Abetalipoproteinemia: decrease ApoB-48, Apo B-100; pigmentary degeneration of retina, acanthocytes, steatorrhea, cerebellar ataxia.
Acute Fatty Liver of Pregnancy: microvesicular steatosis in the liver, mitochondrial dysfunction in the oxidation of fatty acids leading to an accumulation in hepatocytes
Alkaptonuria: homogentisate oxidase deficiency, increase homogenistic acid, ochronosis, dark blue urine.
AcylCoA Dehydrogenase deficiency (MCAD): fasting hypoglycemia, no ketone bodies, dicarboxilic acidemia.
Bernard Soulier Sd: gp1b deficiency, prolonged bleeding time
Bloom Sd: chromosome 15, Ashkenazi Jews, BLM gene.
Carpenter Sd: craniosynostosis, acrocephaly, craniofacial asymmetry, increased ICP, cutaneous syndactyly, polydactily, mild-profound MR.
Chediak Higashi Sd: Lyst gene mutation, microtubule polymerization defect, no phagolysosome formation, albinism.
Chondrodystrophy: normal-sized trunk and abnormally short limbs and extremities (dwarfism)
Congenital Adrenal Hyperplasia: 17alpha or 21beta or 11 beta hydroxylase deficiency; enlargemente od adrenal glands due to increase ACTH
Congenital Hepatic Fibrosis: hepatic (periporta) fibrosis, irregularly shaped proliferating bile duct, portal hypertension, renal cystic disease.
Cystic Fibrosis: CFTR gene, Phe508, defective Chloride channel, chromosome 7.
Dubin-Johnson Sd: direct hyperBbnemia, cMOAT deficiency, black liver
Endocardial Fibroelastosis: restrictive/infiltrative cardiomyopathy, thick fibroelastic tissue in endocardium of young children, <2yo
Familial Mediterranean Fever: chromosome 16, recurrent autoinflammatory disease, characterized by F°, PMN disfx, sudden attacks pain/inflammation (7 types of attacks (abdominal, joints, chest, scrotal, myalgias, erysipeloid, fever). Complication: AA-amyloidosis
Fanconi Anemia: genetic loss of DNA crosslink repair, often progresses to AML, short stature, ↑incidence of tumors/leukemia, aplastic anemia
Friedreich’s Ataxia: GAA triplet repeat, chromosome 9, neuronal degeneration, progressive gait & limb ataxia, arreflexia, hypertrophic cardiomyopathy, axonal sensory neuropathy, kyphoscoliosis, dysarthria, hand clumsiness, loss of sense of position, impaired vibratory sensation.
Gaucher’s disease: glucocerebrosidase deficiency, glucocerebroside accumulation, femur necrosis, crumpled paper inclusions in macrophages.
Ganzman’s thromboasthenia: gpIIbIIIa deficiency, deficient platelet aggregation.
Hartnup Disease: tryptophan deficiency, leads to niacin deficiency, pellagra-like dermatosis
Hemochromatosis: HFE gene, C282Y MC mutation, chromosome 6, unrestricted reabsorption of Fe+ in SI, iron deposits in organs, bronze diabetes, DM1, malabsorption, cardiomyopathy, joint degeneration, increased iron, ferritin, TIBC. Complications: liver cirrhosis, hepatocelullar carcinoma
Homocystinuria: due to B6 deficiency (defective Cystathionine synthase) or due to B9,B12 deficiency (defective Homocysteine Methyltrasnferase), dislocated lenses (in & down), DVT, stroke, atherosclerosis, MR.
Krabbe's Disease: Galactocerebrosidase deficiency, galactocerebroside accumulation, gobloid cells, optic atrophy, peripheral neuropathy.
Leukocyte Adhesion Defect (LAD): CD-18+ deficiency, omphalitis in newborns, chronic recurrent bacterial infxs, increase WBC count, no abscess or pus formation.
Metachromic Leukodystrophy: Aryl-sulfatase A deficiency, sulfatides accumulation, Demyelination (central & peripheral), Ataxia, Demantia (DAD)
Niemann-Pick Disease: sphingomyelinase deficiency, sphingomyelin accumulation, HSM, cherry-red macula, foam cells.
Phenylketonuria (PKU): phenylalanine hydroxylase deficiency, Phe accumulation, MR, microcephaly, diet low in Phe!!! also in pregnancy, avoid aspartame, musty odor.
