Pathology

lecture 6

prof. dr hab. n. med. Andrzej Marszałek

Genetic diseases

Genetic diseases• mutations:

– point m. • missense m. • „nonsense” m.

– frameshift m. – trinucleotide repeat mutations (→ in gene fmr1 →

fragile x syndrome from 200 to 4000 cgg repeats [n=29])

Genetic diseases• mendelian disorders

– AD, AR, chr X

➢ abnormal structural proteins ➢ abnormal receptors ➢ abnormal enzymes ➢ cytogenetic diseases ➢multi-gene dioseases

von Recklinghausen disease• neurofibromatosis type 1

– neurofibromas – acoustic nerve schwannomas – optic nerve gliomas – meningiomas – Lisch nodules (pigmented nodules of iris) – cafe-au-lait spots – 17q 11.2 → neurofibromon → GTPase-activating enzyme

• neurofibromatosis type II – skin lesion less prominent than in type I – bilateral schwannomas of VIII n – multiple mengiomas – chr 22

• neurofibromatosis type III – glial tumors (brain stem, hiasma opticum, optic nerves)

Marfan s.➢ connective tissue, main changes in:

➢ bones ➢ ocular system ➢ cardio-vascular s. and skin

➢ clinically: ➢ arachnodactyly ➢ 70-85% familial, AD (15q21.1 → FBN1 [500mutations] → fibrillin), + TGFβ and

TGFβ rec II ➢ ± 15% sporadic m. ➢ ± 2-3/10,000 (USA); 1/20,000 ➢ ♂ die 3rd decade, ♀ 4th decsade

• Patogeneza:

• - fibrillin gene ➔ fibrillin (glycoprotein) ➔ aggregates ➔ microfibrillar network ➔ scaffolding for elastin depositions

Marfan’s s.morphology: • - unusually tall (no invariably) • - the lower body segment is longer than the upper body • - exceptionally long extremities • - long, tapering fingers and toes (arachnodactyly) • • - lax join ligaments (hands, feet); hyperextending (double-

jointedness) of the thumb back o the wrist • the tendons, ligaments andjoint caplsule are weak • • - dolichocephalic head (long-haeded) • + bossing of the frontal eminences • + prominent supraorbital ridges •

Ehlers-Danlos syndromes

• - clinically and genetically heterogenous group of disorders taht results from some defects in collagen synthesis or structure

• the common features include: remarkable hyperelasticity and fragility of the skin, joint hypermobility, and often bleeding diathesis

Ehlers-Danlos syndromesPathogenesis: • defects in the biochemical structure, synthesis, secretion,

and degradation of collagen.

• e.g.: in EDS I-IV, VI and X increased size of the collagen fibrils with unusually small bundles

• Molecular lesions are associated with conspicious weakness of the supporting structures of the skin, joints, arteries, and visceral organs.

Ehlers-Danlos syndromesPathology: • - soft, fragile and hyperextensible skin • - „human pretzel” • -a tendency to spontaneous rupture of the large arteries,

the bowel, and the gravid uterus (EDS IV the most dangerous variety)

Osteogenesis imperfecta• “brittle bone disease” • hereditary disease (heterogeneous group) • defective collagen type I synthesis (lower amount of procollagen

→ OI type I) • deletions and mutations of collagen type I gene → OI type II, III, and

IV • characterized by generalized osteoporosis with slender bones

(↑ tendency for pathologic fractures; they heal sometimes exuberant callus formation)

• the long bones have narrow and poorly formed cortices composed by immature, woven bone

Osteogenesis imperfecta• symptoms when child learns to walk → “fragile as a china doll” • thin, bulging skull and blue sclera, defness (mulitiple farctures) • hypermobile joints and thin translucent skin and heart valve defects • associated with dentinogenesis imperfecta (mainly deciduous dentition) • in OI type I because of hypolpalsia of the dentine and pulp, the teeth are

misshapen and bluish yellow • four types:

– type I most common (blue sclera, bone fragility and deafness) – type II most severe (bone factures in utero) – type III some defects visible at birth but latter progressive deformities

occur; growth retardation; common the teeth abnormalities – type IV similar to type I, but sclerae are normal; colagen forms

delicate thin fibrils (improper cross-linking)

Cystic fibrosis

• is an autosomal recessive disorder affecting children characterized clinically by: – chronic pulmonary disease – deficient exocrine pancreatic function – complications of thick mucus in many organs

• 95% cases of cystic fibrosis in Whites • exceptional in Blacks • almost never in Asians

