SINGLE GENE DISORDERS
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1 Umm AL Qura University SINGLE GENE DISORDERS Dr Neda M Bogari
2 To date over single gene traits and disorders have been identified. Most of these are individually rare but together they affect between 1% and 2% of the general population. The management of these disorders in affected individuals and in their extended families presents a major challenge for clinical genetics.
3 HUNTINGTON'S DISEASE (HD)
4 The natural history of HD is characterised by slowly progressive cell death in the central nervous system, for which there is no effective treatment or cure. The prevalence in most parts of the world is approximately 1 in 15,000. Generally HD is a disorder of middle to late adult life.
5 In adult HD disease is characterized by: a slowly progressive movement disorder. impairment of intellectual function with psychiatric disturbance and eventual dementia. The average age of onset is around 40 years and the mean duration of the illness is approximately 15 years.
6 In approximately 10% of cases the disorder presents before the age of 20 years, and so called Juvenile HD disease. The average duration of the illness is around years
7 HD is an autosomal dominant disease, close to complete penetrance. It has been noted that the disorder often shows anticipation. HD gene was located on the short arm of chromosome 4. Mapping the gene providing the first means of predictive testing for HD This work also revealed that HD homozygote are no more severely affected than heterozygote
8 the HD gene contain a highly polymorphic CAG repeat sequence located in the 5' region. The messenger RNA codes for a protein of approximately 350 kda, known as huntingtin. Huntingtin is expressed in many different cells throughout the central nervous system although its function remains unclear. One proposed role is that it is involved in apoptosis, i.e. cell death.
9 Normal alleles: containing 26 or fewer CAG repeats. Allele sizes of 27 to 35 CAG repeats do not cause disease but show meiotic instability with a potential increase or decrease in size. These 'mutable' alleles, constitute a reservoir for new mutations.
10 Reduced penetrance alleles are the third category, these alleles containing 36 to 39 CAG repeats. These are associated with either late onset disease or complete absence of disease expression, i.e. non-penetrance.
11 Disease alleles contain 40 or more CAG repeats. There is a direct relationship between length of repeat and disease expression: the average age of onset for repeat sizes of 40, 45 and 50 being 57, 37 and 26 years respectively. Most affected adults have repeat sizes of between 36 and 55, whereas juvenile cases often have an expansion greater than 60 repeats.
12 SUMARY
13 HD is an Autosomal dominant inheritance with an offspring risk of 1 in 2 regardless of whether the affected parent is male or female. For reasons which are not understood, meiotic instability appears to be much greater in spermatogenesis than in oogenesis.
14 The discovery of the HD gene has meant that accurate predictive testing is possible, although this should only be offered as part of a well-planned and carefully monitored counselling package. Experience to date indicates that more women than men take up the offer of predictive testing, with the degree of psychological disturbance in those given positive results being less than was expected. Prenatal diagnosis is also possible for those couples who feel that this is acceptable.
15 Obviously there are considerable emotional and ethical issues associated with termination of pregnancy on the grounds that a child could go on to develop a neurodegenerative disease in middle age. This will be particularly important when effective therapeutic strategies have been devised. One appealing approach is based on the observation that large CAG repeats result in intracellular accumulation of huntingtin 'aggregates', which are cleaved by a protease known as caspase to form a toxic product which causes cell death (apoptosis). Caspase inhibitors have been shown to have a beneficial effect in an HD mouse model. Other suggested therapeutic approaches include injection of fetal stem cells into affected regions of the brain.
16 MYOTONIC DYSTROPHY
17 Multisystem disorder. associated with cataracts, myotonia, weakness, frontal baldness and mental retardation. Gene on chromosome 19q13.3 called myotonin. Its an autosomal dominant disease and it becomes more severe as it is passed from generation to generation.
18 MYOTONIC DYSTROPHY
19 The increasing severity of the disease through generation called anticipation. mutation is expansion of a CTG repeat in the 3 untranslated region of protein kinase gene (Dystrophia myotonica protein kinase (DMPK). the expansion increases as it goes from one generation to the next via a female affected.
20 In unaffected: CTG repeats 37 times. Affected: CTG repeats 50 time or greater. Close correlation between the number of CTG expansion and the severity of the disease. Larger CTG expansion increase the severity of the disease.
