GENETIC DISORDERS Dr. Smriti Arora Professor Amity College of Nursing, Amity University Gurgaon smritiamit@msn.comIntroduction Genetic disorder is a disease that is caused by an abnormality in an individual's DNA. Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes. A mutation is a permanent change in the DNA sequence of agene. Mutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the gene.Terminology Genetics - study of heredity and its variation Gene — basic unit of heredity, located in on chromosome. Chromosome- long continuous strand of DNA that carries genetic information Each somatic cell has 46 chromosomes (23 pairs) 22 pairs- autosomes , 1 pair- sex chromosome Genotype- specific genetic makeup of the individual, internally coded inheritable information Allelle- alternative versions of a gene at a given point on chromosomeTerminology Phenotype- outward characteristics of the individual Homozygous- same allelles for a given characteristic Heterozygous- different allelles, one from father and one from mother , of a given characteristic. Genome — entire heredity information encoded in the DNA of an organismCell division There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell i process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. Meiosis , ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are divChromosomes — 23 pairs The chromasome Is. made up of genes.Chromareine ous DNA, is the molecular basis for inheritance. Each strand of DNA is a chain of nucleotides, matching each other in the center to form what look like rungs on a twisted ladderHemizygous Homozygous -- | |, Heterozygous es allele Pp B Pp a 6 Recessive allele Genotype: PP aa Bb Homozygous Homozygous Heterozygous for the for the dominant allele recessive alleleBecause both copies of the genes, iLe., both alleles have gone bad, the child will suffer from the disease, Note that the child must receive a double dose of the gene to get sick. ‘The child is said to possess a reces- sive allele. A recessive allele hides its effects when it occurs with the normal allele in the father and mother. Here father and mother are carriers. This is the situation in diseases such as Tay- ‘Sachs disease, thalassemia and sick- le-cell anemia. In contrast, in the case of Huntington's disease, only one of the two alleles has to go bad in order to get the dis: ease, i.e, Huntington's allele is dominant.sete for purpia RowersHuman genome project * Coordinated by US department of Energy and National Institute of Health * Goals: — Identify all 20,000-25000 genes in human DNA — Determine the sequence of 3 million chemical base pairs that make up human DNASas TCPatterns of inheritance + Mendelian or monogenic disorders — Single gene is defective * Autosomal dominant * Autosomal recessive * X linked dominant * X linked recessiveAutosomal dominant + A pattern of inheritance in which an affected individual has one copy of a mutant gene and one normal gene ona pair of autosomal chromosomes. * Individuals with autosomal dominant diseases have a 50-50 chance of passing the mutant gene and therefore the disorder onto each of their children. + Examples : Huntington disease, neurofibromatosis, achondroplasia, and polycystic kidney disease.Father with abnormal gene on Mother with normal autosomal chromosome autosomal chromosome Parents: AA AA Ofspring: AA AA AA AA Each pregnancy beats a50-0 chance of carrying the abnormal geneAutosomal recessive A genetic condition that appears only in individuals who have received two copies of an autosomal gene, one copy from each parent. The gene is on an autosome, a non sex chromosome. The parents are carriers who have only one copy of the gene and do not exhibit the trait because the gene is recessive to its normal counterpart gene. Autosomal recessive is one of several ways that a trait, disorder, or disease can be passed down through families. Two copies of an abnormal gene must be present for the disease or trait to develop. Eeemple: Cystic Fibrosis, phenylketonuria, Tay- sachs, Sickle cell seasethin Normal Carrier Carrier AffectedX linked dominant * X linked dominant inheritance is present if heterozygous female carriers demonstrate sign and symptoms of the disorder * Rare * Eg hypophosphatemic (vitamin D resistant) ricketsX-linked dominant, affected mother X-linked dominant, affected father. . . X linked recessive Demonstrate a recessive pattern of inheritance Males are more affected as they have only one X chromosome Females are generally carriers Eg- hemophilia, color blindness, Duchenne muscular dystrophyX-linked recessive, affected father X-linked recessive, carrier mother Affected Unaffected = Unaffected (Carer fainer mother mother hi ; } Wi Unattected Mi unattected i hifi | a auger coger a hoMultifactoral Inheritance Most diseases have multifactorial inheritance pattems. As the name implies, multifactorial conditions are not caused by a single gene, but rather are a result of interplay between genetic factors and environmental factors. Diseases with multifactorial inheritance are not genetically determined, but rather a genetic mutation may predispose an individual to a disease. Other genetic and environmental factors contribute to whether or not the disease develops. Numerous genetic alterations may predispose individuals to the same disease (genetic heterogeneity). For instance coronary heart disease risk factors include high blood pressure, diabetes, and hyperlipidemia. All of those risk factors have their own genetic