11-27-2007, 06:02 PM
GENETICS
Chromosomes
¢ Humans have 22 pairs of homologous chromosomes (autosomes) and 2 sex chromosomes.
¢ Homologous means the same chromosomes have the same genes but may have different versions (alleles) of these genes.
¢ The X and Y chromosomes (sex chromosomes) are not homologous.
¢ Each gene is represented by a pair of alleles
¢ A homozygous condition occurs when both alleles are identical.
¢ A heterozygous condition occurs when both alleles are different.
¢ Chromosomes are numbered according to size, with 1 being the largest and 21 being the smallest (actually 22 is a little larger than 21, but it was numbered before resolution improved enough to notice!).
¢ The sex chromosomes are labeled X and Y and are numbered after Chromosome 22; this position does not correlate to size.
¢ When autosomes are arranged numerically by size followed by the sex chromosomes, this is called a karyotype.
¢ A karyotype is produced when autosomes are arranged numerically by size followed by the sex chromosomes.
¢ A karyotype is designated as the total number of chromosomes followed by the sex chromosomes, i.e. 46, XX or 46, XY.
¢ Chromosomes are divided by a centromere into "p" arms and "q" arms, with p (think 'petite') being the shorter arm and q being the longer arm.
¢ The centromere lies between the p and q arms.
¢ The location of the centromere defines the chromosome as follows:
o Metacentric: p and q arms are of approximately equal lengths
o Submetacentric: the centromere falls nearer to one end of the chromosome than the other
o Acrocentric: the centromere is near the terminus
o Telecentric: the centromere is near the terminus
Modes of Inheritance
Mendelian Inheritance
Autosomal Dominant
¢ The allele is expressed in both homozygous and heterozygous conditions.
¢ Most alleles segregate randomly during gamete formation.
¢ Characterisitcs of transmission, (i.e. inheritance, of a dominant allele) are:
o affected children have an affected parent
o males and females are affected in equal numbers
o each child of an affected parent has a 50% chance of inheriting the abnormal allele.
o it occurs in every generation
Autosomal Recessive
¢ The allele is expressed in the homozygous condition only.
¢ Patients are homozygous for the disorder.
¢ Characteristics of transmission of a recessive allele are:
o generally, parents of an affected individual do not express the recessive allele, (i.e. they are heterozygous for the allele.)
o two heterozygous parents have a 25% chance of having an affected child.
o affected parents have only affected children.
o it affects males and females in equal numbers.
o it may not be present in successive generations.
¢ Once it is known that two recessive alleles for a particular condition are not present because the individual does not demonstrate the disorder, there is 66% chance the individual is heterozygous for one normal and one abnormal allele, and 33% chance of being homozygous for two normal alleles.
X-linked
¢ The X Chromosome carries many important alleles that have no counterpart on the Y Chromosome.
¢ Males carry one X Chromosome, with single alleles of each gene, while females have two alleles for each gene.
¢ Generally, all alleles on the X Chromosome are expressed in males whereas the situation in females is not as straightforward.
¢ In inheritance:
o males pass X-linked alleles to all daughters, but not to sons.
o females pass X-linked alleles to 50% of their sons and daughters.
¢ X-linked expression can be dominant or recessive, but since males only have one X-chromosome, they express the disorder either way.
¢ Expression may be affected by penetrance and expressivity.
o an individual may possess a combination of alleles that should be expressed, but a proportion of these individuals has no expression - in these cases, penetrance is incomplete or reduced; expression of alleles as expected in all cases is known as 'complete penetrance'
o the expression of alleles has variable presentations - for example café-au-lait spots may occur in different numbers and positions among the same family members - this demonstrates variable expressivity.
Non-Mendelian Inheritance
Mitochondrial
¢ Sometimes called 'maternal inheritance',
o mitochondria are cellular organelles containing their own DNA (mtDNA). Unlike nuclear DNA that is inherited from both parents, mitochondria are inherited only through the mother via cytoplasm in the ova.
o each somatic cell contains mtDNA.
o some mtDNA may develop independent mutations.
o cells with only one type of mtDNA are homoplasmic.
o cells with mutant and non-mutant mtDNAs are heteroplasmic.
o as the amount of mutant mtDNA increases, a threshold is reached and the cell no longer compensates with the non-mutant mtDNA; a disease occurs.
