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GENETICS RELEVANT TO
ANAESTHESIA
Dr. MRIDUL M. PANDITRAO Consultant
Department of AnesthesiologyRand Memorial Hospital
FREEPORT, BAHAMAS
Introduction
• “ All humans are born Equal ”• Irrespective of our Color, Creed, & Race, we all
share 99.9% genetic material.• 0.1% variability: Polymorphisms• Polymorphisms differentiate us• Phenotypically these are expressed as genetically
transmitted diseases• Polymorphisms play role pharmacodynamically/
kinetically through biologically active substances
Introduction
• Via functioning of various enzymes, neurotransmitters / modulators
• Polymorphisms: May occur at single or multiple nucleotides , as insertions or deletions
• May be of importance for anaesthestic practice• A wide spectrum From mild influence to life
threatening consequences• Well acquainting by anaesthesiologist is must
Introduction
• Some early examples, which made us aware: Prolonged apnea after Succynil Choline Thiopentone induced Porphyria Malignant Hyperthermia
• In addition to Certain Factors like age, sex etc, genetic profile is also assuming utmost importance
Types of Genetic disorders
• Single gene disorders : Mendelian/ monogenic
• Polygenic disorders
• Multi Factorial Problems
• Chromosomal Abnormalities
Single gene disorders
• Autosomal : Achodroplasia• Autosomal Recessive: Sickle Cell
disease, Cystic Fibrosis• X linked Disorders: Mother to offspring
e.g. hemophilia• Y linked Disorders: father to son
Polygenic disorders
By combination of 2 or more genes e.g. • Coronary Artery Disease• Diabetes Mellitus• Hypertension• Peptic Ulcer
Multi Factorial Problems
Combination of Polygenic and environmental factors
e.g.• Asthma• Autism• Mental Retardation• Cleft Palate
Chromosomal Abnormalities
• Due to abnormalities of Number or structure of chromosomes
• Chromosomal sequence – deletions, inversions or translocations
e.g.• 21 Trisomy- Down’s Syndrome• Turner’s Syndrome
Mitochondrial Mutations
• Exclusively through mitochondrial DNA• Mitochondria are kept in egg cells during
fertilization• So always inherited from female pattern e.g.• Leber’s Hereditary Optic neuropathy• MERRF (type of epilepsy)
Genetics and Anaesthesia
• What do genetic variations do to Pre-operative assessment/ Preparation, anaesthetic/ Intra-operative management & Post operative Care
• How do the anaesthtic agents/ management influence the genetic make up of the humans
Influence of Genetic Expression/ Disorders on Anaesthetic Management
• Developmental anomalies• Affect anaesthetic management• Anatomic / physiologic changes• Challenges from pharmacological,
biochemical, structural, functional and procedural point of view
• Specific problems must be considered
Problems
• Airway Abnormailities / difficulties
• Micrognathia and relative macroglossa
• Congenital / developmental cardiac defects
• Renal / Hepatic
• CNS / Mental Retardation
Airway Abnormalities/difficulties
• Major concern for Anaesthesiologist• Anatomical/ developmental defects (Cranio-facial)• Anomalies of airway e.g. Cleft Lip/ palate Developmental Tumors ; Neuromas Choanal atresia Tracheo-oesophagial fistula
Micrognathia and relative macroglossa
• Difficult airway: intra as well as post –operative e.g. Achondrogenesis I & II Pierre- Robin WAGR Noonan’s, Fryn’s Brachio-Occulo- Facial
Congenital/ developmental cardiac defects
• Second most common set of anomalies• Usually in association with other
developmental anomalies especially Cranio-facial, vertebro-skeletal, thoracic many examples
Congenital/ developmental cardiac defects
• Antley- Bexeler• Klippel Feil, PKU, Fryn’s• Goldenhar• Trisomies 8 & 9• Turner’s, WAGR• Foetal diphenyl Hydantoin syndrome
Renal/ Hepatic
• Rarely singly, always in association• Always complicate post-operative mgt. e.g. Alpha Thallasemia Antley-Bixler BOF, Foetal Diphenyl Gopldenhar, Klippel-Feil Turner, Miller, WAGR
CNS/ Mental Retardation
• Mental retardation, a common and classical feature in syndromes:
Down’s Acrodystosis Alpha thallasemia Watson, Angelman’s, Cowden’s, Costello’s
Turner’s Syndrome
• Genotype: XO, Phenotype: Female• Broad chested, Web necked, Widely placed
nipples• Female Genital tract abnormalities• Anaesthetic Cosiderations : coexistance of
Micrognathia, Coarctation Of Aorta, Horse shoe Kidney and Vertebro- thoracic anomalies
Trisomies: 8, 8 mosaic, 9, 9 mosaic,13, 18, & 21
• Variety of presentations• Common to all : Growth and Mental deficiencies
/ retardation• Abnormal Facial features: difficult Airway• Cleft Lip/Palate, Micrognathia and Macroglossa• Cardio-thoracic defects,• Rarely, Cardiac and renal defects
Trisomies
• Anaesthetic consideration:• Complete haematological work up,• Radiological profile• Anticipated difficult intubation• Difficulties of co-existing other system
anomalies• Post-op speciallized care
Sickle Cell Disease
• Autosomal recessive, haemoglobinopathy• Altered RBC shape & increased viscosity of
blood secondary to hypoxemia• Anaesthesia: Must avoid Hypoxia, Hypercapnea, dehydration, hypothermia and acidosis G.A is preferred technique
Goldenhar Syndrome (Hemifacial microsomia)
