Genetic Disorders Summary Table (3) PDF

Disease Type of Genetic Disease Phenylketonu Autosomal ria (PKU) Recessive (metabolic disorder) Mechanism Mutation in PAH gene (most common p.Arg408Trp; missense non-conservative) so phenylalanine hydroxylase (PAH) enzyme is deficient. No break down of phenylalanine so it accumulates in tissues....

Disease Type of Genetic Disease Phenylketonu Autosomal ria (PKU) Recessive (metabolic disorder) Mechanism Mutation in PAH gene (most common p.Arg408Trp; missense non-conservative) so phenylalanine hydroxylase (PAH) enzyme is deficient. No break down of phenylalanine so it accumulates in tissues. Most are compound heterozygotes. In affected individuals and carriers the amount of PAH enzyme is the same, but the quality/ activity of the enzyme is affected. Carriers not affected as 50% PAH activity is enough. Symptoms/ Manifestation of Disease Screening & Diagnosis Early symptoms in infant; vomiting, irritability, eczema-like rash, mousy odour to urine. Subtle signs of nervous system function problems; increased muscle tone, more active muscle tendon reflexes. Microcephaly, prominent cheek & upper jaw bones, decreased body growth. If not controlled, PKU causes cognitive impairment and seizures. In Australia all newborns are screened for PKU for early identification and management; screened for phenylalanine levels at 3 days old; Guthrie card Management Maintain a blood level of phenylalanine within normal levels; 2-10mg/ dL We all need some phenylalanine for normal growth, so can’t be deficient entirely; reduce High protein foods such as meat, fish, poultry, eggs, cheese, milk, dried beans and peas are avoided. Instead, measured amounts of cereals, starches, fruits and vegetables along with a milk substitute are recommended Quality of Life & Outlook If vigilant about diet and keep low phenylalanine, normal quality of life and life span. Maternal Effect: homozygous women with PKU have difficulties producing healthy babies because need proteins for both mother and baby to grow & develop; mother changes diet and has phenylalanine build up; babies have risk of intellectual disability from exposure to high phenylalanine levels Disease Thalassemia Type of Genetic Disease Autosomal Recessive (blood disorder) Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Deletions in globin chains of haemoglobin so blocks protein production: - 4 ⍺ globin genes (2 on each chromosome 16); HBA1 or HBA2 genes affected - 2 β globin genes (chromosome 11); HBB gene affected ⍺-Thalassemia: silent carrier (1 gene mutated), minor (2 genes mutated), Haemoglobin H (HbH, 3 genes mutated), Haemoglobin Barts Syndrome (all genes mutated) β-Thalassemia: minor (1 mutated), intermedia (both mutated, milder), major (both mutated, severe) Haemoglobin H (HbH): mild-moderate anaemia, blood infusions, enlarged spleen, jaundice Hb Barts Syndrome: severe anaemia, excess fluid build up in baby, doesn’t survive long after birth. β-Thalassemia intermedia: mildmoderate anaemia, blood transfusions, slow growth, bone changes (may be child or older onset) β-Thalassemia major: develop life-threatening anaemia within first year blood transfusions, failure to thrive, jaundice, enlarged spleen, bone changes, developmental delay Screening determines how much of β-globin is mutated. Molecular genetic testing of HBB identifies all variant types. Molecular genetic testing of HBA1 & HBA2 detects deletions and point mutations in affected individuals. Methods; haematology testing of red blood cell indices, peripheral blood smear, supra vital stain to detect RBC inclusion bodies and qualitative & quantitative haemoglobin analysis (electrophoresis) Management Hb Barts = no effective treatment. HbH disease = occasional red blood cell transfusions during haemolytic/aplastic crises β-Thalassemia intermedia; symptomatic therapy based on splenectomy, sporadic red cell transfusions, folic acid supplementation and iron chelation β-Thalassemia major: regular transfusions correct anaemia, suppress erythropoiesis and inhibit increased gastrointestinal absorption of iron; definitive treatment is bone marrow/cord blood transplantation New treatment; embryonic = epsilon & theta subunits, foetal have ⍺ & 𝛾, adult have ⍺ & β; replace β with embryonic/foetal globin proteins Quality of Life & Outlook Heterozygotes have mild symptoms & undiagnosed due to incomplete dominance β-Thalassemia major affected babies normal and birth but