Hereditary pathology

The State Education Institution of Higher Professional Training The First Sechenov Moscow State Medical University

under Ministry of Health of the Russian Federation

Lecture presentation

Professor Pirozhkov S.V.

 Department of Pathophysiology

2014-2015 education year

CLASSIFICATION OF MUTATIONS

Single base or point mutations

Chromosome mutations

Genome mutations

● Substitution

- synonimous

- missense

- nonsense

● Insertion

● Deletion

● Amplification of trinucleotide repeats

● Translocation

● Deletion

● Inversion

● Duplication

● Monosomy

● Trisomy

Frameshiftmutations

TYPES OF CHROMOSOMAL REARRANGEMENTS

TRANSLOCATIONS

ISOCHROMOSOMES

INVERSIONS

DELETIONS

RING CHROMOSOMES

CATEGORIES OF GENETIC DISORDERS

● Monogenic

● Complex disease traits

● Chromosomal disorders

MENDELIAN TYPE DISEASES

AUTOSOMAL DOMINANT DISORDERS● Manifest in heterozygous state

● Each affected individual has an affected parent (unless the condition arise by a new mutation in the sperm or ovum)

● Both males and females can be affected

● There is a 50% probability that the offspring of an affected heterozygote will inherit the mutant allele

EXAMPLES OF AUTOSOMAL DOMINANT DISORDERS

■ Familial hypercholesterolemia

■ Amyloidosis

■ Hereditary spherocytosis

■ Osteogenesis imperfecta

■ Hereditary retinoblastoma

■ Neurofibromatosis

■ Marfan’s syndrome

■ Polydactily

Penetrance is the proportion of individuals with a given genotype who present with any phenotypic features of the disorder

Expressivity, or variability in clinical expression, describes the range of phenotypic effects in individuals carrying a given mutation

AUTOSOMAL RECESSIVE DISORDERS

● Clinically apparent only in the homozygous state

● The parents are clinically normal

● Males and females are affected in equal proportions

● Consanguinity can be a contributing factor

● If both parents are carriers for the same abnormal allele, the probability of disease in offspring is 25%, for a heterozygous (carrier) it is 50%, for a normal (noncarrier) offspring it is 25%

EXAMPLES OF AUTOSOMAL RECESSIVE DISORDERS

■ Fenylketonuria

■ Alkaptonuria

■ Lysosomal storage diseases

■ Glycogenoses

■ Hemochromatosis

■ α1-Antitrypsin deficiency

■ Galactosemia

■ Sickle cell anemia

X-LINKED DISORDERS

● Males usually display the full phenotype, regardless of whether the mutation produces a recessive or dominant allele in the female

● An affected male does not transmit the disorder to his son, but all daughters are carriers

● Sons of heterozygous women have one chance in two of receiving the mutant gene

● Expression of disease in females is often variable and influenced by random X-chromosome inactivation

EXAMPLES OF X-LINKED RECESSIVE DISORDERS

■ Hemophylia A and B

■ Glucose-6-phosphate dehydrogenase deficiency

■ Color blindness

■ Bruton agammaglobulinemia

■ Wiscott-Aldrich syndrome

■ Chronic granulomatous disease

■ Diabetes insipidus

COMPLEX DISEASE TRAITS (MULTIFACTORIAL DISEASES)Multiple genes and nongenetic factors interact to contribute to the presence or absence of disease in a single individual

Examples:● Diabetes mellitus type I ● Coronary heart disease

● Cleft lip

● Peptic ulcer ● Essential hypertension

● Schizophrenia

● Gout

KARYOTYPE OF A MALE WITH TRISOMY 21

Trisomy 21 – Down syndromeClinical features:● Moderate-to-severe mental retardation

● A flat nose or absent bridge, oblique palpebral fissures

● Sloping forehead

● Short broad hands with a single palmar crease (simian crease)

● Generally dwarfed physique

● Approximately 40% of patients have congenital heart disease (atrial or ventricular septal defect, atrioventricular valve malformation)

● 10-fold to 20-fold increased risk of leukemia

● Abnormal immune responses that predispose to infection

Prominent occiputMental retardation

Micrognathia

TRISOMY 18: EDWARDS SYNDROME

Low set ears

Short neck

Overlapping fingers

Congenital heart defects

Renal malformations

Limited hip abduction

Rocker-bottom feet

Karyotype:

47,XX,+18

Incidence: 1 in 8,000 births

Short stature

Coarctation of aorta

Cubitus valgus

Streak overies, infertility, amenorrhea

Peripheral lymphedema at birth

Low posterior hairline

Webbing neck

Broad chest and widely spaced

nipples

Pigmented nevi

MONOSOMY OF THE X CHROMOSOME: TURNER SYNDROME

Karyotype:

45, X

Incidence: 1 in 3,000 female births

MOSAICISM – the presence in the same individual of two or more populations of cells that differ in karyotype due to mitotic errors in early development

Examples:

46,XY/47,XY,+21 – mosaic Down type; 45,X/46,XX – mosaic Turner type;

46,XY/47,XXY or 47,XXY/48,XXXY – mosaic Klinefelter type