Cystic fibrosis• Pathogenesis: • every 1 in 25 Whites is a heterozygous carrier of CF gene • in the whole population 2%-4% are carriers • it is the most common lethal autosomal recessive disorder

(even in general, most common lethal genetic disease) in the white population

• there is simple AR transmission → homozygotes → full expression

• occurs in 1 in 2500 newborns (some authors estimate incidence as 1/5000 to 1/4000 live births)

• chromosome 7 (7q31-32) → CFTR (cystic fibrosis transmembrane conductance regulator)

• 550 mutations, but only 70 mutations responsible for 90% of cases → now clinical test available

Cystic fibrosis

• Pathology: • In lung (almost 100% of cases) → ↑

predisposition for Pseudomonas aeruginosa

• Pancreatic involvement in 85%-90% • Salivary grands – often • Epidydimis and vas deferens (of course in ♂) 95% of cases

• Meconium ileus – 5% to 10%

Cystic fibrosis

Clinic: • Symptoms are present usually before the

age of 1 year • Recurrent pulmonary infections → cause of

80%-90% of patients’ deaths • Median life expectancy → ± 30yrs • ↑ GI cancer (GI + biliary tract + liver +

pancreas)

GLYCOGEN STORAGE DISEASE LYSOSOMAL STORAGE DISEASE (MISSING ENZYME SYNDROME)

• (autophagy, heterophagy)

• inherited deficiency of functional lysosomal enzyme → incomplete substrate catabolism → accumulation within the lysosomes → lysosomal enlargement → interferetion with normal cell function

• - synthesis of catalytically inactive protein • - defects in post-translational processing • - lack of an enzyme activator or protector protein • - lack of a substrate activator protein • - lack of a transport protein

GLYCOGEN STORAGE DISEASE LYSOSOMAL STORAGE DISEASE (MISSING ENZYME SYNDROME)

• organs affected:

• 1) the site where most of the material to be degraded is found

• 2) the location where most of the degradation normally occurs

• 3) mononuclear phagocyte system

GLYCOGENOSES:

• defect in the synthesis/catabolism of glycogen

• depending on specific enzyme deficiency: – a few tissues – widespread (while affecting all tissues) – systemic

GLYCOGENOSES:• A) hepatic form: • - organ for glycogen storage • - the storage of glycogen in the liver + hypoglycemia

• B) myopathic form: • - glycogen → a source of energy • - muscular weakness, rise in blood lactate levels, myoglobinuria

• C) multiorgan • - detrimental effects on: • - brain • - heart (cardiomegaly) • - skeletal muscles • - liver

glikogenoses: hepatic type

type Ia/von GIERKE disease• glucose-6-phosphatase deficiency • autosomal recessive (incidence1/100,000 - 400,000) • first symptoms → within first 12 months of live • - hypoglycemia • - hepatomegaly

characteristics: - full-cheeked, rounded facial appearance

• - protuberant abdomen • - thin extremities • - hiperlipidemia (xanthomas, retinal lipemia) • - splenomegaly (mild or absent) (left liver lobe) growth of child: • normal - first few months • retardation (altered levels of insulin and glucagon) • delayed adolescence • mental development → normal (but hypoglicemic injury)

type Ia/von GIERKE disease• laboratory finding: • - hypoglycemia 0.8mmol/L (15mg/L) • - AspAT, AlAT ↑ • - lactic acidosis • - hyperlipedemia (TG, Ch ↑) • - hyperuricemia

• short stature • renal enlargement • mild anemia • bleeding diathesis

morphology: • - ↑ glycogen (cytoplasm, nucleus) • - lipid vacuoles in hepatocytes • - absent fibrosis

type Ib/ pseudo type I• glucose-6-phosphatase microsomal

translocase deficiency • incidence: 1/5 - 1/100 of type I clinically like type I, (more severe) • but additionally: • - neutropenia • - impaired neutrophilic migration • - recurrent pyogenic infections

type III/ CORI disease• debranching enzyme deficiency • autosomal recessive (one of the more frequent GSD;

mainly North African Jews)

during first year of live: • - hypoglycemia and hepatomegaly • - splenomegaly more prominent than type Ia • - skeletal abnormalities • - cardiac myopathy (insignificant/mild -childhood • disabling/progressive - adults)

type III/ CORI disease• laboratory findings: • - blood lactate - N • - ketosis • - AspAT, AlAT ↑ • - hiperlipidemia (Tg, Ch ↑ in 75% of cases) • - hyperuricemia (rare)

morphology: • - like type Ia but: • - less lipid deposites • - more promonent fibrous septae • - liver tumors not reported