become anaemic between 3-18 months (still have foetal subunit) If untreated, most will die mild have shortened life span Disease Sickle Cell Anaemia Type of Genetic Disease Autosomal Recessive (blood disorder) Haemochrom Autosomal atosis Recessive (blood disorder) Mechanism Symptoms/ Manifestation of Disease Single amino acid change caused by mutation on the HBB gene which then produces abnormal version of β-globin known as haemoglobin S (HbS) instead of HbA; changes structure and function of haemoglobin; change in shape means can’t go through capillaries so go through haemolysis. Single DNA base change: glutamic acid —> valine: pGlu6Val Mutations in the HFE (High Fe - iron) gene; most commonly missense Cys282Try and secondly His63Asp. Mutant HFE does not bind properly to transferrin receptor which normally is important for regulation of Hepcidin (master iron regulator hormone); body absorbs too much iron, no natural way to reduce body iron so accumulates stored in body tissues Screening & Diagnosis Management Blood screening for deformed erythrocytes using a microscope & quantitative haemoglobin analysis (electrophoresis) = testing to see for sickle shaped red blood cells Included in newborn screening Prevention of crisis through regular transfusions to allow there to be enough blood Fatigue, lack of energy, joint paint, abdominal pain, loss of sex drive and heart problems. Iron content in blood (serum transferrin saturation) and liver/ tissues (serum ferritin) Regular phlebotomy is most common form of treatment Many people show few symptoms before irreversible organ damage commences Genetic defect has likely proven a selective advantage in the past during times of famine when food supply was limited and times when iron deficiency was very common. Quality of Life & Outlook If routinely checked and managed correctly, outlook is good Life expectancy can be slightly reduced Heterozygote advantage with HbS not be conducive to malaria so provides protective advantage against malaria Symptoms tend to occur in men between 30-50yrs, and women over 50yrs; women’s menstruation gets rid of some of the excess iron so when go into menopause this is no longer happening, so iron levels will build up Disease Cystic Fibrosis (CF) Type of Genetic Disease Autosomal Recessive (multitissue syndrome) Mechanism Mutation in the transmembrane transporter CFTR gene which functions as a Clselective channel gated by ATP binding and hydrolysis; blocks the movement of chloride ions through membranes, which normally carry water with them, resulting in mucus build up. Most common mutation is deletion; delta F508 (p.Phe508del) Can be missense, frameshift, nonsense, changes in enhancer sequences Different Classes of Mutation in CFTR Gene: 1. No protein synthesised 2. Protein not transported to membrane 3. Channel doesn’t function 4. Reduced function 5. Less protein made 6. Stability/half life reduced so turned over faster Symptoms/ Manifestation of Disease Screening & Diagnosis Lungs: mucus thicker, not moved by ciliated cells Pancreas: glands become clogged (may cause cysts) so can’t secrete necessary digestive enzymes Intestine: lack of digestive enzymes for fats; undernourishment & excess fat in stool Reproductive ducts: vas deferens can become blocked leading to sterility Sweat Glands: salt secreted for water movement for cooling is not taken back up; salty sweat Screening test at birth on Guthrie card (checks for raised immunoreactive trypsinogen released by pancreas), assign a risk of a particular diagnosis through an ultrasound. Diagnostic tests are confirmatory and at individual levels; chronic villus sampling, amniocentesis, genetic sequencing. Many different mutations so if continue to show symptoms despite negative test, secondary confirmatory tests done Management - antibiotics to treat & - - - prevent lung infections * bacteria blood up Mucus thinning drugs to help cough up mucus and improve lung function Bronchodilators to keep airways open by relaxing the muscles Oral pancreatic enzymes to help digestive tract absorb nutrients Chest physical therapy Pulmonary rehabilitation Organ transplat (lungs) Quality of Life & Outlook Life difficult as spend lots of time managing the symptoms; physio, up to 40 tablets per day, nutrition, as much exercise as able to keep lungs moving, psychological counselling If ample antibiotics, will improve outlook. 