Deficiency: RBC's

Caused by formation of acanthocytes: excess cholesterol is transferred to outer leaflet, makes flat cells, increase SA of outer bilayer so less deformable which = sequenstration and destruction by spleen

Deficiency: Membrane Proteins

non-functional spectrin, ankyrin, protein 4.1: spectrin deficiency causes unstable membrane - loses fragments and is less deformabile causes sequestration and destruction in spleen -> "Heamolytic Anemia".
This can lead to splenomgealy, jaundice, gall stones, etc

Deficiency:Nuclear Lamins

a RARE cause is lamin A/C defect, leads to fragile nuclear lamina and cell death, congestive heart failure due to dilated heart and damaged tissue, heart can't contract efficiently.

mutation in actin (cardiac muscle isoform). Mutated where binds to Z disc → defective transmission of force in  cardiac myocytes → early heart failure. symptoms of CHF develop gradual: dyspnoea, weakness, fatigue, palpitations, ankle oedema….risk of PE & sudden death

Deficiency: Mutation of Emerin (transmembrane protein that attaches to lamins; X-linked) or Lamin A/C (autosomal dominant)

Contractures (shortening of muscle or joint), especially in elbows, ankles, neck.  Flexion deformity of elbows, limited neck flexion.  Muscle weakness and atrophy, conduction defects and arrhythmias, sudden heart failure common

Deficiency: Nuclear Lamins

lamin A/C defect: preLamin A interacts with adipocyte TF (impaired adipocyte differentiation), accumulation of adipocyte in face/neck, peripheral lipatrophy with muscle prominence

Deficiency: Nuclear Lamins (autosomal dominant-sporadic)

altered lamin A (unstable nuclear envelope),

bleb formation, loss of peripheral heterochromatin, NPC clustering.
symptoms: aopecia, prominent eyes, loss subcutaneous fat, aged-looking skin, joint stiffness, arteriosclerosis, 18-24 months failure to thrive, 80% die from MI or CH

Deficiency: Nucleolar Defect

mutation in SMN proteins(survival of motor neurons) located in Gems -> defective snRNP assembly and pre-mRNA splicing, loss of motor neurons, most common neonatal death that is genetically determined, sudden onset, rapid progression: hypotonia, muscle weakness, atrophy

Mutation in CFTR : Cl- ion channel (plasma membrane protein across epithelial membranes) - mutation in folding of protein so it is ejected from ER back to the cytosol and degraded. Would function normally if transported to plasma membrane, but it never gets there.  Mucoid impaction → obstruction & 2y infection → fibrosis → bronchiectasis

Respiratory failure: most common cause of death

Deficiency: Protein folding

Class I: no protein, Class II: defective transport of LDL receptors from rER to Golgi (doesn't reach plasma membrane), folding problem, no LDL receptors on PM to bring in cholesterol, high levels of circulating cholesterol in blood.
Mutations LDL-R → ↑ Plasma cholesterol, ↑ synthesis LDL
xanthomata (ankle deposits) xanthelasmata (eyelid deposit), corneal arcus (white ring of cholesterol around iris), premature atherosclerosis

Deficiency: Protein Tagging

Deficiency of N-acetylglucosamine phosphotransferase which helps in attaching M6P tag→ Absense of M6P tag
Acid hydrolases lacking M6P are secreted extracellularly → Waste products accumulate as inclusion bodies
Symptoms: Skeletal abnormalities (lack of growth), Coarse facial features, Restricted joint movement, Psychomotor retardation, Enlarged liver, spleen, heart valves
Death CHF / RTI Life expectancy <10yrs

Deficiency: Snare

toxin that is found in inadequately sterilized food
neurotoxin that cleaves synpatobrevin (v-snare in neuron). It inhibits ACh release at NMJ (no muscle contraction and reults in flaccid paralysis and paralysis of respiratory and skeletal muscles

Deficiency: Snare

caused by: Wound contamination (Tetanus Toxin), this cleaves synaptobrevin (v-SNARE) and prevents vesicle fusion & release of GABA & glycine (= inhibitory NTs) from motor neurons.  No inhibition of contraction.
→ Prolonged contraction of skeletal muscles = violent Spastic paralysis
1st sign: trismus (lockjaw), then there is neck stiffness, dysphagia, pectoral & calf muscle rigidity can test with spatula test

Deficiency: endocytosis

Class IV: LDL-R not localised to coated pits (III - binding problem).  Causes ineffective endocytosis because receptors aren't clustering.
major risk for CAD (coronary artery disease) CVA (cerebrovascular disease), premature atherosclerosis (build up of foam cells in vessels (V - recycling)