• Defects in Facial structures• Mostly in first and second branchial arches• Vertebral and cardiac defects• Anaesthetic consideration• Pre-op: evaluation of upper and lower airway• Pulmonary, Hepatic and renal function tests• Intra op: I.V. Induction preferred ( inhalational
avoided)
Goldenhar Syndrome ( Hemifacial microsomia)
• NMBDs to be avoided• Smaller doses of Anti-cholinergics to be
used• Post-operative care absolutely essential
Klippel- Feil Syndrome
• Extremely short neck• Fusion of Cervical vertebrae• Other vertebral and cardiac abnormalities• Airway and neuraxial Block difficulties to
be anticipated
Marfan’s Syndrome
• Tall stature, archnodactyly & hyperextensibility
• Aortic Dilatation and subluxation of Lens• Scoliosis and Cleft Lip• Hypertensive response to Laryngoscopy• use of Beta Blockers recommended
Multiple Neuroma syndrome (MEN Type II)
• As in Marfans; Tall stature with Multiple neuromata of Facial structures ;
• lips, tongue, ganglia, oral & pharyngeal structures
• Medullary Ca. Thyroid, Kypho-scoliosis/lordosis• Difficult airway• Phaeochromocytoma
Poly-cystic kidney Disease
• Auto-somal dominant• Presents in 5th decade of life, • Cysts in Kidney, Lungs, liver, pancreas, spleen,
thyroid etc.• Leading to slow but progressive failure of
organs involved• ESRDS, pneumothorax, Hypertension• Other systemic problems
Polycystic Kidneys
Osteogenesis imperfecta Type I & II, Arthrogryposis Multiplex congenita
and others • Autosomal Dominant• Defect in Type I collagen synthesis• Resulting in defective connective tissue
synthesis and bone formation• Fragile, abnormal bones, growth and dental
anomalies• Blue sclera• Easy brusing and vertebral anomalies
Osteogenesis imperfecta
Arthrogryposis Multiplex congenita
Osteogenesis imperfecta Type I & II, Arthrogryposis Multiplex congenita
and others
• Pre-op airway , vertebro-skeletal assessment
• Anticipated difficult airway• Intra-op careful handling• Post-op ventilatory support?
Noonan syndrome
• Short stature, Web neck & pectus excavatus• Micrognathia, Cranio-facial • Pulmonary stenosis and cardiac • At very high risk of developing Malignant
Hyperpyrexia• GA to be avoided• Spinal is the technique of choice
Pierre Robin Syndrome
• Micrognathia, Macroglossa/ glossoptosis• Cleft lip/ palate• May have cardiac defects • Airway difficulties anticipated• Inhalational induction
Prader Willi
• Pronounced structural, truncal obesity• Short stature, scoliosis• Hypogonadism, mental defects• Cardio-respiratory problems: arrythmias,
conduction defects, COPD• Convulsions• Diabetes
Prader Willi
Neurofibromatosis
• Autosomal dominant, Multiple neufibromata• Not only in neuraxis, but in lx/ Nasophx• May have pulm. Fibrosis, Pheochromocytoma• Renal artery stenosis & hypertension• Carcinoids• Type I: von Recklinghausen • Type II: Bilateral Acoustic Neurofibroma
Neurofibromatosis
• Von Recklinghausen’s : Multiple neurofibromata, café au lait spots,
• Airway major problem• Inhalational induction recommended• Pulm fibrosis; complicates, Higher FiO2, • Enhanced sensitivity to NMBDs.
Achondrodysplasias
• Short limbed dwaqrfism, 1:15000-40000• Autosomal Dominant, defect in fibroblast
growth factor receptor 3 gene(FGFR3)• Short limbs, saddle nose, ant. epiglottis, small
chest, Pulmonary hypoplasia and Lordosis• Spinal, renal, anomalies• High anxiety and hydrocephalous• Extensive Pre-op and intra op care
Thalassemias α &β
• Classical X linked recessive disorders• Severe form of mental retardation • Typical cranio-facial defects, macroglossa• CNS, Vertebral and genital anomalies• Renal agenesis• & haemolytic anaemia
•
TEF/ Esophagial Atresia/VATER
• Vertebral Anomalies, Traheo Esophgial Fitula & radial dysplasia: singly or as Trisomy 18
• Laryngeal stenosis, pulmonary & Rib defects, limb deficiencies,
• Hemorrhages and hyperbilirubinemia• Detailed Radiological workup, systemic
evaluation
Cystic Fibrosis
• Autosomal recessive, mainly in Caucasian race• Chromosome 7 : gene mutation• New born; meconeum obstruction in 1st 24 hrs.• GI malabsorption, recurrent Pulm infection• Failure to thrive, late puberty, infertility• Coagulation defects : Vit K absorption deficient• Thorough work up
Anaesthesia on Genetic Make up
• Controversial, delicate yet important topic• No clear opinion: Mutagenecity/ teratogenecity• Nitrous Oxide controversy • Recent ‘evidence’: • Prevention and precaution , prudent decision
making imperative
Recent: Pharmacogenomics
• Defn.• Synchrony of two words: pharmacology and
genomics• intersection of pharmaceuticals and genetics• Of great importance from anaesthesia • Customization as per pt’s genetic make up,
specific conditions• tailor made applicability of anaesthesia
Pharmacogenomics: projected benefits
• Better, safer, trial-error free drugs• More appropriate methods for dosages• Advanced screening for diseases• Better vaccines• Faster drug discovery and approval process
Pharmacogenomics
• Cytochrome P 450 genes used to screen/ monitor patients
• Still in the trial phases
Conclusion
• Advances in genetics: opening new vistas,horizons of knowledge and understanding
• Anaesthesiologists: peri-op physicians• More and more challenges• This is Future
Thank
you!