and environmental components. Thus multifactorial inheritance is far more complex than Mendelian inheritance and is more difficult to trace through pedigrees. A combination of genes from both parents and environmental factors produces the trait. Pattern of inheritance is not as predictable as in single gene disorders. E.g. congenital disorders: cleft lip, cleft palate, spina bifida, pyloric stenosis, club foot, congenital hip dysplasia, cardiac defectsNon traditional inheritance patterns + Mitochondrial inheritance — Mitochondria are organelles found in the cytoplasm of cells. Mitochondria are unique in that they have multiple copies of a circular chromosome. Mitochondria are only inherited from the mother's egg, thus only females can transmit the trait to offspring, however they pass it on to all of their offspring. The primary function of mitochondria is conversion of molecule into usable energy. Thus many diseases transmitted by mitochondrial inheritance affect organs with high-energy use such as the heart, skeletal muscle, liver, and kidneys. — Inherited almost exclusively from mother. — E.g.- Kearns Sayre syndrome, Leber’s hereditary optic neuropathyMitochondrial+ Genomic imprinting: Even though both parents contribute equally to the genetic content of their offspring, a developmental process called genomic imprinting sometimes leads to the exclusive expression of specific genes from only one parent. — E.g. - Prader Willi syndrome, Angelman syndrome, Beckwith- Wiedemann syndromeChromosomal abnormalitiesChromosomal abnormalities Chromosome diseases are genetic diseases where a large part of the genetic code has been disrupted. Chromosomes are long sequences of DNA that contain hundreds or thousands of genes. Every person has 2 copies of each of the 23 chromosomes, called chromosomes 1..22 and the 23rd is the sex chromosome, which is either X and Y. Men are XY and women are XX in the 23rd chromosome pair.Chromosomal abnormalities * Chromosomal diseases arise from huge errors in the DNA that result from — having extra chromosomes, — large missing sequences, or — other major errors. * These are usually caused by a random physical error during reproduction and are not inherited diseases.* Nondisjunction — abnormal number of autosomal chromosomes when chromosomes fail to separate during replication. — 2n-1=monosomic — 2n+1=trisomic * Examples — Down's -- trisomy 21 mean life expectancy 17 years. Short in stature, round face and mental retardation — Patau's -- trisomy 13 mean life expectancy 130 days — Edward's --- trisomy 18 mean life expectancy afew weeks* Structural Changes in Chromosomes — Inversion - occurs when a chromosome segment turns around 180 degrees. — Translocation — is movement of chromosomal segments to another non-homologous chromosome — Deletion — occurs when a portion of the chromosome breaks off. — Duplication - when a portion of a chromosome repeats itself.Down’s Syndrome + also called Trisomy 21, is a condition in which extra genetic material causes delays in the way a child develops, both mentally and physically. It affects about 1 in every 800 babies. * Normally, at the time of conception a baby inherits genetic information from its parents in the form of 46 chromosomes: 23 from the mother and 23 from the father. * In most cases of Down syndrome, a child gets an extra chromosome 21 — for a total of 47 chromosomes instead of 46. It's this extra genetic material that causes the physical features and developmental delays associated with DS.at) OK Hg Wu if we ig BoE a 3E 38 aad je _ 13 20 21 W 22 x vv_ Deno _ Three copies of chromosome 21 is og Gg EP AEE a u 0 +eChild with Down syndrome Note: * up-slanting palpebral fissures, * bilateral epicanthal folds, * asmall nose with flat nasal bridge, * open mouth with tendency for tongue protrusion, and * small ears with overfolded helix.« Characteristic small ear with overfolded helix.Causes In most cases, Down syndrome occurs when there is an extra copy of chromosome 21. This form of Down syndrome is called Trisomy 21. The extra chromosome causes problems with the way the body and brain develop. Down syndrome is the most common single cause of human birth defects.Symptoms vary from person to person and can range from mild to severe. widely recognized characteristic appearance. The head may be smaller than normal and abnormally shaped. For example, the head may be round with a flat area on the back. The inner corner of the eyes may be rounded instead of pointed. Common physical signs include: — Decreased muscle tone at birth — Excessive skin at the nape of the neck — Flattened nose — Separated suturesCont... Single crease in the palm of the hand Small ears Small mouth Upward slanting eyes Wide, short hands with short fingers White spots on the colored part of the eye (Brushfield spots)Diagnostic tests include Chorionic villus sampling (CVS) * CVS involves taking a tiny sample of the placenta, either through the cervix or through a needle inserted in the abdomen. + Advantage : it can be performed during the first trimester, between 8 and 12 weeks. * Disadvantage : carries a slightly greater risk of miscarriage as compared with amniocentesis and has other complications.Cont... Amniocentesis . performed between 15 and 20 weeks of pregnancy, Involves the removal of a small amount of amniotic fluid through a needle inserted in the abdomen. The cells can then be analyzed for the presence of chromosomal abnormalities. Carries a small risk of complications, such