Genetics Flashcards

Question

Von-Hippel Lindau syndrome

Answer 1

An autosomal dominant condition of mutations in the VHL protein leading to neoplasia Most commonly haemoangiomas with risk of secondary haemorrhage Features: - Cerebellar haemangiomas - Retinal haemangiomas - Renal and extra-renal cysts - Phaeochromocytoma - Clear cell renal cell carcinoma

Answer 2

Mutations to ENaC such that excessive sodium reabsorption occurs in the collecting ducts Features: - Hypokalaemia - HTN - Metabolic alkalosis

Answer 3

Barters - Thick loop of Henle - Impaired Na+/Cl- reabsoprtion - Normotensive - Failure to thrive - Normal magnesium - Elevated renin + aldosterone - Hypokalaemia + metabolic alkalosis Gitelman - Distal convoluted tubule - Impaired Na+/Cl- reabsorption - Normotensive - Normal development - Hypomagnesaemia - Elevated renin + aldosterone Liddle - Collecting ducts - Excessive Na+ reabsorption - Early-onset hypertension - Normal development - Normal magnesium - ?normal renin + aldosterone

Answer 4

Inherited disorder of type IV collagen synthesis - Variable inheritance patterns, majority X-linked - Most notably affects glomerular basement membrane - Also impacts function of inner ear Features: - Progressive renal failure - FSGS with haematuria, proteinuria, HTN - Sensorineural hearing loss - High frequency lost first - Lenticonus Investigations: - Bloods - Echo - LVH or aortic abnormalities - Renal biopsy - Genetic testing

Answer 5

Aetiology: - Mutations in muscle VGCCs - AD - Onset in adolescence Features: - Episodic severe muscle weakness - Triggered by strenuous exercise or high carbohydrate diet - Resolve over 24-72hr - Hypokalaemia Management: - Acute - KCl, although normally self-resolves - Long-term - Trigger avoidance - Acetazolamide or spironolactone

Answer 6

Autosomal recessive Features: - Hypoparathyroidism (90%) - Mucocutaneous candidiasis - Adrenal insufficiency (60%) - Primary gonadal failure - Primary hypothyroidism - Rarely, hypopituitarism or diabetes insipidus

Answer 7

Autosomal recessive, autosomal dominant, or polygenic Features: - Adrenal insufficiency - Hypothyroidism - T1DM - Gonadal failure - Rarely, diabetes insipidus

Answer 8

Types of error: - Disorders of carbohydrate metabolism e.g. glycogen storage disease, G6PD deficiency - Disorders of amino acid metabolism - Organic acidaemias - Urea cycle defects - Disorders of fatty acid oxidation e.g. MCADD - Disorders of porphyrin metabolism e.g. AIP - Disorders of purine/pyramidine synthesis e.g. Lesch-Nyhan syndrome - Peroxisome disorders e.g. Zellweger syndrome - Mitochondrial disorders - Lysosomal disorders e.g. Fabry, Gaucher, Niemann-Pick Heelprick screening - phenylketonuria (PKU) - medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - maple syrup urine disease (MSUD) - isovaleric acidaemia (IVA) - glutaric aciduria type 1 (GA1) - homocystinuria

Answer 9

Aetiology: - Autosomal recessive mutations in cystathione beta synthetase - involved in conversion of methionine to cystine + serine, homocystine is intermediate Features: - Mental retardation - Appearance: - Tall - Arachnodactyly - High-arched palate - Pectus excavatum - Cardiac: - AR and MR - Coronary artery thrombosis - Vascular - Increased risk of DVTs - Ophthalmological: - myopia - Lens dislocation - Retinal detachment - Osteoporosis Investigations: - May be picked-up on neonatal heelprick screening - Urine - Positive cyanide nitroprusside test - Presence of homocysteine Management: - Folic acid supplementation - Pyridoxine - Low methionine diet

Answer 10

X-linked recessive disorder - More common in Mediterranean, Middle-Eastern, and African patients Pathophysiology: - Involved in the pentose phosphate pathway - Roles in maintaining red cell membrane flexibility and haem oxygenation - Deficiency leads to increased rigidity + methaemoglobinaemia which together promote haemolysis Features: - Acute haemolytic anaemia - Triggers include infection and medications e.g. quinines, trimethoprim, fava beans - Gallstones - Neonatal jaundice - Methaemoglobinaemia Investigations: - Blood film - Heinz bodies - denatured haemoglobin - G6P assay Management: - Treat/avoid triggers - Blood transfusion

Answer 11

Mutation of 1-4 of the alpha-haemoglobin chain genes causing inactivation Phenotypes: - Single inactivation - 'Trait' - Microcytic hypochromic cells, no anaemia - Double inactivation - Microcytic hypochromic cells +/- mild anaemia - Triple inactivation - HbH disease - Microcytic hypochromic anaemia - Splenomegaly - Complete inactivation - Hydrops fetalis with death in utero

Answer 12

Mutation in beta-haemoglobin genes leading to inactivation or reduced function Absence/reduction in beta-chains also leads to overproduction of alpha chains and alternative types of haemoglobin Phenotypes: - Major - no functional copies - Microcytic anaemia beginning at young age (3-6 months) - Mild jaundice - Failure to thrive - Splenomegaly - Bone deformities - Regular transfusions + iron chelation - Intermedia - reduced function/quantity - Microcytic anaemia require occasional transfusions - Trait - Mild microcytic anaemia - Raised HbA2 - Raised red cell count Management: - Monitoring - Hb - need for transfusion - Ferritin - need for iron chelation - Blood transfusions - Prophylactic splenectomy - Bone marrow transfusion

Answer 13

Pathophysiology: - Glu -> Val in the haemoglobin beta-chain - Causes chain to become insoluble and crystallise whilst in the deoxy state - Haemolysis - Cell deposition/entrapment in small blood vessels Features: - Chronic haemolytic anaemia - Hyposplenism - Increased infection risk Management: - Avoid any triggers for crises - Vaccination + prophylactic antibiotics if hyposplenic - Hydroxycarbamide - Stimulates production of HbF which does not sickle - Exchange transfusion - Bone marrow transplant Complications: - Stroke - Avascular necrosis of the large joints (e.g. hip) - Pulmonary HTN - Priapism - CKD secondary to papillary necrosis - Retinopathy - Acute chest crisis - Acute pain crisis - Osteomyelitis of the long bones

Answer 14

A rare autosomal recessive disorder of the bone marrow - Due to mutations in the FA/BRCA DNA repair pathway Features: - Aplastic anaemia - Presents at c. 5 years - Short with microcephaly - Horseshoe kidney - Abnormal pigmentation

Answer 15

Aetiology: - Autosomal dominant - Inactivating mutation of protein kinase A (PKA) on Chr 17 Features: - Spotty skin pigmentation - Myxoma - Psammomatous melanotic schwannoma (PMS) - Endocrine tumours Diagnosis: - Two features - One feature + affected relative