of the most common genetic disorders in the United States, affecting about 1 million people. It most often affects people of Northern European descent. The other types of hemochromatosis are considered rare and have been studied in only a small number of families worldwide.

DIAGNOSTIC PROCEDURE
The doctor or nurse will perform a physical exam. This may show liver and spleen swelling, and skin color changes. Blood tests may help make the diagnosis. Tests may include:

Ferritin level Iron level Percentage of transferrin saturation (high)

Other tests may include:

Blood sugar (glucose) level Alpha fetoprotein Echocardiogram to examine the heart's function Electrocardiogram (ECG) to look at the electrical activity of the heart Imaging tests such as CT scans, MRI, and ultrasound Liver function tests

The condition may be confirmed and treated with a liver biopsy or phlebotomy, a procedure that removes blood to lower the amount of iron in the body. If a genetic defect is confirmed, other blood tests can be used to determine if other family members are at risk for iron overload. References: http://www.nlm.nih.gov/medlineplus/ency/article/000327.htm http://ghr.nlm.nih.gov/condition/methylmalonic-acidemia

Polycystic kidney disease

Polycystic kidney disease is a disorder that affects the kidneys and other organs. Clusters of fluid-filled sacs, called cysts, develop in the kidneys and interfere with their ability to filter waste products from the blood. The growth of cysts causes the kidneys to become enlarged and can lead to kidney failure. Cysts may also develop in other organs, particularly the liver. The two major forms of polycystic kidney disease are distinguished by the usual age of onset and their pattern of inheritance. The autosomal dominant form (sometimes called ADPKD) has signs and symptoms that typically begin in adulthood, although cysts in the kidney are often present from childhood. Autosomal dominant polycystic kidney disease can be further divided into type 1 and type 2, depending on which gene is mutated. The autosomal recessive form of polycystic kidney disease (sometimes called ARPKD) is much rarer and is often lethal early in life. The signs and symptoms of this condition are usually apparent at birth or in early infancy.

GENETIC FACTOR
Mutations in either the PKD1 or PKD2 gene can cause autosomal dominant polycystic kidney disease. These genes provide instructions for making proteins whose functions are not fully understood. Researchers believe that they are involved in transmitting chemical signals from outside the cell to the cell's nucleus. The two proteins work together to promote normal kidney development, organization, and function. Mutations in the PKD1 or PKD2 gene lead to the formation of thousands of cysts, which disrupt the normal functions of the kidneys and other organs. People with mutations in the PKD2 gene, particularly women, typically have a less severe form of the disease than people with PKD1 mutations. The signs and symptoms, including a decline in kidney function, tend to appear later in adulthood in people with a PKD2mutation. Mutations in the PKHD1 gene cause autosomal recessive polycystic kidney disease. This gene provides instructions for making a protein whose exact function is unknown; however, the protein likely transmits chemical signals from outside the cell to the cell nucleus. Researchers have not determined how mutations in the PKHD1 gene lead to the formation of numerous cysts characteristic of polycystic kidney disease.

EPIDEMIOLOGY
Polycystic kidney disease is one of the most common disorders caused by mutations in a single gene. It affects about 500,000 people in the United States. The autosomal dominant form of the disease is much more common than the autosomal recessive form. Autosomal dominant

polycystic kidney disease affects 1 in 500-1,000 people, while the autosomal recessive type occurs in an estimated 1 in 20,000-40,000 people.

DIAGNOSTIC PROCEDURE
An examination may show:

Abdominal tenderness over the liver Enlarged liver Heart murmurs or other signs of aortic insufficiency or mitral insufficiency High blood pressure Growths in the kidneys or abdomen

Tests that may be done include:

Cerebral angiography Complete blood count (CBC) Urinalysis

People with a personal or family history of PKD should be tested to determine if cerebral aneurysms are causing headaches. Polycystic kidney disease and cysts on the liver or other organs may be found with the following tests:

Abdominal CT scan Abdominal MRI scan Abdominal ultrasound Intraveno us pyelogram (IVP)

If several members of your family have PKD, genetic tests can be done to determine whether you carry the PKD gene. References: http://www.nlm.nih.gov/medlineplus/ency/article/000502.htm http://ghr.nlm.nih.gov/condition/polycystic-kidney-disease

Narcolepsy
Narcolepsy is a chronic sleep disorder that disrupts the normal sleep-wake cycle. Although this condition can appear at any age, it most often begins in adolescence. Narcolepsy is characterized by excessive daytime sleepiness. Affected individuals feel tired during the day, and several times a day they may experience an overwhelming urge to sleep. "Sleep attacks" can occur at unusual times, such as during a meal or in the middle of a conversation. They last from a few seconds to a few minutes and often lead to a longer nap, after which affected individuals wake up feeling refreshed. Most affected individuals have trouble sleeping for more than a few hours at night. They often experience vivid hallucinations while falling asleep (hypnogogic hallucinations) or while waking up (hypnopompic hallucinations). Many people with narcolepsy also experience sleep paralysis, which is an inability to move or speak for a short period while falling asleep or awakening. The combination of hallucinations, vivid dreams, and sleep paralysis is often frightening and unpleasant for affected individuals

GENETIC FACTOR
The most well-studied of these genes is HLA-DQB1, which provides instructions for making part of a protein that plays an important role in the immune system. The HLA-DQB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). The HLA-DQB1 gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. A variation of the HLA-DQB1 gene called HLA-DQB1*06:02 has been strongly associated with narcolepsy, particularly in people who also have cataplexy and a loss of hypocretins. Most people with narcolepsy have the HLA-DQB1*06:02 variation, and many also have specific versions of other, closely related HLA genes. It is unclear how these genetic changes influence the risk of developing the condition.

EPIDEMIOLOGY
Narcolepsy affects about 1 in 2,000 people in the United States and Western Europe. However, the disorder is likely under-diagnosed, particularly in people with mild symptoms. Worldwide, narcolepsy appears to be most common in Japan, where it affects an estimated 1 in 600 people.

DIAGNOSTIC PROCEDURE
Sleep Studies If your doctor thinks you have narcolepsy, he or she will likely suggest that you see a sleep specialist. This specialist may advise you to have sleep studies to find out more about your condition. Sleep studies usually are done at a sleep center. Doctors use the results from two tests to diagnose narcolepsy. These tests are a polysomnogram (PSG) and a multiple sleep latency test (MSLT). Polysomnogram. You usually stay overnight at a sleep center for a PSG. The test records brain activity, eye movements, heart rate, and blood pressure. A PSG can help find out whether you:

Fall asleep quickly Go into rapid eye movement (REM) sleep soon after falling asleep Wake up often during the night

Multiple sleep latency test. This daytime sleep study measures how sleepy you are. It's often done the day after a PSG. During the test, you're asked to nap for 20 minutes every 2 hours throughout the day. (You will nap a total of four or five times.) A technician checks your brain activity during this time. He or she notes how quickly you fall asleep and how long it takes you to reach various stages of sleep. An MSLT finds out how quickly you fall asleep during the day (after a full night's sleep). It also shows whether you go into REM sleep soon after falling asleep. Other Tests Hypocretin test. This test measures the level of hypocretin in the fluid that surrounds your spinal cord. Most people who have narcolepsy have low levels of hypocretin. Hypocretin is a chemical that helps promote wakefulness. To get a sample of spinal cord fluid, a spinal tap (also called a lumbar puncture) is done. For this procedure, your doctor inserts a needle into your lower back area and then withdraws a sample of your spinal fluid. References: http://www.nhlbi.nih.gov/health/health-topics/topics/nar/diagnosis.html http://ghr.nlm.nih.gov/condition/narcolepsy