as preterm labor and miscarriage.Diagnosis Percutaneous umbilical blood sampling (PUBS) * Usually performed after 20 weeks, + This test uses a needle to retrieve a small sample of blood from the umbilical cord. * risks are similar to those associated with amniocentesis.Diagnostic test Karyotyping It is a test to examine chromosomes in a sample of cells, which can help identify genetic problems as the cause of a disorder or disease. Count the number of chromosomes Look for structural changes in chromosomesCont... The sample is placed into a special dish and allowed to grow in the laboratory. Cells are later taken from the growing sample and stained. A microscope is used to examine the size, shape, and number of chromosomes in the cell sample. The stained sample is photographed to provide a karyotype, which shows the arrangement of the chromosomes. Certain abnormalities can be identified through the number or arrangement of the chromosomes. Chromosomes contain thousands of genes that are stored in DNA, the basic genetic material.Screening tests include Nuchal translucency testing * This test, performed between 11 and 14 weeks of pregnancy, * Uses ultrasound to measure the clear space in the folds of tissue behind a developing baby's neck. + Babies with DS and other chromosomal abnormalities tend to accumulate fluid there, making the space appear larger. * This measurement, taken together with the mother's age and the baby's gestational age, can be used to calculate the odds that the baby has DS. * Nuchal translucency testing is usually performed along with a maternal blood test.Cont... The triple screen or quadruple screen (also called the multiple marker test). * These tests measure the quantities of normal substances in the mother's blood. * As the names imply, triple screen tests for three markers and quadruple screen includes one additional marker and is more accurate. * These tests are typically offered between 15 and 18 weeks of pregnancy.Integrated screen. * This uses results from first trimester screening tests (with or without nuchal translucency) and blood tests with second trimester quad screen to come up with the most accurate screening results.Cont... Genetic ultrasound. * A detailed ultrasound is often performed at 18 to 20 weeks in conjunction with the blood tests, and it checks the fetus for some of the physical traits abnormalities associated with Down syndrome. * Other tests that may be done include: — Echocardiogram — ECG — X-rays of the chest and gastrointestinal tractTreatment No specific treatment Gastrointestinal blockage: may need major surgery immediately after birth. Certain heart defects : surgery Special education and training is offered in most communities for children with delays in mental development. — Speech therapy : help improve language skills. — Physical therapy : to teach movement skills. closely screen for eye problems, hearing loss, thyroid disease, and other medical conditions associated with the syndrome. Support Groups = National Down Syndrome Society - www.ndss.org — National Down Syndrome Congress -- www.ndsecenter.orgPrognosis Persons with Down syndrome are living longer than ever before. Many live independent and productive lives, well into adulthood. About half of children with Down syndrome are born with heart problems, including ASD and VSD. Heart problems may lead to early death. Persons with Down syndrome have an increased risk for certain types of leukemia, which can also cause early death. The level of mental retardation varies from patient to patient, but is usually moderate. Adults with Down syndrome have an increased risk for dementiaComplications Airway blockage during sleep Compression injury of the spinal cord Eye problems Frequent ear infections and increased risk of other infections Hearing loss Heart problems Gastrointestinal blockage Weakness of the back bones at the top of the neckEdwards Syndrome In Trisomy 18 (Edwards syndrome), there is an extra chromosome with the 18th pair. Like Trisomy 21 (Down syndrome), Trisomy 18 affects all systems of the body and causes distinct facial features. It is estimated to occur in 1 in 6,000-8,000 live births. Unfortunately, about 95% of fetuses die before birth, so the actual incidence of the disorder may be higher. Of those born, approximately 80% are females. Trisomy 18 affects individuals of all ethnic backgrounds.a female with Edwards syndrome (47,XX,+1 IN rit i HE WO WC Us ae Hh at nw ule!Symptoms Trisomy 18 severely affects all organ systems of the body. Symptoms may include: * Nervous system & brain - mental retardation and delayed development (100% of individuals), high muscle tone, seizures, and physical malformations such as brain defects * Head and face - small head (microcephaly), small eyes, wide- set eyes, epicanthal folds, small lower jaw * Heart - congenital heart defects (90% of individuals) such as VSD and valve defects * Bones - severe growth retardation, clenched hands with 2nd & 5th fingers on top of the others, other defects of the hands & feet * Malformations of digestive tract, urinary tract, & genitalsCont... Patient find difficulty in growth. They face difficulty in feeding and breathing. Mental retardation Polyhydramnios and small placenta. Small head, small mouth and small jaw. Widely-spaced eyes and upturned nose. Underdeveloped thumb and nails or may be absent. Kidney malformations Heart defects.Symptoms Crossed legs Malformed kidney Affected baby may have umbilical or inguinal