21
22 Summary
23 NEUROFIBROMATOSIS
24 There are two main types of neurofibromatosis, NF1 and NF2.
25 Autosomal dominant Prevalence 1 in 3000 diagnostic criteria - need 2+ for diagnosis café au lait spots (CAL) - 6 or more: it s a small lightbrown pigmented lesions. neurofibromas - 2 or more: it s a benign tumours which arise most commonly in the skin.
26 axillary freckling Lisch nodules (specks in iris): These are small harm less raised pigmented hamartomata of the iris. optic glioma thinning of long bone cortex family history
27 Macrocephaly ( head is abnormal large) Short stature Dysmorphic features (difference of body structure) Learning difficulties Epilepsy Scoliosis Pseudoarthrosis of the tibia Raised blood pressure Neoplasia ( abnormal mass of tissue ) CNS (optic gliomas), endocrine
28 Autosomal dominant Variable expression inter-familial and intra-familial Gene identified - 17q tumour suppressor gene Mutations different in different families therefore no simple diagnostic test 50% due to new mutations usually paternal in origin
29 Neurofibromas Neurofibromas: These many be frequent and very prominent as in the individual in (A). They also may be more subtle and isolated as in (B).
30 Sequence analysis of the NF1 gene has shown that it encodes a protein, known as neurofibromin. plays an important role in signal transduction by down regulating RAS activity. Mapping of the NF1 gene has provided a means of offering both presymptomatic and prenatal diagnosis using either linkage or direct mutation analysis.
31 The main features of NF2 are: CNS and spinal tumours a few CAL spots NF2 gene is on Chromosome 22q
32 Sumary
33 Summary
34 CYSTIC FIBROSIS IN CHILDHOOD
35 The commonest inherited life-shortening disorder amongst Northern European populations Inherited as an autosomal recessive trait CF incidence = 1 in 2000
36 The abnormality in CFTR explains the pathology of cystic fibrosis. High sodium sweat: Primary secretion of sweat duct is normal, but CFTR does not absorb chloride ions, which remain in the lumen and prevent sodium absorption. Pancreatic insufficiency: Production of pancreatic enzymes is normal but defects in ion transport produce relative dehydration of pancreatic secretions causing their stagnation in the pancreatic ducts. Biliary disease: Defective ion transfer across bile duct causes reduced movement of water in the lumen so that bile becomes concentrated causing plugging and local damage.
37 GI disease: Low volume secretions of increased viscosity, changes in fluid movement across both small and large intestine, dehydrated biliary and pancreatic secretions cause intra luminal water deficiency. Respiratory disease: Dehydration of the airway surfaces reduces mucociliary clearance and favors bacterial colonization, local bacterial defenses are impaired by local salt concentrations and bacterial adherence is increased by changes in cell surface glycoproteins. Increased bacterial colonization and reduced clearance produces inflammatory lung damage due to an exuberant neutrophilic response involving mediators such as IL8 and neutrophil elastase.
38 Cloned in 1989 Lies on the long arm of chromosome 7 Codes for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR) CFTR acts as a chloride transport channel The net effect is to reduce the level of intracellular sodium chloride, which improves the quality of cellular mucus secretions
39 The Cystic Fibrosis Gene
40 CF shows autosomal recessive inheritance ΔF508 mutation accounts for the majority of mutations a deletion of three adjacent base pairs which results in the loss of a phenylalanine residue Over 1300 other mutations in CFTR have been identified. These include missense, frameshift, nonsense and deletion mutations. Most of these are extremely uncommon, although a few can account for a small but significant proportion of mutations in a particular population.
41 Cystic fibrosis (CF) Gene The remarkable spectrum of mutations (and polymorphisms) in the CFTR gene. The density of the lower line emphasizes the broad spectrum of changes and the difficulties that can develop attempting testing on the basis of suspected mutation(s).
42
43 Mutations in CFTR can influence the function of the protein product by: 1. causing a complete or partial reduction in its synthesis, e.g. G542X and IVS8-6(5T) 2. preventing it from reaching the epithelial membrane, e.g. AF causing it to function incorrectly when it reaches its final location, e.g. G551D and R117H. The net effect of all these mutations is to reduce the normal functional activity of the CFTR protein.
