MD

 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.

Beta thalassemia

- most commonly seen in people of Mediterranean descent

Etiology

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

Pathophysiology

Inefficient erythropoiesis → anemia

Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF  and ↑ HbA2

 

Alpha thalassemia

most commonly seen in people of Asian and African descent

Etiology

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

Pathophysiology

Alpha thalassemia major (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ α-chains → ↑ β-, γ-chains → ↑ HbH, ↑ Hb-Bart's

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.

  1. Type I – Von Gierke’s disease
  2. Type II – Pompe’s disease
  3. Type III – Cori’s disease
  4. Type IV – Anderson’s disease
  5. Type V – McArdle’s disease
  6. Type VI – Her’s disease
  7. Type VII – Tauri’s disease

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

Type IV (Branching Enzyme deficiency)-Andersons disease of Amylopectinosis

- 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.

TYPE VI (LIVER PHOSPHORYLASE DEFICIENCY)- HERS’ DISEASE

- 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.

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