U
niparental Disomy (UPD)
¢ Both homologous chromosomes come from one parent rather than one chromosome from each parent.
¢ This usually results from nondisjunction and then loss of the third chromosome (rescue) during meiosis.
Genomic Imprinting
¢ Some alleles are expressed only if they are inherited from a specific parent. The general mechanism of imprinting is methylation to down-regulate expression of a gene. Consequences of imprinting are seen when:
o one allele is imprinted and the other allele is nonfunctional, (i.e. deleted or mutated)
o UPDs have both alleles down-regulated;
o both alleles are imprinted.
Triplet Repeats
¢ Di- or trinucleotides become amplified during gametogenesis and amplification occurs preferentially in a specific parent of origin.
¢ A threshold number of repeats will result in an abnormal presentation.
¢ Amplifications may occur in the 5' promoter region of the gene, an exon, an intron, or the 3' region of the gene.
Mosaicism
¢ Different cells have different karyotypes.
¢ The total karyotype reflects the individual cell karyotypes, for example, 45,X/46,XX:
o this, however, does not imply the percentage of cells with each karyotype.
o the greater the abnormal karyotype percentage, the worse the clinical presentation.
Common Genetic Disorders
Autosomal dominant
Marfans Syndrome
¢ A mutation in the fibrillin gene.
¢ Presenting symptoms include tall stature, arachnodactyly, scoliosis, high-risk of dissecting aortic aneurysm, ectopic lentis, and emphysema.
Beckwith-Weidemann syndrome
¢ One of the most common congenital overgrowth syndromes.
¢ Congenital findings include macroglossia, omphalocele, gigantism, hemihypertrophy, advanced bone age, visceromegaly, microcephaly, renal medullary dysplasia, facial nevi, and distinctive ear creases.
¢ Correct diagnosis is important because patients are at an increase risk for neoplasia.
¢ Patients must be monitored for hypoglycemia and hypocalcemia.
Osteogenesis imperfecta, type I
¢ The most common form of osteogenesis imperfecta is caused by a reduction in Type I procollagen.
¢ Patients have skeletal osteopenia, fractures that may be present at birth, and blue sclerae throughout life.
Ehlers-Danlos syndrome
¢ A mutation in Type V collagen.
¢ Patients present with skin hyperextensibility, joint hypermobility, and abnormal wound healing.
Autosomal recessive
Cystic Fibrosis
¢ The most common autosomal recessive disease.
¢ Caused by a mutation in the CFTR gene.
¢ The mutation leads to an ineffective chloride transporter.
¢ Over 900 mutations cause variable expression of disease.
¢ Presenting symptoms include meconium ileus, bronchiectasis, pancreatic problems, and pseudomonas pneumonia.
Phenylketonuria (PKU)
¢ A mutation of the phenylalanine hydroxylase gene (PAH) gives rise to classical PKU.
¢ Nonclassical forms arise with other mutations in the phenylalanine to tyrosine pathway affecting the level of tetrahydrobiopterin.
¢ Phenylalanine diet restriction after birth will avoid serious mental retardation and neurological sequelae.
Galactosemia
¢ The inability to utilize galactose found in milk.
¢ Galactose is not converted to glucose by galactose-1-phosphate uridyl transferase and accumulates in tissues.
¢ Infants suffer from malnutrition and failure to thrive if a galactose-free diet is not initiated after birth.
H
urler syndrome
¢ The most severe of the mucopolysaccharidoses, this results from a mutation in alpha-L-iduronidase.
¢ Heparin and dermatan sulphate cannot be degraded and accumulate in tissues and urine.
Trisomy - three of the same chromomsome resulting from nondisjunction
Downs Syndrome
¢ Trisomy 21
¢ The most common chromosomal cause of mental retardation
¢ Patients have 3 copies of chromosome 21.
¢ It is the most common cause of mental retardation.
¢ Patients present with simian crease, brushfield spots, epicanthal folds, and congenital heart problems, and Alzheimer's disease by age 40.