44 Acts as a chloride transport channel Expressed in epithelial cells Pancreas cystic fibrosis (reduced enzyme secretion) Bronchial tree recurrent infections Sweat glands useful diagnostic test Rectum can result in rectal prolapse Cervix female underfertility Epididymis male infertility Upper respiratory tract sinusitis and polyposis
45 Summary
46 Pancreatic insufficiency Maldigestion Abnormal stools Failure to thrive Recurrent bronchopulmonary infection Pneumonitis Bronchiectasis Scarring Abscesses
47 Reduced or absent secretions Enzymes (lipase, amylase, trypsin) Bicarbonate Malabsorpition Fat, protein, complex carbohydrates Not simple carbohydrates Fat soluble vitamins: A, D & E
48 Early years Staph aureus Homophiles influenza Later years Pseudomonas aeruginosa Prone to have antibiotic resistant organisms Improved antibiotic therapy probably main reason for enhanced survival Choice of antibiotic best left to specialist clinic
49 Mainly older children and adults Symptoms may be severe due to underlying lung disease Strong tendency to recur Surgical management with pleurodesis best for the pneumothorax may inhibit later transplantation
50 Symptoms Wheeze Cough Shortness of breath Rust-colored sputum (occasionally) Focal infiltrates on chest X-ray Aspergillus & anti-aspergillus Antibodies Treatment with corticosteroids
51 Following neonatal screening Neonatal meconium ileus Intestinal obstruction by inspissated undigested intestinal contents, often with perforation and peritonitis
52 Neonatal meconium ileus Failure to thrive
53 Neonatal hepatitis syndrome Recurrent rectal prolapse Heat stroke due to salt loss Delayed growth and pubertal development Upper respiratory tract involvement Male infertility
54 Affects about 10% eventually Impaired glucose tolerance even commoner Not necessarily easily managed Anorexia Malabsorpition Refined CHO easily absorbed Adverse effects of infection Liver disease
55 Malabsorpition Abdominal pain Diarrhoea Flatus Recurrent infection Liver disease Inactivity Avoidance of enzymes
56 CF - Complications Diabetes Anorexia CF Hepatopathy Picture shows ascites in a child with abdominal scars from surgery for meconium ileus
57 Sedentary indoors existence Hypoxia Chronic infection and inflammation Bone density correlates with C-reactive protein Liver disease Malabsorpition of fat soluble vitamins Pubertal delays
58 Malabsorption, esp fat malabsorption Diabetes Hepatopathy Anorexia Lack of exercise
59 CF - Complications Diabetes Anorexia Hepatopathy Osteoporosis Arthritis
60 CF - Complications Diabetes Anorexia Hepatopathy Osteoporosis Arthritis Psychological disturbances Almost invariable Involve family as much as patient Requires professional input Clinical psychologist Social worker
61 CF - Other GI Complications Neonatal jaundice Distal intestinal obstruction syndrome Gastro-oesophageal reflux Rectal prolapse Pancreatitis Gall stones
62 Salt depletion Acrodermatitis enteropathica Hypoprothrombinaemia Rickets & other fat-sol vitamin deficiencies
63 Constantly improving Median age at death projected around 30 yrs
64 CF - Prognosis Constantly improving Median age at death projected around 30 yrs Main causes of death Respiratory failure Hepatopathy Male Female 3-D Column <5 5-<10 10-<15 15-<20 20-<25 25-<30 30-<35 35+
65 May thrive surprisingly well on breast milk May not have obviously malabsorptive stools, but classically stools are Pale or orange Very offensive Greasy or oily Importance of record-keeping, charts,etc May have deficiencies of fat soluble vitamins
66 CF - Antenatal Screening Establish CF gene distribution in local population Couple screening vs sequential screening Ethical issues re improving prognosis Economic issues re increasing costs of CF care May be combined with post-natal screening
67 Raised immunoreactive trypsin (IRT) on heelprick blood (performed with Guthrie, thyroid and other neonatal screening tests) High false positive rate So combined with gene mutation analysis But will miss up to 30% by including gene testing
68 Probably improves prognosis to be identified early Does permit rational decisions re future reproduction - including extended family Does avoid unnecessary investigation, confusion of wrong diagnoses (and hence wrong treatment), etc
69 Now parents of an affected child can almost always be offered prenatal diagnosis, either by direct mutational analysis of DNA from chorionic villi, or by linkage analysis using polymorphic markers if one or both of the mutations in the affected child cannot be identified.
