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Questions and Answers
What type of mutation is primarily associated with autosomal recessive diseases?
What type of mutation is primarily associated with autosomal recessive diseases?
Which characteristic distinguishes a disorder with autosomal dominant inheritance from one with autosomal recessive inheritance?
Which characteristic distinguishes a disorder with autosomal dominant inheritance from one with autosomal recessive inheritance?
In which inheritance pattern is the onset of the disorder likely to be variable and may occur in adulthood?
In which inheritance pattern is the onset of the disorder likely to be variable and may occur in adulthood?
What is the typical penetrance of autosomal recessive diseases?
What is the typical penetrance of autosomal recessive diseases?
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Which of the following is the most common autosomal recessive disorder noted for its lethal outcome in Caucasians?
Which of the following is the most common autosomal recessive disorder noted for its lethal outcome in Caucasians?
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What is the primary cause of Down Syndrome?
What is the primary cause of Down Syndrome?
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Which of the following is NOT a feature of Turner Syndrome?
Which of the following is NOT a feature of Turner Syndrome?
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Cystic Fibrosis is primarily caused by a defect in which gene?
Cystic Fibrosis is primarily caused by a defect in which gene?
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What type of genetic disorder is Edward's Syndrome classified as?
What type of genetic disorder is Edward's Syndrome classified as?
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Which of the following clinical features is typically associated with Patau Syndrome?
Which of the following clinical features is typically associated with Patau Syndrome?
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What is the common consequence of cystic fibrosis affecting the lungs?
What is the common consequence of cystic fibrosis affecting the lungs?
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How is Cri du Chat Syndrome primarily characterized?
How is Cri du Chat Syndrome primarily characterized?
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Which genetic disorder is characterized by the accumulation of homogentisic acid?
Which genetic disorder is characterized by the accumulation of homogentisic acid?
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What is a distinctive clinical feature of Klinefelter Syndrome?
What is a distinctive clinical feature of Klinefelter Syndrome?
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Phenylketonuria leads to which primary clinical manifestation if untreated?
Phenylketonuria leads to which primary clinical manifestation if untreated?
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Which of the following involves a deficiency in glucose-6-phosphatase?
Which of the following involves a deficiency in glucose-6-phosphatase?
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What consequence does the absence of a Y chromosome have on sexual differentiation?
What consequence does the absence of a Y chromosome have on sexual differentiation?
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Which class of cystic fibrosis mutations involves abnormal protein folding and trafficking?
Which class of cystic fibrosis mutations involves abnormal protein folding and trafficking?
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Albinism occurs as a result of a deficiency in which of the following?
Albinism occurs as a result of a deficiency in which of the following?
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Which mutation is responsible for Fragile-X syndrome?
Which mutation is responsible for Fragile-X syndrome?
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What is a common clinical feature of Prader-Willi syndrome?
What is a common clinical feature of Prader-Willi syndrome?
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Which disease is characterized by a bilateral atrophy of the caudate nucleus?
Which disease is characterized by a bilateral atrophy of the caudate nucleus?
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Which disorder is caused by a mutation in the Huntingtin gene?
Which disorder is caused by a mutation in the Huntingtin gene?
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What defines genomic imprinting?
What defines genomic imprinting?
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What clinical feature is associated with Angelman syndrome?
What clinical feature is associated with Angelman syndrome?
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Which option describes the genetic cause of Duchenne muscular dystrophy?
Which option describes the genetic cause of Duchenne muscular dystrophy?
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What distinguishes X-linked severe combined immunodeficiency from other X-linked disorders?
What distinguishes X-linked severe combined immunodeficiency from other X-linked disorders?
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What specific gene is associated with Friedreich ataxia?
What specific gene is associated with Friedreich ataxia?
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What major structural change occurs in the brains of patients with Huntington disease?
What major structural change occurs in the brains of patients with Huntington disease?
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What is a characteristic symptom of myotonic dystrophy?
What is a characteristic symptom of myotonic dystrophy?
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Which type of mutation leads to intellectual disability in the majority of Fragile-X syndrome cases?
Which type of mutation leads to intellectual disability in the majority of Fragile-X syndrome cases?
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Which is a common feature of G6PD deficiency?
Which is a common feature of G6PD deficiency?
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Which syndrome is linked to the UBE3A gene?
Which syndrome is linked to the UBE3A gene?
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What is the genetic basis for Tay-Sachs disease?
What is the genetic basis for Tay-Sachs disease?
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Which accumulating substance is primarily associated with Niemann-Pick disease?
Which accumulating substance is primarily associated with Niemann-Pick disease?
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Gaucher disease is characterized by a deficiency in which enzyme?
Gaucher disease is characterized by a deficiency in which enzyme?
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What is a common clinical manifestation of Tay-Sachs disease?
What is a common clinical manifestation of Tay-Sachs disease?
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Which clinical features are NOT associated with Ehlers-Danlos syndromes?
Which clinical features are NOT associated with Ehlers-Danlos syndromes?
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Which of the following is a characteristic of Marfan syndrome?
Which of the following is a characteristic of Marfan syndrome?
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What type of accumulation occurs in Gaucher disease?
What type of accumulation occurs in Gaucher disease?
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What is a common feature of neurofibromatosis type 1?
What is a common feature of neurofibromatosis type 1?
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Which enzyme deficiency leads to Niemann-Pick disease?
Which enzyme deficiency leads to Niemann-Pick disease?
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Which variant of Ehlers-Danlos syndrome would likely lead to ocular fragility?
Which variant of Ehlers-Danlos syndrome would likely lead to ocular fragility?
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What is a proposed mechanism of familial hypercholesterolemia?
What is a proposed mechanism of familial hypercholesterolemia?
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What is a distinctive histological feature of Niemann-Pick disease?
What is a distinctive histological feature of Niemann-Pick disease?
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What is the primary clinical manifestation of Neurofibromatosis Type 2?
What is the primary clinical manifestation of Neurofibromatosis Type 2?
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Study Notes
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.
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