¢ Can also occur from a translocation, but this is less common.
Edward's Syndrome
¢ Trisomy 18
¢ Patients have 3 copies of chromosome 18.
¢ Leads to mental retardation, rocker-bottom feat, congenital heart problems, and flexion deformities.
¢ Most patients die by age 1 year.
¢ Associated with increased maternal age at birth.
Patau's Syndrome
¢ Trisomy 13
¢ Three copies of chromosome 13
¢ Present with mental retardation, cleft lip, cleft palate, polydactyly, and congenital heart problems.
¢ Patients generally die by age 6 months.
Klinefelter's Syndrome
¢ Sex Chromosome (47,XXY).
¢ One of the most common forms of primary hypogonadism and infertility in males.
¢ These patients are genetically male and present with hypogonadism, tall stature, abnormal upper:lower body ratio and gynecomastia.
Monosomy
¢ The presence of only one member of a homologous chromosome pair
¢ Results from nondisjunction.
Turner's Syndrome
¢ Sex Chromosome (45,X).
¢ The most common cause of primary amenorrhea.
¢ Non-disjunction of the sex chromosome during Meiosis.
¢ Patient presents with streak gonads, webbed neck, short stature, and poorly developed genitalia.
¢ Patients are also at increased risk for coarctation of the aorta, diabetes, autoimmune disorders, and inflammatory bowel disease.
X-linked
Duchenne Muscular Dystrophy (DMD)
¢ An X-linked disorder that affects only males.
¢ The mutation leads to the absence of the dystrophin protein needed to keep skeletal muscle cells intact.
¢ Patients present with generalized weakness and muscle wasting in hips, pelvic region, thighs, and shoulders.
¢ Calves often are enlarged (pseudohypertrophy)
Becker's Muscular Dystrophy
¢ An X-linked disorder affecting males only.
¢ Compared to DMD it has a later onset (2-16 years of age), but the symptoms are similar, though less severe and progress more slowly.
Hemophilia A
¢ X-linked disease leading to a deficiency of Factor VIII, which leads to blood clotting problems.
¢ Affects only males and presents with a history of hemorrhage, hematuria and hemarthrosis.
Hemophilia B
¢ X-linked disease leading to a deficiency of Factor IX.
¢ Similar to Hemophilia A, but milder.
Lesch-Nyhan disease
¢ A mutation in the HGPRT gene. The enzyme is necessary for the recycling of purine components and the mutation leads to a build-up of purine degradation byproducts.
¢ Symptoms begin to present at 3-6 months of age.
¢ Most prominent symptom is self-mutilation, along with mental retardation, gout and orange uric acid crystals in the urine.
Mitochondrial
MELAS - Mitochondria Encephalomyopathy with Lactic Acidosis and Stroke-like episodes.
¢ The most common mutation is in tRNALeu.
¢ This mutation causes reduced activity of mitochondrial Complexes I and IV that lead to respiratory chain dysfunction.
¢ Lactic acidosis occurs in the blood and CSF.
¢ Cerebral necrosis and cortical atrophy develop in patients.
¢ Presents with visual defects, blindness, hearing loss, seizures, dementia and loss of consciousness.
¢ Mean age of onset is 10 years.
MERRF - Myoclonic Epilepsy and Ragged Red Fibers.
¢ The most frequent mutations occur in tRNALys (>80%), tRNASer, and tRNALeu.
¢ Lactic acidosis is variable and ragged red fibers in muscle biopsy are a hallmark.
¢ Most frequently presents with myoclonus, epilepsy, ataxia, myopathy and hearing loss.
LHON - Leber Hereditary Optic Neuropathy.
¢ One of three mutations in mitochondrial complex I accounts for approximately 95% of cases.
¢ Optic nerve degeneration leads to central vision loss in 2-8 weeks.
¢ Generally, the first eye is affected followed by the second eye within 6 months.
¢ Mean age of onset varies for each mutation, but the 95th percentile for onset for the three most common mutations is age 50 years.
Triplet Repeats
Fragile X Syndrome
¢ This disorder represents both X-linked inheritance and triplet repeat amplification.