Affected patients have had children

type IV/ HERS disease• hepatic phosphorylase* deficiency *active/inactive form • phophorylase b kinase (→ activates *) → N • autosomal recessive mutation (?) clinical and laboratory features like type III

but milder • - hypoglycemia • - hepatomegaly

type VIa; VIII; IX• - phosphorylase b kinase deficiency • - X-linked variety (genetic

heterogeneity) • - benign • - affected males - mild symptoms

glikogenoses: muscle type

type V/ McArdl’s disease• myophosphorylase deficiency** symptoms: • - pain and cramps after exercise (2-3 decade) • - myoglobinuria • - renal failure • - no hepatic/cardiac metabolic disturbances • - after exercise → blood lactate - N • → blood phosphokinase morphology: • glycogen → subsarcolemmal regions

fatal infantile form - due to hypotonia related to ** (rare)

type VII• muscle phosphofructokinase deficiency • - muscles, RBC

symptoms like type V • but additionally: • - mild nonspherocytic hemolytic anemia

glikogenoses: mixed type type II/ POMPE dis.• - α-glucosidase deficiency • - incidence > 1/100,000 • - no association to hypoglycemia and ketosis • infantile form - symptoms within first 6 months (even at birth) • - skeletal muscle hypotonia, weakness • - massive cardiac enlargement • - enlargement of tongue • - hepatomegaly • - creatine phosphokinase ↑ • - aldolase ↑ • death 2-3 year (cardiac involvement) • juvenile form - progressive form of muscular dystrophy • - no cardiac symptoms • survival even 2-3 decade • EM: in muscle biopsy → membrane-bound vacuoles containing glycogen • excessive glycogen storage: liver and CNS (mainly anterior horns of spinal cord)

type IV/ ANDERSEN’s dis.• AMYLOPECTINOSIS

• - branching enzyme deficiency • - rare autosomal recessive • a) hepatomegaly*** + hypotonia • ***progressive cirrhosis • b) cardiac involvement + extreme

hypotonia (death 2-3yrs) MPS

Muscular dystrophy• disease characterised by progressive weakness of the voluntary

muscle • caused by primary muscle degeneration or by nervous system

involvement • primary muscular degeneration → hereditary/familial; relentlessly

progressive • morphology: • degeneration of muscle fibers • regenerative activity • progressive fibrosis • infiltration of the muscle with fatty tissue • no inflammation

Duchenne Muscular Dystrophy (1)

(proressive muscular dystrophy//DMD) • non-inflammatory myopathy • severe, progressive and fatal, appears before the age of

4 • inherited, X-linked, DMD and Becker muscular dystrophy

(BMD) occurs in 1/3,500 males (almost like cystic fibrosis)

• ⇒ the Duchenne-Becker gene (one of the largest known human genes → 2x106 base pairs) located on the chromosome X

Duchenne Muscular Dystrophy (2)

• boys suffer from progressive degeneration of muscles (mainly the pelvic and shoulder girdles)

• ⇒ caused by deficiency of dystrophin (a cytoskeleton protein located on the cytoplasmic face of the plasma membrane, which linked to by an integral membrane protein; play role in mechanical properties and flexibility during contraction and relaxation)

• DMD - no dystrophin • BMD - smaller then normal amount of dystrophin • DMD - 33% new mutations • 33% mutations in mother • 33% family disease (more then one generation)

Duchenne Muscular Dystrophy (3)

• pathology: • → relentless degeneration • → prolonged efforts to repair and regeneration • → progressive fibrosis • ⇒ progressively decreasing number of muscle fibers + ↑fibro-fatty connective tissue

• ⇒ early development of endomysial fibrosis

Duchenne Muscular Dystrophy (4)

• clinical diagnosis • → elevelated of creatine kinase levels in the blood +

muscle biopsy (morphologica changes observed even in utero)

• → prenatal diagnosis (DNA analysis and/or elevated serum creatine kinase levels ⇒ found in ‘up to 75% of carrier mothers)

Duchenne Muscular Dystrophy (5)

clinical features: • normal growth within 1 year of life → by the age of 18 months

50% of patients fail to walk → proximal muscle weakness and pseudohypertrophy of the calf muscles

• striking tendency to form contractures when immobilized for short time period

• more then 90% affected boys are chair-bound by the age of 11 years

• patients are bedridden by the age of 15 • decreased intelligence (20% are significantly retarded) • death occurs at the mean age of 17 years → respiratory

inssuficiency and cardiac arrythmia

Becker Muscular Dystrophy

• → milder form of DMD • → later onset • → at the age of 12, all patients are still walking • → 95% survive beyond the age of 21