80-95% die of respiratory failure due to bacterial infections (Pseudomonas aeruginosa); stop bacteria reaching peak levels. 50% live past 41yrs 1 in 25 unknown carriers in the population 1 in 2500 babies born with CF Disease Type of Genetic Disease Achondropla sia Autosomal Dominant 80% from de novo mutations Mechanism FGFR3 Gene (fibroblast growth factor receptor 3) is responsible for signalling growth using receptor tyrosine kinases; stimuli, activation, dimerisation, phosphorylation. Normally limits bone formation from cartilage Mutations are hypermorphic (gain of function) so receptor is constitutively active; decreased endochondral ossification, inhibited proliferation of chondrocytes at growth plate, decreases cartilage matrix production; bones develop too short. Mutation occurs in the transmembrane domain of the receptor. Symptoms/ Manifestation of Disease Screening & Diagnosis Abnormal bone growth that results in short stature with disproportionate short arms and legs, a large head, characteristic facial features, trident hands (divergence of ring and middle fingers), average trunk length. Motor development somewhat delayed. Diagnosis: based on symptoms = trident hand, short stature with disproportionate short arms and legs and average trunk length. In general population, frequency is 1 in 15,000 to 1 in 40,000 = rare mutation and rare disorder Management Quality of Life & Outlook Intelligence and life span are usually normal, although an increased risk is present for death in infancy from compression of spinal cord or upper airway obstruction. Mating between two affected individuals (heterozygotes) will result in 2/3 dwarf and 1/3 normal Lethal allele; homozygous dominant will not survive 100% penetrance Disease Type of Genetic Disease Hypochondro Autosomal plasia Dominant 80% from de novo mutations Huntington’s Disease Autosomal Dominant Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Mutation to the FGFR3 gene; most common is missense p.Asn540Lys or p.Lys650Met. Hypermorphic gain of function; increased cartilage growth limiting. Mutation occurs in the first tyrosine kinase domain (within cell) (responsible for downstream phosphorylating) More mild compared to achondroplasia. Short stature and disproportionate limbs as age. Motor milestones usually normal; fine and gross motor skills in early development are normal HTT gene mutated with expansion in glutamine (CAG) repeats within the huntingtin protein; results in increased protein aggregation causing damage to neuronal cells. Normal CAG repeats 10-26. 27-35 little risk themselves but at risk of having an affected child. 36-41 reduced penetrance; may or may not develop symptoms. 40-55 adult onset. Above 60 juvenile onset Progressive motor Penetrance and severity disability featuring vary depending on the chorea, voluntary number of CAG repeats. movements affected, mental disturbances including cognitive decline, changes in personality, depression. Progression and severity depend on number of CAG repeats; the more trinucleotide repeats, the more severe the disease is Management Birth weight and length often normal, and disproportionate limb:trunk is easy to overlook in infancy. Present as toddlers/ school age with failure to grow. No trident hands or facial features seen in achondroplasia Quality of Life & Outlook 100% penetrance No cure so just management of the symptoms and assisting the person to remain comfortable and as healthy and happy as they can be Symptoms appear well after reproductive age (mostly) so often pass on expansion repeat with risk of getting worse (anticipation) to offspring. Quality of life after symptoms occur deteriorates, especially with loss of independence; transition is devastating. Disease Type of Genetic Disease Myotonic Dystrophy Autosomal Dominant Retinoblasto ma Autosomal Dominant Mechanism Expansion of the CTG trinucleotide repeat in the DMPK gene (Dystrophia Myotonica protein kinase) at chromosomal locus 19q13 Myotonia = inability to relax muscles after vigorous effect CTG repeat exceeding 37 repeats is abnormal Penetrance and expression vary based on number of CTG repeats. Mutation of the retinoblastoma protein which protects the cell 30% cases from going through cell are division inappropriately; inherited regulates transition from G1 phase into S phase. 70% are When cell is damaged, sporadic the retinoblastoma mutation of protein will bind to E2F somatic receptors, regulates cells so downstream targets and can’t be inhibits entry into S passed on phase. Mutated protein means cells proceed regardless, causing replication of damaged cells. 