¢ Disease occurs due to a mutation of the FMRP gene promoter on chromosome X, which leads to an increase in the size of the non-coding 5' promoter region of the gene.
¢ Amplification of CGGs provides additional cytosines for methylation and gene downregulation.
¢ Gene product actually prevents disease.
¢ Patients present with mental retardation, long face, large ears, dental problems and large testes.
Huntington's disease
¢ An autosomal dominant disease.
¢ Has 100% penetrance, and presents with progressive dementia with adult onset.
¢ Amplification of CAG (codes for glutamine) triplet in exon.
¢ Mean age of onset ~40 years.
¢ Patients usually die within 10-15 years of first symptoms.
Myotonic dystrophy
¢ The most common form of muscular dystrophy affecting adults.
¢ It results from amplification of CTG in the 3' region of the DMPK gene.
¢ Three forms exist - classical, mild, and congenital (the most severe form).
¢ Muscular weakness is apparent early in the neck muscles.
¢ Distal limb muscles are affected and proximal limb muscles remain stronger throughout disease. (Note that with Duchenne and Becker's muscular dystrophy the proximal muscles are more affected.
Microdeletion Syndromes
Cri du Chat Syndrome
¢ A deletion of the long arm of Chromosome 5.
¢ Patient presents with severe mental retardation, microcephaly, 'cry of the cat' sounds, hypertelorism, and low-set ears.
Prader-Willi Syndrome (PWS)
¢ The most common microdeletion syndrome
¢ The most common form of genetic obesity
¢ The first recognized microdeletion syndrome
¢ The first recognized imprinting disorder
¢ The first recognized uniparental disomy disorder.
¢ The multiple modes of inheritance make this an important disorder to know.
¢ The gene responsible is SNRPN on Chromosome 15.
¢ An understanding of imprinting is important to understanding PWS.
¢ Patient presents with hypotonia (pre- and post-natally) followed by hyperphagia.
¢ Hypothalamic hypogonadism, short stature, hypopigmentation, small hands and feet, skin picking, behavioral problems.
Angelman Syndrome
¢ This disorder is often studied along with Prader-Willi syndrome and represents a microdeletion disorder and an imprinting disorder.
¢ The gene responsible is UBE3A on Chromosome 15.
¢ Patients are severely mentally retarded and often mute with inappropriate laughter.
Chromosomes
¢ Humans have 22 pairs of homologous chromosomes (autosomes) and 2 sex chromosomes.
¢ Homologous means the same chromosomes have the same genes but may have different versions (alleles) of these genes.
¢ The X and Y chromosomes (sex chromosomes) are not homologous.
¢ Each gene is represented by a pair of alleles
¢ A homozygous condition occurs when both alleles are identical.
¢ A heterozygous condition occurs when both alleles are different.
¢ Chromosomes are numbered according to size, with 1 being the largest and 21 being the smallest (actually 22 is a little larger than 21, but it was numbered before resolution improved enough to notice!).
¢ The sex chromosomes are labeled X and Y and are numbered after Chromosome 22; this position does not correlate to size.
¢ When autosomes are arranged numerically by size followed by the sex chromosomes, this is called a karyotype.
¢ A karyotype is produced when autosomes are arranged numerically by size followed by the sex chromosomes.
¢ A karyotype is designated as the total number of chromosomes followed by the sex chromosomes, i.e. 46, XX or 46, XY.
¢ Chromosomes are divided by a centromere into "p" arms and "q" arms, with p (think 'petite') being the shorter arm and q being the longer arm.
¢ The centromere lies between the p and q arms.
¢ The location of the centromere defines the chromosome as follows:
o Metacentric: p and q arms are of approximately equal lengths
o Submetacentric: the centromere falls nearer to one end of the chromosome than the other
o Acrocentric: the centromere is near the terminus
o Telecentric: the centromere is near the terminus
Modes of Inheritance
Mendelian Inheritance
Autosomal Dominant
¢ The allele is expressed in both homozygous and heterozygous conditions.
¢ Most alleles segregate randomly during gamete formation.