Deficiency: Mucopolysaccharidoses (defective degradation of GAGs - mucopolysaccharides)

Most severe MPS, Deficiency of α-L-iduronidase → accumulation of dermatan sulphate & heparan sulphate
At few months old: Physical & mental deterioration, growth stops at 2-4 yrs, hepatosplenomegaly, Deafness, Skeletal deformity, Coarse facial features, Hirsutism (women have excess facial and body hair that is dark and coarse) ,Thickened skin, Corneal clouding
Death ≤10 yrs

Deficiency: Mucopolysaccharidoses

Residual α-L-iduronidase activity
Milder disease (Scheie = mildest MPS I)

Deficiency: Mucopolysaccharidoses, X-linked

Deficiency of iduronodate sulphatase → accumulation of dermatan sulphate & heparan sulphate
Similar to Hurler syndrome BUT - Later presentation (2-4 yrs) & milder course (survival into 30’s), no corneal clouding

Deficiency: Mucopolysaccharidoses

Defect in heparan sulphate degradation (types A-D)
Normal first 1-2 yrs, followed by progressive mental retardation & increasing behavioural disturbance. Aggressive behaviour & destructiveness, Hyperactivity, Sleep disturbance, Hearing loss, Progressive immobility, dysphagia, seizures & dementia, Mild facial dysmorphism (no hirsurtism). Death late teens/early 20’s
(Hurler = most severe MPS but children with Sanfilippo live longer with more severe behavioural problems)

Deficiency: Mucopolysaccharidoses

Defective degradation of keratan sulphate, Deficiency of: Galactosamine-6-sulphatase (MPS IV A) β-galactosidase (milder) (MPS IV B).  Keratan sulphate in urine, Short stature, Kyphoscoliosis, Pectus carinatum (pigeon chest), Deafness, Weakness, Aortic regurgitation → cardiomegaly, Normal IQ
Often considered skeletal dysplasia rather than storage disease

Deficiency: Mucopolysaccharidoses

Deficiency of arylsulphatase B
Similar to Hurler but normal IQ

Deficiency:Mucopolysaccharidoses

Deficiency of β -glucoronidase
Wide variability in severity; different mutations

Deficiency: Leukodystrophies

Mutation CHS1/LYST = lysosomal trafficking regulatory protein normally involved in vesicle fusion, delayed fusion of phagosome with lysosome in leukocytes, Autophagocytosis of melanosomes in melanocytes → albinism, Granular defects in NK cells & platelets
Recurrent infections (life threatening), Hypopigmentation, Mild coagulation defects.  USMLE = DEFECT IN MICROTUBULE POLYMERIZATION THAT CAUSES DEFECTS IN CYTOPLASMIC GRANULES

Deficiency: Lipid storage disorders / Sphingolipidoses

Most common lysosomal storage disease.  Deficiency of glucocerebrosidase.  Accumulation of glucocerebroside (a glycosphingolipid) in macrophages called a "gaucher's cell". Progressive hepatosplenomegaly (Hypersplenism - increased destruction of RBCs, WBCs and platelets). 3 types, I= 99% (no brain involvement), in II/III - progressive CNS involvement.  

Deficiency: Lipid storage disorders / Sphingolipidoses

accumulaiton of gangliosides, rapid neurodegeneration, blindness

Deficiency: residual alpha-1-L-iduronidase

Milder form of I-cell disease, later onset, survival into adulthood.  

Deficiency: enzyme

Hyperuricaemia: high levels of uric acid in the blood – start to get crystallizaiton formation -> deposit at big toe, etc
Eventually deposits will destroy surrounding tissue from inflammatory response (defect in xanthine oxidase enzyme)

PEX mutations

Failure to import peroxisomal proteins due to defective peroxin channels = empty peroxisomes.  Peroxins don’t recognise Ser-Lys-Leu (SKL) signal → Failure to import peroxisomal enzymes: Peroxisome deficiency. Accumulation of VLCFAs in glial cell membrane, (no β-oxidation) → abnormal brain development, neuronal migration defects, hypomyelination

Accumulation of VLCFAs in liver → hepatomegaly & liver failure. Lack of bile acids → ↓ fat absorption → ↓ ATP → muscle weakness
Severe neurological dysfunction: Hypotonia, Hyporeflexia, Seizures, Mental retardation,Dysphagia, Dysmorphic features, Prominent forehead, Hypertelorism (Widely spaced eyes), large fontanelles 

Deficiency: enzyme

Defect in transport of VLCFA into peroxisome. 