Polycystic Kidney Disease (children): ARPKD, rogressive & fatal renal failure, multiple enlarged cysts perpendicualr to renal capsule, association with liver cysts. Bilateral palpable mass.
Rotor Sd: direct hyperBbnemia, cMOAT deficiency, no black liver
Shwaman Diamond Sd: exocrine pancreatic insufficiency (2°MCC in children after CF), bone marrow dysfunction, skeletal abnormalities, short stature.
Situs inversus: assoc w/ Kartagener sd
Sicke Cell Disease and Trait: Hb S, beta globin chain, chromosome 11, position 6, nucleotide codon change (glutamic acid --> valine), vaso-occlusive crisis (pain), autosplenectomy, acute chest pain sd, priapism, hand-foot sd, leg ulcers, aplastic crisis, drepanocytes & Howell-Jolly bodies, hemolytic anemia, jaundice, bone marrow hyperplasia
Tay-Sachs Disease: Hexoaminidase A deficiency, GM2 accumulation, cherry-red macula, onion skin lysosomes.
Thalasemia: alpha (chromosome 16, gene deletion), beta (chromosome 11, point mutation)
Werner Disease: adult progeria
Wilson’s Disease: Chromosome 13, WD gene, ATP7B gene (encondes for Copper transporting ATPase), copper accumulation in liver, brain (putamen), eyes (Descemet membrane - Kayser-Fleischer ring), decreased ceruloplasmin.
Xeroderma Pigmentosa: defective excision endonuclease, no repair of thymine dymers caused by UV radiation, excessive freckling, multiple skin cancers.
Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia
Thalassemia provides partial resistance against malaria.
- most commonly seen in people of Mediterranean descent
usually due to point mutations in promoter sequences or splicing sites
β-globin locus - short arm of chromosome 11
In a normal cell, the β-globin chains are coded by a total of two alleles . Thus, there are two forms of the disease.
Beta thalassemia minor (trait): one defective allele
Beta thalassemia major (Cooley's anemia): two defective alleles
Inefficient erythropoiesis → anemia
Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2
most commonly seen in people of Asian and African descent
usually due to deletion of at least one out of the four existing alleles
Inheritance pattern: autosomal recessive
In a normal cell, the α-globin chains are coded by a total of four alleles.
Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.
- Silent carrier (minima form): one defective allele (-α/αα)
- Alpha thalassemia trait (minor form) -Two defective alleles ,Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
- Hemoglobin H disease: three defective alleles
- Hemoglobin Bart disease (major form): four defective alleles
Alpha thalassemia major (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ α-chains → ↑ β-, γ-chains → ↑ HbH, ↑ Hb-Bart's
Tissue conduction velocity (m/s)
SA node - 0.05
Atrial pathways - 1
AV node - 0.02- 0.05
Bundle of His - 1
Purkinje system - 4
Ventricular muscles -1
These are short vessels connecting ventral and dorsal aortae.
On each side they run within branchial i.e pharyngeal arches are based gradually the 4th and 5th week, in 6 pairs in total the first,
second and fifth pairs are developmental in perspective and they soon disappear.
1st aortic arch:
It disappears into a small portion persists, It also forms a piece of the maxillary artery.
2nd aortic arch:
It disappears into small portions of this arch contributing to the hyoid and stapedial arteries
3rd aortic arch:
It commonly carotid and initial segments of internal carotid artery.
4th aortic arch:
It has ultimate fate different on the right and left side on the left.
1. LEFT, both the proximal and distal segments are retained they are incorporated into the descending arch of the aorta.
2. RIGHT, the proximal segment of the right dorsal aorta persists and they are incorporated into the R subclavian artery
whereas the distal segment regresses.
5th aortic arch -
It is transient and soon obliterates.
6th aortic arch - pulmonary arch
1. RIGHT arch: this proximal segment is incorporated into the R pulmonary artery and the distal segment regresses.
2. LEFT arch: this proximal segment is incorporated into the L pulmonary artery and the distal segment persists as the ductus arteriosus.
A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by enzyme deficiencies affecting either glycogen synthesis, glycogen breakdown or glycolysis (glucose breakdown), typically in muscles and/or liver cells. GSD has two classes of cause: genetic and acquired.
Mnemonic:VP CAM HT.– Very Poor Carbohydrate Affects Muscle and Hepatic Target.