¢ Characterisitcs of transmission, (i.e. inheritance, of a dominant allele) are:
o affected children have an affected parent
o males and females are affected in equal numbers
o each child of an affected parent has a 50% chance of inheriting the abnormal allele.
o it occurs in every generation
Autosomal Recessive
¢ The allele is expressed in the homozygous condition only.
¢ Patients are homozygous for the disorder.
¢ Characteristics of transmission of a recessive allele are:
o generally, parents of an affected individual do not express the recessive allele, (i.e. they are heterozygous for the allele.)
o two heterozygous parents have a 25% chance of having an affected child.
o affected parents have only affected children.
o it affects males and females in equal numbers.
o it may not be present in successive generations.
¢ Once it is known that two recessive alleles for a particular condition are not present because the individual does not demonstrate the disorder, there is 66% chance the individual is heterozygous for one normal and one abnormal allele, and 33% chance of being homozygous for two normal alleles.
X-linked
¢ The X Chromosome carries many important alleles that have no counterpart on the Y Chromosome.
¢ Males carry one X Chromosome, with single alleles of each gene, while females have two alleles for each gene.
¢ Generally, all alleles on the X Chromosome are expressed in males whereas the situation in females is not as straightforward.
¢ In inheritance:
o males pass X-linked alleles to all daughters, but not to sons.
o females pass X-linked alleles to 50% of their sons and daughters.
¢ X-linked expression can be dominant or recessive, but since males only have one X-chromosome, they express the disorder either way.
¢ Expression may be affected by penetrance and expressivity.
o an individual may possess a combination of alleles that should be expressed, but a proportion of these individuals has no expression - in these cases, penetrance is incomplete or reduced; expression of alleles as expected in all cases is known as 'complete penetrance'
o the expression of alleles has variable presentations - for example café-au-lait spots may occur in different numbers and positions among the same family members - this demonstrates variable expressivity.
Non-Mendelian Inheritance
Mitochondrial
¢ Sometimes called 'maternal inheritance',
o mitochondria are cellular organelles containing their own DNA (mtDNA). Unlike nuclear DNA that is inherited from both parents, mitochondria are inherited only through the mother via cytoplasm in the ova.
o each somatic cell contains mtDNA.
o some mtDNA may develop independent mutations.
o cells with only one type of mtDNA are homoplasmic.
o cells with mutant and non-mutant mtDNAs are heteroplasmic.
o as the amount of mutant mtDNA increases, a threshold is reached and the cell no longer compensates with the non-mutant mtDNA; a disease occurs.
U
niparental Disomy (UPD)
¢ Both homologous chromosomes come from one parent rather than one chromosome from each parent.
¢ This usually results from nondisjunction and then loss of the third chromosome (rescue) during meiosis.
Genomic Imprinting
¢ Some alleles are expressed only if they are inherited from a specific parent. The general mechanism of imprinting is methylation to down-regulate expression of a gene. Consequences of imprinting are seen when:
o one allele is imprinted and the other allele is nonfunctional, (i.e. deleted or mutated)
o UPDs have both alleles down-regulated;
o both alleles are imprinted.
Triplet Repeats
¢ Di- or trinucleotides become amplified during gametogenesis and amplification occurs preferentially in a specific parent of origin.
¢ A threshold number of repeats will result in an abnormal presentation.
¢ Amplifications may occur in the 5' promoter region of the gene, an exon, an intron, or the 3' region of the gene.
Mosaicism
¢ Different cells have different karyotypes.
¢ The total karyotype reflects the individual cell karyotypes, for example, 45,X/46,XX:
o this, however, does not imply the percentage of cells with each karyotype.
o the greater the abnormal karyotype percentage, the worse the clinical presentation.
Common Genetic Disorders
Autosomal dominant
Marfans Syndrome
¢ A mutation in the fibrillin gene.
¢ Presenting symptoms include tall stature, arachnodactyly, scoliosis, high-risk of dissecting aortic aneurysm, ectopic lentis, and emphysema.
Beckwith-Weidemann syndrome
¢ One of the most common congenital overgrowth syndromes.
¢ Congenital findings include macroglossia, omphalocele, gigantism, hemihypertrophy, advanced bone age, visceromegaly, microcephaly, renal medullary dysplasia, facial nevi, and distinctive ear creases.