2 hit hypothesis; need 2 mutated alleles Symptoms/ Manifestation of Disease Screening & Diagnosis Management Quality of Life & Outlook A range of severity based on number of trinucleotide repeats. Multi-system disorder that affects skeletal muscle (progressive muscle wasting and weakness), smooth muscle, eye, heart, endocrine and central nervous systems Affects at least 1 in 8000 No cure, manage people worldwide symptoms: manage pain Treatment of hypothyroidism, use ankle-foot orthoses, wheelchairs or other assistive devices, consultation with cardiologist for evidence arrhythmia, removal of cataracts, hormone replacement therapy for males with hypogonadism, surgical excision of polomatrixoma Mild: 50-150 repeats; onset 20-70yrs, life expectancy 60yrsnormal life span Classic: 100-1000 repeats: onset 10-30yrs, life expectancy 48-55yrs Congential: >1000, onset birth-10yrs, life expectancy 45yrs The loss of a tumour suppressor gene means that there will be a malignant tumour arising in the retina of one or both eyes during infancy or early childhood. Disease begins to form during foetal development when retinal cells (retinoblasts) are rapidly dividing. Leukocoria = abnormal white reflection from the retina of eye Leukocoria = abnormal white reflection from the retina of eye Expressed by 5 years of age in nearly all cases 90% penetrance; only develops if individuals are homozygous so have the two hit mutation Expression varies: sporadic form of mutation more mild & family inheritance is severe Treatment for cancerous tumours: chemotherapy, radiation, laser therapy People who have only sporadic mutations are unable to pass the mutation onto their offspring as it occurs in the somatic cells rather than the germ-line cells. Disease Type of Genetic Disease Neurofibrom atosis Type 1 Autosomal Dominant 50% inherited 50% de novo mutations Neurofibrom atosis Type 2 Autosomal Dominant Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Management Mutation in the NF1 gene from missense, nonsense, insertions or deletions. Normally NF1 is a tumour suppressor gene that produces neurofibromin which causes a block of the oncogene RAS function, preventing tumour growth. Mutations result in a loss of function. Requires 2 hits of mutated allele; often one inherited then other will be somatically inactivated. Changes in skin colouring (pigmentation = café-au-lait macules) and the growth of tumours along nerves in the skin, brain and other parts of body. Neurofibroma = swelling of a peripheral nerve caused by the thickening of the nerve sheath or connective tissue; tumour growth around the neurons. 50% have learning difficulties or ADHD —> pleiotropy 1 in 3,000 to 4,000 people are affected worldwide Surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas; surgery needs to be complete or will re-grow and need to be repeated. Mutations in the NF2 gene that cause a loss of function of the tumour suppressor protein merlin; missense, nonsense or frameshift. Requires; first allele inherited from parents, second has been somatically inactivated. Additional genetic changes can also facilitate tumour growth in these patients Results in the growth of noncancerous tumours in the nervous system and leads to deafness; vestibular schwannomas or acoustic neuromas. Loss of hearing in teens with tinnitus and balance problems, tumours in both ears by 30yrs; tumours can develop elsewhere in the nervous system and symptoms vary according to location. Incidence of 1 in 33,000 Treatment of vestibular people worldwide; less schwannoma is primarily common than surgical neurofibromatosis type 1 and less severe Quality of Life & Outlook Life span is approximately 8 years lower than the general population 100% penetrance (if inherit the allele, will express the phenotype) but there is a range of expression Normal lifespan Quality of life; loss of hearing Need to be aware of insidious problems with balance and underwater disorientation which can result in drowning Penetrance is 100% Disease Colour Vision Deficiency (colour blindness) Hypophosph atemic Rickets Type of Genetic Disease X-linked Recessive X-linked Dominant (bone disorder) Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Management Quality of Life & Outlook Red-green colour deficiency results from unequal cross over when homologous chromosomes misalign during