Most common peroxisomal disorder: Defective membrane protein that imports VLCFAs.  Defective breakdown of VLCFAs
Therefore, VLCFAs accumulate in Brain (glial cells) → myelin breakdown, Adrenal cortex → adrenal atrophy
NOT MUTATION OF PEX GENE

Deficiency: protein

Cardiomyopathy, Generalised muscle weakness & chronic fatigue, Neutropenia. High mortality in infancy, Sudden infant death, Infection, Cardiac failure.  Inner membrane is highly impaired, messes up ATP synthesis.

Deficiency: giant mtDNA deletions

late onset: 18-40, bilateral ptosis, progressive weakening of external eye muscles, Proximal muscle weakness and wasting, exercise intolerance, biochemical/histological muscle pathology, mtDNA depletion or multiple large deletions
Caused by mutation in polymerase domain for Pol Y or mutation in TWINKLE gene for mitochondrial helicase

Deficiency:giant mtDNA deletions

Without bone marrow involvement, late onset, mtDNA deletion in muscle (not blood), ragged red fibers, cerebellar ataxia, heart block

Deficiency: giant mtDNA deletions

bone marrow involvement, pediatric disease, pancytopenia (all tissues have deletion), anemia, pancreative (exocrine) failure

Deficiency: mt tRNA deletion

Mitochondrial Encephalomyopathy Lactic Acidosis, Stroke like episodes: short stature, stroke-like episodes: vomiting, headache, visual disturbance, diabetes, sensorineural hearing loss, maternally trasmitted
mutation in tRNA(leu)

Deficiency: mt tRNA deletion

Myoclonus Epilepsy & Ragged Red Fibers: progressive myoclonic epilepsy and seizures.
Mutation in tRNA(lys) - heteroplasmic

Deficiency: mt mRNA

Leber's hereditary optic neuropathy

subacute painless bilateral visual failure, male:female 4:1 (x-chromosome involved),
mutated gene: missense mutation (G to an A) in subunit of Complex 1 (may be homoplasmic, but only affected tissue = optic nerve)

Deficiency: mt mRNA

Neurogenic muscle weakness, ataxia, retinitis, pigmentosa: late-childhood/adult onset peripheral neuropathy. Ataxia, pigmentation, retinopathy, maternally inherited Leigh Syndrome is a more severe form with more mutated mtDNA
Mutated gene: ATPase 6 gene (missense mutation in one of the two complex V subunits)

Deficiency: Subunits of G-protein

ADP ribosylation (toxins attach ADP-ribose residue to Gα subunit of Gs) Locks stimulatory Gs into the active state by blocking GTPase activity → Activates secretion pathways and regulates ion channels in small intestine (opens Cl- and Na+ channels), get large amount of watery diarrhea with water secretion too.

Deficiency: Subunits of G-protein

Traveller’s disrrhoea: mechanism same as Cholera.  Activates response

Deficiency: Subunits of G-protein

whooping cough (Bordetella pertussis): ADP ribosylation Locks Gi into GDP-bound state;  inactivates Gi  → Prolonged & inappropriate response

Deficiency: RTK Receptor

Non Insulin-Dependent diabetes mellitus: hyperglycemia (bv's, kidneys, eyes), type II - b/c has insulin production with down regulated insulin receptor so decrease kinase activity and TK activity (GBR2) and secondary messengers. insulin resistance in skeletal m, liver, adipose tissue and pancreatic B cell dysfunction -> insulin deficiency.  #1 risk factor is obesity.

Deficiency: microtubule deformation

Most common cause of dementia.  Caused by NFTs (intraneuronal neurofibrillary tangles made up of clumps of tau protein): hyperphosphorylated tau (MAP protein) which ↓ functional MT (depolymerisation & disruption of axon transport) and accumulate in β-amyloid / senile plaques (extracellular) (β-A42/43, apoE also present → progressive neuronal damage.)  Progressive impairment of visual-spacing skill (gets lost), memory and cognition. 
If genetically derived: Familial, autosomal dominant (5-10%) - Early onset (<60): Presinilin , Presinilin 2, β-amyloid precursor, (trisomy 21, beta amyloid protein coded on 21)
Predisposition - Late onset (>60):  Senile, Apolipoprotein E (ε4 allele), Late onset = Multifactorial
Multifactorial: Apo E4 : major genetic risk-factor, earlier age of onset of LATE ONSET AD, also earlier age of onset in early onset autosomal dominant disease. 
Apo E2: reduced risk

Deficiency: cilia (microtubules)

immotile cilia & sperm → retention of secretions & recurrent infection (bronchitis, otitis media & sinusitus) → infertility.  Mutation in dynein arms 

50% = Kartagener syndrome; Bronchiectasis, Situs inversus, Chronic paranasal sinusitis, Infertility