¢ Correct diagnosis is important because patients are at an increase risk for neoplasia.
¢ Patients must be monitored for hypoglycemia and hypocalcemia.
Osteogenesis imperfecta, type I
¢ The most common form of osteogenesis imperfecta is caused by a reduction in Type I procollagen.
¢ Patients have skeletal osteopenia, fractures that may be present at birth, and blue sclerae throughout life.
Ehlers-Danlos syndrome
¢ A mutation in Type V collagen.
¢ Patients present with skin hyperextensibility, joint hypermobility, and abnormal wound healing.
Autosomal recessive
Cystic Fibrosis
¢ The most common autosomal recessive disease.
¢ Caused by a mutation in the CFTR gene.
¢ The mutation leads to an ineffective chloride transporter.
¢ Over 900 mutations cause variable expression of disease.
¢ Presenting symptoms include meconium ileus, bronchiectasis, pancreatic problems, and pseudomonas pneumonia.
Phenylketonuria (PKU)
¢ A mutation of the phenylalanine hydroxylase gene (PAH) gives rise to classical PKU.
¢ Nonclassical forms arise with other mutations in the phenylalanine to tyrosine pathway affecting the level of tetrahydrobiopterin.
¢ Phenylalanine diet restriction after birth will avoid serious mental retardation and neurological sequelae.
Galactosemia
¢ The inability to utilize galactose found in milk.
¢ Galactose is not converted to glucose by galactose-1-phosphate uridyl transferase and accumulates in tissues.
¢ Infants suffer from malnutrition and failure to thrive if a galactose-free diet is not initiated after birth.
H
urler syndrome
¢ The most severe of the mucopolysaccharidoses, this results from a mutation in alpha-L-iduronidase.
¢ Heparin and dermatan sulphate cannot be degraded and accumulate in tissues and urine.
Trisomy - three of the same chromomsome resulting from nondisjunction
Downs Syndrome
¢ Trisomy 21
¢ The most common chromosomal cause of mental retardation
¢ Patients have 3 copies of chromosome 21.
¢ It is the most common cause of mental retardation.
¢ Patients present with simian crease, brushfield spots, epicanthal folds, and congenital heart problems, and Alzheimer's disease by age 40.
¢ Can also occur from a translocation, but this is less common.
Edward's Syndrome
¢ Trisomy 18
¢ Patients have 3 copies of chromosome 18.
¢ Leads to mental retardation, rocker-bottom feat, congenital heart problems, and flexion deformities.
¢ Most patients die by age 1 year.
¢ Associated with increased maternal age at birth.
Patau's Syndrome
¢ Trisomy 13
¢ Three copies of chromosome 13
¢ Present with mental retardation, cleft lip, cleft palate, polydactyly, and congenital heart problems.
¢ Patients generally die by age 6 months.
Klinefelter's Syndrome
¢ Sex Chromosome (47,XXY).
¢ One of the most common forms of primary hypogonadism and infertility in males.
¢ These patients are genetically male and present with hypogonadism, tall stature, abnormal upper:lower body ratio and gynecomastia.
Monosomy
¢ The presence of only one member of a homologous chromosome pair
¢ Results from nondisjunction.
Turner's Syndrome
¢ Sex Chromosome (45,X).
¢ The most common cause of primary amenorrhea.
¢ Non-disjunction of the sex chromosome during Meiosis.
¢ Patient presents with streak gonads, webbed neck, short stature, and poorly developed genitalia.
¢ Patients are also at increased risk for coarctation of the aorta, diabetes, autoimmune disorders, and inflammatory bowel disease.
X-linked
Duchenne Muscular Dystrophy (DMD)
¢ An X-linked disorder that affects only males.
¢ The mutation leads to the absence of the dystrophin protein needed to keep skeletal muscle cells intact.
¢ Patients present with generalized weakness and muscle wasting in hips, pelvic region, thighs, and shoulders.
¢ Calves often are enlarged (pseudohypertrophy)
Becker's Muscular Dystrophy
¢ An X-linked disorder affecting males only.