Type 0 (Glycogen synthase deficiency)
There is hypoglycemia; hyperketonemia and early death.
Type I (Glucose-6-phosphatase deficiency)-Von Gierke’s disease
- most common autosomal recessive disease.
- characterized by severe hypoglycemia that coincides with metabolic acidosis,
- ketonemia and elevated lactate (due to excess glycolysis) and alanine
Type II (Lysosomal α1->4 and α1->6 Glucosidase deficiency)- Pompes disease
- It affects predominantly the heart and skeletal muscle, producing muscle weakness and cardiomegaly. Liver function is normal and patients do not have hypoglycemia. Two forms identified;
(1) infantile (pompes disease) that develop in first few months of life with weakness and respiratory difficulties and
(2) juvenile that is present in second or third decade of life with difficulty in walking.
Type III (Amylo-1,6-Glucosidase deficiency)-Forbe’s or Cori’s disease
- Deficiency of glycogen debranching enzyme results in storage of an abnormal form of glycogen (limit dextrinosis).
- Both liver and muscle are affected (type IIIA), producing hepatomegaly and muscle weakness. About 15% have only liver involvement (Type IIIB).
Differentiation from type I is by hyperglycemic response to galactose, low concentration of urate and lactate in blood, and elevated serum transaminases and creatinine kinase activities
- production of an abnormal form of unbranched glycogen in all tissue.
- Patients exhibit hepatospleenomegaly with ascites and liver failure.
- There is death from heart or liver failure before 5 years of age.
Type V (Muscle Phosphorylase deficiency)-McArdle’s disease
- Increased plasma creatine kinase activity at rest,
- failure of ischemic exercise to increase serum lactate concentrations while producing an exaggerated increase in ammonia,
- myoglobinuria and diminished activity of muscle phosphorylase establish the diagnosis.
- It manifest as hepatomegaly caused by increased deposits of normal glycogen in liver or in red or white blood cells.
Type VII (Muscle and erythrocyte phosphofructokinase deficiency)-Taruis’ disease
- Abnormal glycogen in muscle.
- Exercise intolerance, unresponsiveness to glucose administration, and hemolysis (caused by decreased glycolysis in RBC) are noted clinically,
- hyperbilirubinemia, pigmenturia and reticulocytosis.
Purines synthesis and metabolism
Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ribose 5-phosphate. Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which is the first compound in the pathway to have a completely formed purine ring system
The major site of purine synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP). This pathway is diagrammed below. The purine base without the attached ribose moiety is hypoxanthine.
Biosynthesis of purine and pyrimidine nucleotides requires carbon dioxide and the amide nitrogen of glutamine. Both use an amino acid nucleus – glycine in purine biosynthesis and aspartate in pyrimidine biosynthesis. Both use PRPP as the source of ribose 1-phosphate.
The end product of purine catabolism in man is uric acid.
Biosynthesis Of Pyrimidine Nucleotides
CO2 reacts with N of glutamine to form carbamoyl phosphate, which fuses with aspartate to form carbamoyl aspartate.
Carbamoyl aspartate on ring closure forms the first pyrimidine ring named OROTATE.
Orotate combines with PRPP to form OMP which is the first pyrimidine nucleotide.
OMP forms UMP which can be converted to CMP or dTMP
Types of Haemorrhage
Hemorrhaging is broken down into four classes
Class I Hemorrhage involves up to 15% of blood volume.
There is typically no change in vital signs and fluid resuscitation is not usually necessary.
Class II Hemorrhage involves 15-30% of total blood volume.
A patient is often tachycardic (rapid heart beat) with a reduction in the difference between the systolic and diastolic blood pressures.
The body attempts to compensate with peripheral vasoconstriction. Skin may start to look pale and be cool to the touch.
The patient may exhibit slight changes in behavior.
Volume resuscitation with crystalloids (Saline solution or Lactated Ringer's solution) is all that is typically required. Blood transfusion is not usually required.
Class III Hemorrhage involves loss of 30-40% of circulating blood volume.
The patient's blood pressure drops, the heart rate increases, peripheral hypoperfusion (shock) with diminished capillary refill occurs, and the mental status worsens.
Fluid resuscitation with crystalloid and blood transfusion are usually necessary.
Class IV Hemorrhage involves loss of >40% of circulating blood volume.
The limit of the body's compensation is reached and aggressive resuscitation is required to prevent death.