hernia Abnormal ears Coloboma (hole) of iris and short sternum Short breastbone, Discomfort in the bowels.Diagnosis The physical appearance of the child at birth will point towards Trisomy 18. Prenatal ultrasound can detect abnormalities in the fetus. Genetic testing by amniocentesis before birth or blood test after birth can confirm the diagnosis. Ultrasounds of the heart and abdomen can detect abnormalities X -rays of the skeleton.Treatment Medical — supportive, and — focuses on providing nutrition, — treating infections, and — managing heart problems. During the first months of life, infants with Trisomy 18 require skilled medical care. Due to the complex medical problems, including heart defects and overwhelming infections, infants have a 5% chance of surviving to age 1 year. Advances in medical care over time will, in the future, help more infants with Trisomy 18 live into childhood and beyond.Cont... Treatment is associated with symptoms: * Babies dysphagia clinic or feeding specialist is essential for the feeding problem and for other difficulties G-tube is required. * Parents of baby with low weight gain due to heart defects may consult with nutritionist. * Astool softener medication is useful to reduce irritation of bowel in children. * Hearing aides and glasses is helpful for those who have hearing and visual problem. . Physical and occupational therapy is useful to increase motor s + Anti-gas medication should be used to treat the problem of gas in the bowels. * Surgical treatment may be required for the diseases like spina bifida, and hydrocephalus.Cri-du-chat Syndrome * Cri du chat Syndrome is a uncommon and unusual hereditary disorder which is caused by a deletion of chromosome 5p. + Chromosome 5p deletion syndrome; 5p minus syndrome, Cat cry syndrome, these are some of the alternate name of Cri du chat Syndrome. Pp ‘Centromere qCauses It mostly occurs due to deletion of chromosome 5p. Deletion of gene known as tert may cause the feature of Cri du chat Syndrome. Cause of deletion of chromosome 5p is not known but various cases are because of sudden loss of chromosome 5p at the time of expansion of an egg or sperm. Some cases occur due to translocation i.e. parents carrying reorganization of chromosome. Severe mental retardation may also cause this disease but it is in very rare cases.Symptoms Children with Cri du chat do not develop perfectly They don't get developed larynx because of which when they cry it sounds like cat ery therefore it is also called Cat cry syndrome. Babies who have Cri du chat carry different features like they have small head and round face, wide-set eyes, downward slant to the eyes and skin tags just in front of the ear. These people do not get perfect birth weight and get slow growth.Symptoms Some children experience heart defects, hearing and visual problem, and they always face problem in walking and talking. Some people have mental retardation. These patient experience fusing of fingers or toes, small jaws and slow development of motor skills. Patient of Cri du chat Syndrome may not survive till adulthood.Note Cri -du-chat syndrome. | the round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears.Note + the hypertonicity, * small and narrow face, + dropped jaw, and * open-mouth expression secondary to facial laxity.Diagnosis Molecular cytogenetic studies using FISH (Fluorescence in situ hybridization) allow the diagnosis to be made in patients with very small deletions. Chromosome comparative genomic hybridization (CGH) Imaging studies — MRI — ECHO ° Skeletal radiography Developmental testingKaryotypingSurgical Care * Correction of congenital heart defects may be indicated. + Medical problems involving minor malformations such as strabismus and clubfoot may be amenable to surgical correction. * Orchiopexy may be necessary in patients with undescended testes.Treatment Care must be taken , it is very helpful. No treatment survive for fundamental hereditary disorder. The child may need gastrostomy tube for feeding. Speech therapist should use to improve communication skills Physical therapy is also useful. Chronic medical problems such as upper respiratory tract infections, otitis media, and severe constipation require appropriate treatment.Mortality/Morbidity * With contemporary interventions, the chance of survival to adulthood is possible. * Currently, the mortality rate of cri-du-chat syndrome is 6- 8% in the overall population. * Pneumonia, aspiration pneumonia, congenital heart defects, and respiratory distress syndrome are the most common causes of death.Summary Patterns of inheritance Downs syndrome Edwards syndrome Cri du chat syndromeGENETIC DISORDERS Dr. Smriti Arora Professor Amity College of Nursing, Amity University Gurgaon smritiamit@msn.comIntroduction Genetic disorder is a disease that is caused by an abnormality in an individual's DNA. Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes. A mutation is a permanent change in the DNA sequence of agene. Mutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the gene.Terminology Genetics - study of heredity and its variation Gene — basic unit of heredity, located in on chromosome. Chromosome- long continuous strand of DNA that carries genetic information Each somatic cell has 46 chromosomes (23 pairs) 22 pairs- autosomes , 1 pair- sex chromosome Genotype- specific genetic makeup of the individual, internally coded inheritable information Allelle- alternative versions of a gene at a given point on chromosome