Deficiency: keratin

Keratin 5, 14: Rupture of cells in the epidermis basal layer; Rupture of keratin IFs connecting to basal lamina, Blister forms above basement membrane in fragile skin: minor mechanical friction / trauma recurrent blister formation

Deficiency: keratin

Keratins 1 + 10: suprabasilar differentiation of keratinocytes: defect weakens structural stability of keratinocytes → easy blistering, Chronic wounding → hyperproliferation → thickened skin

Deficiency: keratin

keratin 9, only expressed in palms & soles)

lamin A/C defect (rare), leads to fragile nuclear lamina and cell death, congestive heart failure

actin (cardiac muscle isoform) mutation. Mutated where binds to Z disc → defective transmission of force in  cardiac myocytes → early heart failure. symptoms of CHF develop gradual: dyspnoea, weakness, fatigue, palpitations, ankle oedema….risk of PE & sudden death

Deficiency: myosin II

1 in 500: Mutations: cardiac isoforms – myosin II (70%), tropomyosin, troponin. #1 cause sudden cardiac death in athletes.  Muscle contraction not as effective as it should be.  Cardiac muscles try to compensate with hypertrophy until not effective at all.
Asymptomatic, mildly symptomatic Dyspnoea, Angina, Palpitation, Syncope, Fatigue, Fatal cardiac arrest (5-10%)

Deficiency: dystrophin, X-linked

Most common & most severe degenerative skeletal & cardiac muscle disorder. Genetically lethal in males (2/3 mutation from carrier mother, 1/3 new mutation; 10-20% gonadal mosaicism.  No detectable dystrophin in muscle, total loss of function
Normal at birth, develop muscle weakness by age 3 - 5 (begins pelvic girdle muscles, progresses to shoulder girdle muscles) Leg weakness: Gower’s sign Waddle-like gait, Calf pseudohypertrophy (repeated muscle damage) Lordosis, scoliosis, ↑ serum creatine kinase (CK) levels. Wheelchair bound by 10-12 yrs.  Muscle contractures, Mild cognitive impairment - (20% ↓IQ) Respiratory & cardiac musculature increasingly impaired, Rarely survive beyond 20-30yrs: respiratory failure (70%) or cardiac failure.  Manifesting heterozygotes.

Deficiency: dystrophin, x-linked

Mutation in dystrophin, partial function: inframe insertions / deletions → aberrant but partially functional dystrophin protein → more mild disease form
15% of dystrophin mutations. Onset late childhood / adolescence
Slower progression & significant variability Increased serum creatine kinase (CK) levels.

Deficiency: emerin

Mutation of Emerin (x-linked) or LaminA/C (autosomal dominant) in nuclear envelope.  Fragile nuclear envelop, affects physically stressed tissues: muscle fibers.  Affects skeletal and cardiac muscle.  Onset: Early childhood.  Early contractures: elbows, ankles, neck (flexion deformity of elbows, reduced joint mobility).  Cardiomyopathy, Conduction defects and Arrhythmias in adulthood.  

Deficiency: myotonin protein kinase

Common (2nd after DMD) myotonin protein kinase (MD type 1: 98%) Trinucleotide repeat disorder (CTG): anticipation (expansion of repeats through germ line, will reach symptomatic threshold).  Slowly progressive muscle degeneration & Myotonia = sustained involuntary contraction of muscle group, Weakness: hands, legs (gait abnormalities), sternomastoids, Atrophy of facial muscles → ptosis & haggard appearance

Deficiency: (not listed); autosomal dominant

Rare: Progressive weakness of face, scapula, upper arms Deletion of subtelomeric tandem repeat (CTG). Age onset: 10-40 yrs (95% by age 20): Inability to puff cheeks, Initially facial weakness (expressionless), ptosis, weakness: shoulders, upper arms difficulty raising arms → scapular winging.  Normal life expectancy

Deficiency: sarcoglycans

LGMD 2: Onset: 10-20yrs, Calpain, Mutation in α-, β-, γ-, δ- sarcoglycans. Titin (associated with myosin) Telethonin (onset is later than duchenne's but could be same as Becker's).  Clinically similar to X-linked DMD, "Limb girdle": hip and shoulder.
Slow (& variable) rate of progression, earlier onset, faster progression
Severe disability within 20-25 yrs, Death: respiratory failure
LGMD vs. DMD: Pseudohypertrophy & contractures rare, No cognitive impairment

Deficiency: laminin

Onset: birth. Mutation: Laminin (skeletal muscle isoform) & ……General muscle weakness, respiratory insufficiency, contractures, seizures, mental retardation
impaired myogenesis, synaptogenesis & mechanical stability. Clinically variable

