Genetic Disorders

Genetic Disorders

• The frequency of genetic disorders is estimated at 670 per 1,000.
• Human genetic disorders include chromosomal abnormalities (structural or numerical alterations in autosomes and sex chromosomes) and disorders linked to mutations in single genes (like cystic fibrosis and lysosomal storage diseases).
• Complex multigenic (polygenic) disorders are the most common form of genetic disorders, exemplified by atherosclerosis, diabetes mellitus, and hypertension.

Normal Male Karyotype

• A visual representation of the 23 pairs of chromosomes in a typical male.

Cytogenetic Disorders Involving Autosomes

• A specific category of genetic disorders related to abnormalities in the non-sex chromosomes (autosomes).

Different Genetic Chromosomal Mechanisms

• Diagrams illustrating various chromosomal alterations (translocations, isochromosomes, deletions, inversions, and ring chromosomes).

Down Syndrome (Trisomy 21)

• Karyotype: 47,XX or XY, +21
• The most common chromosomal disorder.
• Incidence increases with maternal age.
• Caused primarily by nondisjunction (95%), rarely by Robertsonian translocation (4%), or mosaicism (1%).
• Clinical features: intellectual disability, a distinctive facial profile, muscle hypotonia, a characteristic crease (Simian crease), epicanthic folds, congenital heart disease (40%), duodenal atresia, acute lymphoblastic leukemia (ALL), and Alzheimer's disease (100%).

Atrioventricular Canal

• A specific congenital heart defect.

Duodenal Atresia ("Double Bubble Sign")

• A blockage in the duodenum, identifiable by a characteristic "double bubble" appearance on X-ray/radiography.

Edwards Syndrome (Trisomy 18)

• Karyotype: 47,XX or XY, +18
• Associated with a very poor prognosis due to severe congenital malformations.
• Increased incidence with maternal age.
• Caused by nondisjunction.
• Clinical features include intellectual disability, low-set ears, micrognathia, prominent occiput, flexion of fingers, and rocker-bottom feet.

Patau Syndrome (Trisomy 13)

• Karyotype: 47,XX or XY, +13
• Very poor prognosis linked to severe congenital malformations.
• Increased incidence with maternal age.
• Caused by nondisjunction.
• Clinical features: intellectual disability, microcephaly, microphthalmia, arrhinencephaly, cleft lip and palate, polydactyly, cardiac dextroposition, and interventricular septal defects.

Cri du Chat Syndrome

• Karyotype: 46, XX or XY, 5p-
• Infants have a characteristic cat-like cry.
• Clinical features: severe intellectual disability, congenital heart anomalies, epicanthic folds, microcephaly, and round facies.

Disorders of Sex Development (Differentiation)

• Factors affecting sex determination include the presence or absence of Y chromosome, gonadal sex, ductal sex, and phenotypic sex.

Klinefelter Syndrome

• Karyotype: 47,XXY (90% of cases).
• Frequent genetic disease affecting sex chromosomes.
• A common cause of hypogonadism in males.
• Clinical features include testicular atrophy, azoospermia, gynecomastia, female distribution of hair, increased risk of breast cancer and certain tumors, and autoimmune diseases (e.g., lupus).

Turner Syndrome (Gonadal Dysgenesis)

• Karyotype: 45,X
• Condition involving monosomy of the X chromosome.
• Primarily characterized by hypogonadism in phenotypic females.
• Second X chromosome is necessary for ovarian development.
• Clinical features include short stature, primary amenorrhea, infertility, neck webbing, preductal coarctation of the aorta, and possible hydrops fetalis.

Intersex (Hermaphrodism)

• True hermaphrodites have both ovarian and testicular tissue (ovotestis).
• Pseudohermaphrodites have a disagreement between their gonadal and phenotypic sex (female or male).

Autosomal Recessive Disorders

• In homozygous individuals, clinical manifestations trends to be more uniform.
• Complete penetrance is common.
• Disease onset is often early in life.
• Enzymes are often affected by the mutation rather than structural proteins.

Cystic Fibrosis (Mucoviscidosis)

• CF is the most frequent lethal genetic disease among whites. A carrier rate of 1 in 20 exists in the U.S.
• Caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
• A 70% fraction of worldwide CF cases involve a deletion of a single amino acid (508) located on chromosome 7q31.2
• Pathology involves epithelial tissues, exocrine glands, and eccrine sweat glands (pancreas, lungs, liver, Brunner glands, and salivary glands).

Phenylketonuria (PKU)

• Decreased phenylalanine hydroxylase activity leads to phenylalanine accumulation.
• Clinical features: intellectual disability, photosensitivity, eczema, and convulsions.
• Manifestations usually become evident by 3 days of age though normal at birth.

