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!