Source of Haemorrhage
- Extra dural haemorrhage - middle meningeal artery
- Sub dural haemorrhage - bridging or diploic veins
- Sub arachnoid haemorrhage - rupture on berry aneursym
- Tennis bal injury to eye - circulis iridis major
- Epistaxis - Sphenopalantine artery
- During tonsillectomy - para tonsilaar veins, tonsilar and ascending palantine artery
- Tracheostomy - isthemus and inferior thyroid vein
- Heamoptysis-bronchial artery
- Gastric ulcer- left gastric, splenic artery
- Duodenal ulcer - gastroduodenal artery
- Hemmorrhoids - submucous rectal venous plexus formed by superior rectal vein & inferior rectal vein
- Retropubic proastatectomy - dorsal venous plexus
- Hysterectomy - internal illac artery
- Menstruation - spiral arteries
Alport’s Sd (most cases): "hereditary nephritis", type IV collagen deficit, mutation of COL4A5 ("colaas" - alpha-5 chain, type 4 collagen), hearing loss, ocular abnormalities (lens & cornea), hematuria since childhood (gross, micro)
Charcot Marie Tooth: loss of motor & sensory innervation, distal weakness & sensory loss, wasting in the legs, decreased deep tendon reflexes, tremor, foot deformity with a high arch is common (pes cavus), legs look like inverted champagne bottles. Most accurate test: electromyography. No tx.
Focal Dermal Hypoplasia: skin abnormalities and a wide variety of defects in eyes; teeth; and skeletal, urinary, gastrointestinal, cardiovascular, and central nervous systems.
Fragile X Syndrome: CGG trinucleotid repeat, FMR 1 gene mutation, mental retardation, large ears and jaw, post-pubertal macro-orchidism (males), attention deficit disorder (females)
Hypophosphatemic rickets: infants may show growth retardation, widened joint spaces and flaring at the knees at age 1 (> boys), bowing of the weight-bearing long bones, young children-dentition absent or delayed, older children-multiple dental abscesses.
Incontinentia pigmenti: skin abnormalities (blister--> warts--> hyperpigmentation--> hypopigmentation), alopecia, hypodontia, cerebral atrophy, slow motor development, mental retardation, seizures, skeletal & structural anomalies. Letal >males.
Orofaciodigital Sd: OFD1 gene mutation, malformations of face, oral cavity, digits with polycystic kidney disease and variable involvement of the central nervous system.
RETT’s Sd: sporadic mutation of MECP2 gene, onset 2yo, acquired microcephaly, stopped development, motor & speech regression, autism-like behavior, self-mutilating behavior, inconsolable crying/screaming fits, emotional inversion, hypotonia, dystonia, chorea, bruxism, scholiosis, long QT
- Caused by fungal organism called Pneumocystis jiroveci. Previously known as Pneumocystis carinii (PCP).
- Causes a pneumonia in the immunosuppressed, typically HIV with CD4 <200 therefore may require prophylaxis. Also seen in lymphoproliferative disorders, organ transplants and chemotherapy patients.
- Insidious onset, increasing dyspnoea, dry cough and fever. Patient may have bilateral fine crepitations and signs of hypoxia.
- CXR - can be normal, or classically showing bilateral perihilar interstitial shadowing. The CXR above also shows cavitating lesions.
- CT - ground glass appearance. This CT shows multiple cavitations.
- Diagnosis - direct visualisation on microscopy specimen from bronchoalveolar lavage or biopsy.
- Management - ASAP give high dose IV co-trimoxazole or IV penamidine. Steroids useful in severe hypoxia. Supportive therapy with oxygen. May require CPAP or mechanical ventilation.
- Copper accumulation in liver, brain and eyes (Descemet Membrane = Kayser-Fleischer ring)
- Decreased ceruloplasmin blood levels.
- Chromosome 13, WD gene, ATP7B gene (encondes for Copper transporting ATPase)
- Lesion in basal ganglia, especially putamen
- Tx: penicillamine, zinc acetate.
Symptoms: tremor, asterixis, parkinsonian sx, chorea, neuropsychiatric, fatty changes, hepatitis, cirrhosis.
Best initial test:
Slit-lamp examination for Kayser-Fleischer rings (brown ring around eye due to copper deposition)
Penicillamine challenge => abnormal increased amount of urinary copper excreation after Penicillamine.