Deficiency: Hydroxyproline

Deficiency of Vitamin C (Ascorbic Acid), fewer H-bonds formed in triple helix, weak connective tissue, bleeding gums, loosened teeth, petechiae, ecchymoses, poor wound healing, poor bone development, decreased wound healing, anemia, fatigue
at risk: infants, elderly, alcoholis, smokers

Deficiency: fibrillar collagen

defect in collagen (fibrillar - I,II,III,V) synthesis --> improper assembly of collagen, connective tissue weakness, hyperextensible fragile skin, joint hypermobility, and dislocation

Type I, 43% EDS (severe)  Collagen I/V mutation, joint hypermobility, hyperextensible skin
Type II, 35% EDS (mild): Collagen I / V mutation
Type IV, 6% EDS: Collagen III mutation - Collagen III found in blood vessels & granulation tissue Vascular type: arterial, intestinal, uterine rupture, easy bruising, thin translucent skin, varicose veins.
Type VI, 2% EDS: Mutations in lysyl hydroxylase, Collagen lacks structural stability. Ocular fragility: retinal hemorrhage and detachment, corneal rupture. Kyphoscoliosis
Type VII, 3% EDS: Defect in converting procollagen I to collagen I Joint hypermobility

Deficiency: elastin (Fibrillin)

Fibrillin gene mutation, weak elastic tissue: aortic root dilatation and dissection, aortic/mitral regurgitation, retinal detachment, lens subluxation, tall, thin, arachnodactyly (long limbs and fingers), pectus excavatum (pigeon chest)

Deficiency: elastase

COPD - mutated alpha1-AT (alpha1-antitrypsin) that binds irreversibly to the active site on elastase. Age of onset is 30-50 and earler if patient is a smoker. Causes dyspnea, hyperventilation, hyper-inflated chest (barrel chest)

Deficiency: HSPG defect

downregulation HSPG (heparin sulfate proteoglycan, losing high negative charge), cause collagen glycosylation & unusual cross-linking →  GBM (glomerular basement membrane) thickening (lose normal filtration properties in membrane): ↑collagen, ↓HSPG →  Expansion of mesangial matrix. Proteinuria & progressive renal failure, #1 indication for renal dialysis.  Diabetes Mellitus is the most common cause of kidney failure in the world.

Deficiency: hemidesmosomal proteins

Common autoimmune blistering disease: autoantibodies to hemidesmosomal protein --> Distrupt dermal-epidermal junction. Subepidermal blisters

Inflammatory Bowel Disease (autoimmune)

Abnormal inflammatory response --> dysplasia --> GI cancer risk
Down-regulation of epithelial TJ protein occludin may play a role in enhanced paracellular permeability and PMN(polymorphin neutrophils) transmigration observed in active inflammatory bowel disease. disease flares characterised by transepithelial migration of neutrophils (PMN) & altered epithelial barrier function

Deficiency: desmosome

Pemphigus (pemphigus vulgaris): autoimmune disorder (defect of desmosomal cadherins) blistering & raw sores on skin & mucous membranes skin pulls apart --> abnormal movement of fluid within skin --> blisters 

Deficiency: connexin, x-linked

progressive degeneration (demyelination) of peripheral nerves, muscle  weakness & atrophy, impairment of deep tendon reflexes. Key characteristics: Foot-drop, High stepping gait, High arched foot, Hammertoes. In the form missing connexin-32; these are necessary for intra-cellular gap junctions between coils of Schwann cell.

Deficiency: integrin

β2 integrin mutation → Leukocyte Adhesion Deficiency (LAD)
Impaired leukocyte chemotaxis & extravasation & phagocytosis
Patients suffer from repeated life-threatening bacterial infections

Mutations in Type I collagen; procollagen a (I) chain genes. Most clinically severe phenotypes from substitutions of invariant glycine. Triple helix forms CN-terminus gly mutations near C-term’ = more deleterious; N-term’ permit substantial triple helix formation

Range of phenotypic severity: Perinatal lethal mild predisposition to fractures. Skeletal deformities, Fractures (bone fragility), blue sclera

Deficiency: (not listed)

Common inherited cause of kidney failure. Mutation α5 chain of Type IV collagen (basal lamina). Type IV important in glomerulus of kidney.  Nephritis & deafness. Haematuria, Proteinuria, HTN

 Rare auto-immune disease (onset: teens-20’s & ↑ males, which is unusual). Auto-antibodies to Type IV collagen (α3 chain) → Inflammatory destruction of BM in kidney glomerulus & lung alveoli

Haemoptysis & glomerulonephritis with progressive renal failure