Alkaptonuria (Ochronosis)

• Homogetisic oxidase deficiency disrupts phenylalanine-tyrosine metabolism resulting in homogentisic acid accumulation.
• Homogentisic acid binds to collagen in connective tissue leading to blue-black pigmentation (ochronosis).
• Severe degenerative joint disease is a key complication.
• Urine turns black due to homogentisic acid oxidation.

Albinism

• Tyrosinase deficiency reduces melanin production.
• Increased risk of basal and squamous cell carcinomas.

Glycogen Storage Diseases

• Deficiency in an enzyme needed for glycogen metabolism leading to glycogen accumulation in various tissues.
• Different types of glycogen storage diseases result in different clinical manifestations (hepatomegaly, hypoglycemia, cardiomegaly, skeletal muscle hypotonia, exercise-induced muscle cramps).

Lysosomal Storage Disorders

• Defects in lysosomal enzymes causing accumulation of specific substances, leading to cellular damage.
• Several types exist resulting in varied clinical manifestations.

Tay-Sachs Disease

• Increased prevalence in Ashkenazic Jews.
• Deficiency of hexosaminidase A.
• Accumulation of GM2-ganglioside in the nervous system.
• Progressive motor incoordination, weakness, mental obtundation, blindness, progressive dementia.
• Often includes a cherry-red spot in the retina.

Niemann-Pick Disease

• Deficiency of sphingomyelinase.
• Accumulation of sphingomyelin and cholesterol in phagocytic cells and neurons
• Several types with different clinical manifestations and underlying mechanisms. A spectrum of types result in variable clinical presentations, ranging from infantile to late-onset forms.

Gaucher Disease

• Deficiency of glucocerebrosidase (a lysosomal enzyme).
• Accumulation of glucocerebroside in reticuloendothelial cells.
• Several types, with type I being the most common non-neuronopathic form.
• Engorged phagocytic cells are called Gaucher cells.

Autosomal Dominant Disorders

• May have delayed onset of clinical features.
• Mutations commonly involve complex structural proteins or regulatory proteins.

Familial Hypercholesterolemia

• Probably the most frequent Mendelian disorder.
• Mutations involve cholesterol metabolism (LDL receptor disorder).
• Presents with early atherosclerosis (coronary, cerebral, and peripheral arteries), and skin xanthomas.

Marfan Syndrome

• Genetic disorder of connective tissue.
• Involves the fibrillin gene on chromosome 15
• Clinical features include skeletal abnormalities (tall stature, long extremities, lax joints, pigeon chest); ocular abnormalities (lens subluxation); and cardiovascular issues (aortic cystic medial degeneration).

Ehlers-Danlos Syndromes

• Heterogeneous group of disorders due to defects in collagen synthesis or structure.
• Inheritance patterns include X-linked and autosomal dominant and recessive.
• Most variants affect skin, ligaments, and joints.
• Manifestations range from hyper-extensible skin and hypermobile joints to internal complications (rupture of colon or large arteries, ocular fragility).

Neurofibromatosis Type I

• Relatively common disorder involving a tumor suppressor gene (NF-1) on chromosome 17q.
• Presents with multiple neural tumors (neurofibromas), numerous pigmented skin lesions ("café au lait" spots), Lisch nodules on the iris, possible skeletal lesions (scoliosis), and increased risk of various tumors (meningiomas, optic gliomas, pheochromocytomas).

Neurofibromatosis Type 2

• Less common form than type I. Involves a tumor suppressor gene (NF-2) on chromosome 22q.
• Characterised by bilateral acoustic neuromas (schwannomas) with or without skin tumors; presence of cafe-au-lait spots without Lisch nodules can be observed.

von Hippel-Lindau Disease

• Characterized by benign and malignant tumors, particularly hemangioblastomas (retinal, cerebellar, spinal cord).
• Associated with a predisposition to angiomas and cysts in various visceral organs.
• 50% of patients with this condition develop bilateral, multicentric renal cell carcinomas and other tumors.

Genomic Imprinting

• Differential expression of maternal and paternal genes due to epigenetic mechanisms (DNA methylation) during gametogenesis.
• Examples include Prader-Willi and Angelman syndromes, caused by different imprinting patterns for genes in the same region.

Fragile-X Syndrome

• Mutation involving a long repeating sequence of CGG nucleotides on the Xq chromosome (involving the FMR-1 gene resulting in intellectual disability).
• Common genetic cause of intellectual disability after Down syndrome.
• Clinical features include intellectual disability more common in males, a distinctive facial appearance, and macro-orchidism.

Huntington Disease

• Genetic disorder linked to an expanded CAG trinucleotide repeat on chromosome 4p16.3.
• Leads to the production of a mutated protein with an abnormal number of glutamines.
• This results in progressive neurological decline and dementia as well as extrapyramidal or choreiform movements.