70 Cystic Fibrosis - Gene Therapy Introduce with adenovirus Inflammation Immunogenic Introduce with liposomes Physically difficult to generate particles in respirable range (2-6 microns) for deposition in airway
71 DUCHENNE MUSCULAR DYSTROPHY
72 1/3500 live born males affected affected boys may appear normal until 4/5 yrs of age when evidence of awkward gait, inability to run and difficulty climbing stairs is noticed progressive weakness and muscle wasting leads to wheelchair by about 14yrs
73 Weakness is predominately proximal Associated with calf muscle hypertrophy Death due to respiratory failure by 20 yrs
74 Affected boys have grossly elevated levels of creatine kinase between ,000 iu (normal to 50) Muscle biopsy shows variation in fiber size, necrosis with replacement of muscle fiber with fat and connective tissue Two thirds of carrier females have and elevated creatine kinase
75 X-Linked Recessive Inheritance Carrier female Affected male Normal male Mutant genes are on the X (sex) chromosome Women must inherit 2 mutated copies to be affected All men who inherit the mutation are affected (only one X chromosome)
76 X-linked recessive gene on Xp21 and called dystrophin mutation in two thirds of cases is a deletion 1/3 cases are a new mutation high new mutation rate due to the large size of the gene (2 x 10 6 bp) Accurate carrier detection can now be achieved for most female relatives of affected DMD males by direct mutation/deletion analysis or indirectly by linkage studies using polymorphic intragenic markers.
77 Dystrophin protein is normal along the plasma membrane of muscle cell In DMD this protein is absent Female heterozygous showed normal and defective cells.
78 There is no known cure for Duchenne muscular dystrophy. Treatment is aimed at control of symptoms to maximize the quality of life. Gene therapy may become available in the future. Activity is encouraged. Inactivity (such as bedrest) can worsen the muscle disease. Physical therapy may be helpful to maintain muscle strength and function. Orthopedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care.
79 Experiments in mice have supported the idea of treating Duchenne muscular dystrophy (DMD) by implanting normal muscle precursor cells into dystrophin-deficient muscles. However, similar experiments on DMD patients have had little success. Gene therapy for DMD, by introducing dystrophin constructs via retroviral or adenoviral vectors, has been shown to be possible in the mouse, but the efficiency and safety aspects of this technique will have to be carefully examined before similar experiments can be attempted in man.
80 Direct injection of dystrophin cdna constructs into mdx muscles has given rise to very low levels of dystrophin and this may be a possibility for the treatment of heart muscle.
81
82 HEMOPHILIA
83 Hemophilia is one of hereditary genetic disorders that damage the body's ability to control blood clotting or coagulation. There is two classes of hemophilia Hemophilia A, clotting factor VIII is absent. In Hemophilia B, factor IX is deficient. These two factor have a major role in the intrinsic pathway activation of prothrombin to thrombin. Which then converts fibrinogen to fibrin which form structural framework of clotted blood The incidence of Hemophilia Hemophilia A is about 1 in 5,000 10,000 male births, whilehemophilia B occurs at about 1 in about 20,000 40,000
84 The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels, which are the most widely used criteria. Persons with less than 1% normal factor (<0.01 IU/ ml) are considered to have severe hemophilia. Persons with 1-5% normal factor ( IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to <0.40 IU/mL) are considered to have mild hemophilia.
85 Clinical bleeding symptom criteria have been used because patients with FVIII or FIX levels less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.
86 The genes for both FVIII (ie, hemophilia A) and FIX (ie, hemophilia B) are located on the long arm of chromosome X. The gene for FVIII (F8C) located within the Xq28 region, is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects.
87 Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor. The FIX gene (F9), located within the Xq27 region, has 34 kb and composes 8 exons and 7 intervening sequences. The mature protein is composed of 415 amino acids. Point mutations and deletions in the FIX gene are the most common causes of hemophilia B.
88 The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.
89 Though there is no cure for hemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in hemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some hemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or nonhuman replacement products must be given, such as porcine factor VIII or by immunosuppresion.
90
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92 Thank you
SINGLE GENE DISORDERS
Umm AL Qura University SINGLE GENE DISORDERS Dr Neda M Bogari To date over 10 000 single gene traits and disorders have been identified. Most of these are individually rare but together they affect between
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