replication; one chromosome gets both copies of green opsin gene. Children that inherit the chromosome without the gene are colourblind. Also OPN1LW (yellow/ orange detection) and OPN1MW (yellow/green detection) code for pigment proteins opsin; without can’t see the colour Depending on which gene is missing will cause the lack of production of an opsin protein which causes the inability to see that colour. Pedigree pattern: need both alleles to be missing the gene, in which case it is common in males and rarely seen in females; a female will inherit from her affected father, be an undetected carrier and then pass on the allele to her son who will be affected —> ‘skips’ a generation as carriers and then expressed in the next generation in sons. Not a lethal disease, just have difficulty distinguishing colours Mutation in the PHEX gene which encodes for a 749 amino-acid polypeptide which plays a role in Vitamin D synthesis and phosphate metabolism Causes low levels of phosphate in the blood (hypophosphatemia) which leads to a lower than normal amount of calcium being deposited in the bones; weakens &softens bones. Bowing of the legs, Individuals are resistant pigeon-breast deformity, to vitamin D treatment curvature of spine, increased tendency for bones to break easily, squaring/flattening of skull. Teeth take longer to appear and enamel is softer. 1 in 20,000 newborns Typically 9:4 (2:1) females:males affected because have double the chance to have mutated allele on X chromosome. Females can inherit from mother or father, males can only inherit from mother. Not a problem if inherit the chromosome with two copies of the gene, only a problem if don’t inherit any copies of the gene at all (after the misalignment when there is one chromosome with both and one with no copy of the gene) Disease Duchenne Muscular Dystrophy (DMD) Haemophilia Type of Genetic Disease X-linked Recessive (muscle disorder) X-linked Recessive (blood disorder) Symptoms/ Manifestation of Disease Screening & Diagnosis Dystrophin Gene (DMD) is the largest known gene in human genome; 2.3mega bases so large area for issues to arise Dystrophin is a critical structural protein in muscle; part of a complex that spans membrane attaching to ECM = connects proteins to actin forming costamere to maintain structure (strength) and function of muscle contraction. Common mutation is deletion of exon 50 = premature stop codon (nonsense = loss of function) Progressive muscle atrophy and weakening; primarily skeletal and cardiac muscles Generally normal muscles until 1-3yrs, delayed milestones, weakness progresses from proximal pelvic girdle, later shoulder girdle then face; problems swallowing and breathing. Gowers’ Manoeuvre to rise from floor (use lock knees and arms rather than core muscles). Hypertrophy (pseudo) of calf muscles; increasing in size due to accumulation of fat and fibrous connective tissue (collagen) because muscle stem cells can’t repair themselves effectively DMD Therapy = exon skipping; get rid of the mutation regions (exon 50 & 51 - use antisense RNA to bind with exon 51 so protein production will skip past this exon) to remove premature stop codon, shift the reading frame still causing truncation, but is still functional (only lose the two exons not everything else that comes after as well) Progressive= wheelchair by10-12yrs, die by 20yrs Most common cause of death is cardiac muscle/ respiratory failure because skeletal muscle in diaphragm needed to breath. Females: generally carries with one working DMD gene is enough to protect from skeletal muscle weakness even with Bar body random inactivation. Still exhibit the cardiac phenotype. Incidence of homozygous females extremely rare and mostly from de novo mutations in germ cells Mutation in F8 gene responsible for making coagulation factor VIII; 80% cases, severe = Haemophilia A. Mutation in F9 gene responsible for making coagulation factor IX; mild = Haemophilia B Mutations in gene mean that there is the inability to properly form blood clots: severity depends on where blood clotting pathway is affected: Haemophilia B interrupt pathway earlier on so only disturbs contact factor pathway = mild; Haemophilia A interrupt later so both contact & tissue factor affected = severe phenotype Haemophilia A = 1:4000 to 1:5000 males —> more severe Treated with blood transfusions and infusions of blood derived anti-haemophilic factor; this is expensive and has risk of contracting