Homocystinuria

- autosomal recessive
- reduced activity of cystathionine B-synthase
- accumulation of homocysteine and methionine interfere with collagen cross-linking
- similar to Marfan's syndrome, but with downward lens dislocation, venous and arterial thrombosis, developmental and mental retardation
- premature cardiovascular risk increased in heterozygote
- cyanide-nitroprusside test showed elevated urinary homocysteine
- management: methionine restriction, cysteine and pyridoxine supplements

Phenylketonuria

- autosomal recessive
- mutation of phenylalanine hydroxylase (chromosome 12)
- incidence 1:10,000
- inability to convert phenylalanine to tyrosine, results in hyperphenylalaninaemia and increased excretion of its metabolite (phenylketone) in urine
- presents with infantile spasm, developmental delay, musty smelling, pale skin, fair haired and blue eyed, eczema
- Guthrie screening test and measure level of phenylalanine by spectrofluorometric methods
- management: restriction of dietary phenylalanine with tyrosine supplement

Chromosome and genetic disease

Mnemonics
Marfan's syndrome : chromosome 15 (15 alphabates)
APKD 1 (Polycystic kidney) : chromosome 16 (16 alphabates)
Neurofibromatosis 1 / Von Recklinghausen : chromosome 17 (17 alphabates)

Note: The above are all autosomal dominant

PKD 2 : chromosome 4
NF type 2 : chromosome 22
Cystic fibrosis : chromosome 7
Haemochromatosis : chromosome 6
Huntington's disease : chromosome 4
Wilson's disease : chromosome 13

Human leukocyte antigen (HLA)

- found on chromosome 6
- HLA corresponds to MHC class I (A,B and C)
- HLA corresponds to MHC class II (D)

HLA associations
- HLA DR2 : SLE
- HLA DR3 : autoimmune hepatitis, Sjogren syndrome
- HLA DR4 : Felty syndrome
- HLA DQ2 / DQ8 : coeliac disease
- HLA B27 : AS, Reiter's syndrome
- HLA Cw6 : psoriasis
- HLA B8 : myasthenia gravis
- HLA B5 / B51 : Behcet's disease

Mucopolysaccharidosis I and II (Hunter's and Hurler's)

- MPS are group of metabolic disorder caused by absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans (lysosomal storage disorder)

MPS type I (Hurler's syndrome)
- autosomal recessive
- cloudy cornea
- severe mental retardation
- gibbus
- coarse facies
- hepatosplenomegaly

MPS type II (Hunter's syndrome)
- X-linked
- clear cornea
- scoliosis, no gibbus
- less severe mental retardation

Incretin

- 2 main incretins, GLP-1 (glucagon-like peptide-1) and GIP (glucose dependent insulinotropic peptide)
- secreted by L cells of ileum and colon
- incretin effect: insulin response to oral glucose is better than intravenous glucose
- promotes glucose induced insulin release from pancreatic beta cells, delays rate of gastric emptying, promotes satiety, reduce appetite in brain
- suppress postprandial glucose secretion
- GLP-1 analogue (exenatide) is given by twice daily subcutaneous injection
- dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1. DPP4 inhibitor (sitagliptin or vildagliptin)

VT versus SVT

Features that favour VT are
- QRS > 140 ms
- cannon a waves on JVP (suggest AV dissociation)
- fusion and/or capture beats
- concordance of QRS complexes in chest leads
- dissociated p waves
- history of ischemic heart disease
- RBBB with left axis deviation
- HR >170bpm

2 algorithms are proposed for prediction of VT versus SVT

i) Brugada
- absence of RS complexes in precordial leads
- RS duration of more than 100ms in any precordial leads
- ventriculoatrial dissociation in any of 12 leads
- certain QRS morphologies, such as QR or QS in V6

ii) Vereckei
- presence of an initial R wave in aVR
- width of an inital r or q wave > 40ms in aVR
- notching on the initial downstroke of a predominantly negative QRS complexes in aVR
- ventricular activation-velocity ratio (Vi/Vt) less than or equal to 1

Coeliac disease

- T cell mediated autoimmune disease of small bowel in which prolamine intolerance causes villous atrophy and malabsorption
- a.k.a gluten sensitive enteropathy
- 95% HLA DQ2 and HLA DQ8
- prevalence : 1 in 300-1500 (more common in Irish)
- occurs at any age (peaks in infancy and 50-60)
- presents with steatorrhea, diarrhea, abdominal pain, bloating, aphthous ulcer, weight loss, iron deficiency anemia, osteomalacia, failure to thrive
- associated with dermatitis herpetiformis
- diagnosis: IgA endomysial antibodies , alpha-gliadin antibodies or anti-transglutaminase antibodies (IgG if IgA deficient - 10% of Coeliac disease)
- duodenal/jejunal biopsy (gold standard): subtotal villous atrophy, hypertrophied crypts of Lieberkuhn, increase in intraepithelial lymphocytes (biopsy reverse/improvement with a gluten free diet)
- treatment: lifelong gluten free diet (wheat, barley, rye, oats)
- complications: risk of malignancy (esophageal, gastric, small bowel), anemia, hyposplenism, lactose intolerance, GI T cell lymphoma (suspect if refractory symptom or weight loss)