severe diseases (AIDS/hepatitis) Recent development of recombinant clotting factors has alleviated this problem Without adequate treatment, very few live to reproductive age as any small cut or haematoma (e.g. small bruise) is fatal Mechanism Occurs almost exclusively in boys (1:2500 to 1:5000) because need two mutated alleles for females. Haemophilia B = 1:20000 —> more mild Management Quality of Life & Outlook Disease Type of Genetic Disease Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Tay-Sachs Disease Autosomal Recessive Single based mutation in the HEX-A gene located on chromosome 15. Is responsible for encoding the betahexosaminidase A alpha subunit of the hexaminidase A proetin. Normally the alpha subunit is present in neurons and destroys the ganglioside chemical to prevent a build-up in nerve cells. Because the protein is not functioning, there will be a build up of chemicals and fat in the nerve cells, which consequently destroy the brain and spinal cord. Appear normal at birth but over the first few years of life start to degenerate and lose the ability to function. Seizures, vision and hearing loss, intellectual disability, paralysis. Most commonly the infant form, but can be later-onset where symptoms don't become present until older childhood, adolescence or adulthood. Kennedy Disease X-linked Recessive Mutation of the AR gene which leads to expansion of CAG repeats (>35) in the Androgen receptor protein. Toxic gain of function; protein aggregates and accumulates becoming toxic to motor neurons. Also loss of function: reduced androgen binding, decreased transcription of androgen receptor, reduced transcriptional activation of targets; androgen receptors abnormal/not functional Neuropathy Progressive muscular atrophy disorder of specialised nerve cells in spinal cord that control muscle movement (motor neurons); spinal & bulbar (face/throat) atrophy. Starts with proximal and as progress becomes more distal; difficulty climbing stairs, 1/3 people in wheelchair 20yrs after onset. Problems with speech and swallowing. Some males infertile due to androgen receptor involvement Age of onset is 30-50 1 in 150,000 males Often misdiagnosed for Amyotrophic Lateral Sclerosis (ALS) which is the absence of muscle nourishment of the side of spine leading to hardening/scaring. Although clear distinctions are affects women as well equally, fast progression, upper motor neurons affected, only inherited in 10% of cases, slightly later onset Management Quality of Life & Outlook Children with the severe infant form generally don’t live past early childhood, and symptoms and quality of life degenerate in the first few years after birth. Wheelchair, modifications in house to assist movement, help with day to day activities. No cure. Normal life expectancy but quality of life much reduced; struggle with every day activities Homozygous females tend to have more mild phenotype with muscle cramps/occasional tremors; lower androgen levels in females so doesn’t affect them as much and have less muscle atrophy Disease Mitochondria l Disease Type of Genetic Disease Mitochondr ial = inherited maternally Mechanism Symptoms/ Manifestation of Disease Screening & Diagnosis Range of different mutations can be inherited due to heteroplasmy of mitochondrial DNA (each mitochondria has multiple copies of the genome and each cell has multiple copies of DNA) e.g. Leigh disease = MT-ATP6 gene mutation that codes ATPase6 = causes ATP & ETC deficiencies Vary variable due to differences in mutations = clinical heterogeneity Predominantly brain (needs glucose for energy can’t get without mitochondria) Muscle disease (mitochondrial myopathy), nerve disease, cardiac disease (cardiomyopathies), endocrine, renal, bone marrow diseases Lactic acid accumulation (acidosis) Very complicated due to the wide range of mutations that can cause the diseases; can be uncertain what percentage of affected mitochondria will be given to the ova Management No cure; manage symptoms and secondary disorders e.g. Leigh Disease: administration of thiamine (Vitamin B1) if a deficiency of pyruvate dehydrogenase is suspected; will allow pyruvate to enter TCA cycle. Oral sodium bicarbonate/citrate to manage lactic acidosis Quality of Life & Outlook Due to the variability in DNA present and the mutation in the mitochondrial gene, it is very hard to predict the outcomes and probabilities of certain events; more an individual patient basis