Scleritis

- associated with RA, Wegener's granulomatosis, SLE, PAN, relapsing polychondritis
- redness of sclera and conjunctiva or dull purple area of inflammation, with severe deep boring pain, photophobia and loss of visual acuity
- scleritis may lead to perforation of eye (scleromalacia perforans)
- treatment: NSAIDs, steroids eye drops or if severe surgery is indicated

Aspergillosis

- caused by A.fumigatus (most common), A.flavus and A.niger
- these fungi are ubiquitous in environment and commonly found on decaying leaves and trees
- human infected by inhalation of spores
- 3 major forms

i) Allergic bronchopulmonary aspergillosis (ABPA)
- commoner among asthmatics with variable airflow obstruction
- Aspergillus grows in the wall of bronchi
- presents with wheeze, cough, fever and malaise, eventually produce proximal bronchiectasis
- type III hypersensitivity reaction
- suspect if asthma is refractory and is associated with fever, cough and grey/black sputum
- eosinophilia and IgE levels extremely high
- serum precipitins and skin prick test both positive
- abnormal chest X ray (transient pulmonary shadow)
- treatment: prednisolone 30mg daily and prolonged course of itraconazole (up to 4 months)

ii) Aspergilloma
- masses of fungal mycelia that grow in pre-existing lung cavities
- hemoptysis is common symptom
- CXR: round lesion with air halo above it
- high serum precipitins (continuing antigenic stimulation), negative skin prick test
- treatment: surgical resection, itraconazole (if unfit for resection), arterial embolisation if life threatening hemoptysis

iii) Invasive aspergillosis
- occurs in immunosuppressed
- presents with acute pneumonia, meningitis or intracerebral abscess, lytic bone lesions, granulomatous lesions in liver
- treatment: IV voriconazole or amphotericin B

Alpha-1 antitrypsin deficiency

- autosomal recessive
- defective gene in chromosome 14
- alpha-1 antitrypsin protein is synthesized by hepatic cells and released into circulation. In lungs, its primary function is to inactivate neutrophil elastase (enzyme released during phagocytosis in alveolus)
- encoded by protease inhibitor (Pi) locus
- most common (90%) allele is M (PiM). Normal is homozygous (PiMM)
- PiZZ have only 15-20% of normal blood alpha-1 antitrypsin level, which is severe
- Heterozygotes (PiMZ, PiMS, PiSZ) have less severe phenotypes
- smoking is the greatest risk factor for development of emphysema in adults with alpha-1 antitrypsin deficiency
- lung compliance increased in emphysema
- majority of patients with clinical liver disease are homozygotes with PiZZ phenotype, which can produce jaundice and liver problems in neonates within few days of birth

Byssinosis

- caused by cotton dust
- symptoms typically start on the first day back at work after a break (Monday sickness) with improvement as the week progresses
- presents with chest tightness, cough and breathlessness
- most likely aetiology is endotoxins from bacteria present in raw cotton causing constriction of airways of the lung
- CXR is normal

X-linked hypophosphataemic rickets

- dominantly inherited (transmitted by affected father to all daughter)
- defect in renal phosphate handling 
- mutation in the PEX or PHEX genes which encode an endopeptidase
- rickets develops in early childhood and is associated with poor growth
- low phosphate, high PTH, high urine phosphate
- treatment: high dose oral phosphate and vitamin D (calcitriol)

Basic respiratory physiology

Carotid artery stenosis

- carotid artery disease accounts for 20% of stroke and TIAs

- 7.5% risk of stroke and death within 30days of endarterectomy

- there is no benefit to treat completely occluded vessel

Management

- Symptomatic patient < 50% stenosis : optimal medical therapy without revascularisation

- Asymptomatic patient < 60% stenosis : optimal medical therapy without revascularisation

- Symptomatic patient >= 50% stenosis : carotid endarterectomy with optimal medical therapy

- Asymptomatic patient >= 60% stenosis with low operative risk : carotid endarterectomy with optimal medical therapy

- Symptomatic patient >=50% stenosis with high operative risk : carotid stenting

- carotid artery stenting is inappropriate for asymptomatic patient with carotid artery stenosis. Possible exception may include patients with acceptable medical risk who present with severe carotid artery stenosis (>= 80%) with high anatomic risk for carotid endarterectomy but with compelling anatomy for stenting

Source: Clinical practice guideline for society of vascular surgery (J Vasc Surg 2008;48:480-6)

   

Progressive multifocal leukoencephalopathy (PML)

-infection of oligodendrocytes by JC virus (a polyomavirus)
- characterised by progressive damage or inflammation of white matter at multiple locations
- occurs almost exclusively in immunosuppressed individuals
- presents with focal neurological deficits such as aphasia, hemiparesis, behavioural changes and cortical blindness.
- MRI: multifocal non enhancing lesions without mass effects
- viral PCR for JC virus
- brain biopsy (asymmetric foci of demyelination and intranuclear inclusion containing JC virus) has sensitivity of 74-92% and specificity of 92-100%
- no effective treatment but progression can be slowed by initiation of antiretroviral therapy