¢ Compared to DMD it has a later onset (2-16 years of age), but the symptoms are similar, though less severe and progress more slowly.
Hemophilia A
¢ X-linked disease leading to a deficiency of Factor VIII, which leads to blood clotting problems.
¢ Affects only males and presents with a history of hemorrhage, hematuria and hemarthrosis.
Hemophilia B
¢ X-linked disease leading to a deficiency of Factor IX.
¢ Similar to Hemophilia A, but milder.
Lesch-Nyhan disease
¢ A mutation in the HGPRT gene. The enzyme is necessary for the recycling of purine components and the mutation leads to a build-up of purine degradation byproducts.
¢ Symptoms begin to present at 3-6 months of age.
¢ Most prominent symptom is self-mutilation, along with mental retardation, gout and orange uric acid crystals in the urine.
Mitochondrial
MELAS - Mitochondria Encephalomyopathy with Lactic Acidosis and Stroke-like episodes.
¢ The most common mutation is in tRNALeu.
¢ This mutation causes reduced activity of mitochondrial Complexes I and IV that lead to respiratory chain dysfunction.
¢ Lactic acidosis occurs in the blood and CSF.
¢ Cerebral necrosis and cortical atrophy develop in patients.
¢ Presents with visual defects, blindness, hearing loss, seizures, dementia and loss of consciousness.
¢ Mean age of onset is 10 years.
MERRF - Myoclonic Epilepsy and Ragged Red Fibers.
¢ The most frequent mutations occur in tRNALys (>80%), tRNASer, and tRNALeu.
¢ Lactic acidosis is variable and ragged red fibers in muscle biopsy are a hallmark.
¢ Most frequently presents with myoclonus, epilepsy, ataxia, myopathy and hearing loss.
LHON - Leber Hereditary Optic Neuropathy.
¢ One of three mutations in mitochondrial complex I accounts for approximately 95% of cases.
¢ Optic nerve degeneration leads to central vision loss in 2-8 weeks.
¢ Generally, the first eye is affected followed by the second eye within 6 months.
¢ Mean age of onset varies for each mutation, but the 95th percentile for onset for the three most common mutations is age 50 years.
Triplet Repeats
Fragile X Syndrome
¢ This disorder represents both X-linked inheritance and triplet repeat amplification.
¢ Disease occurs due to a mutation of the FMRP gene promoter on chromosome X, which leads to an increase in the size of the non-coding 5' promoter region of the gene.
¢ Amplification of CGGs provides additional cytosines for methylation and gene downregulation.
¢ Gene product actually prevents disease.
¢ Patients present with mental retardation, long face, large ears, dental problems and large testes.
Huntington's disease
¢ An autosomal dominant disease.
¢ Has 100% penetrance, and presents with progressive dementia with adult onset.
¢ Amplification of CAG (codes for glutamine) triplet in exon.
¢ Mean age of onset ~40 years.
¢ Patients usually die within 10-15 years of first symptoms.
Myotonic dystrophy
¢ The most common form of muscular dystrophy affecting adults.
¢ It results from amplification of CTG in the 3' region of the DMPK gene.
¢ Three forms exist - classical, mild, and congenital (the most severe form).
¢ Muscular weakness is apparent early in the neck muscles.
¢ Distal limb muscles are affected and proximal limb muscles remain stronger throughout disease. (Note that with Duchenne and Becker's muscular dystrophy the proximal muscles are more affected.
Microdeletion Syndromes
Cri du Chat Syndrome
¢ A deletion of the long arm of Chromosome 5.
¢ Patient presents with severe mental retardation, microcephaly, 'cry of the cat' sounds, hypertelorism, and low-set ears.
Prader-Willi Syndrome (PWS)
¢ The most common microdeletion syndrome
¢ The most common form of genetic obesity
¢ The first recognized microdeletion syndrome
¢ The first recognized imprinting disorder
¢ The first recognized uniparental disomy disorder.
¢ The multiple modes of inheritance make this an important disorder to know.
¢ The gene responsible is SNRPN on Chromosome 15.
¢ An understanding of imprinting is important to understanding PWS.
¢ Patient presents with hypotonia (pre- and post-natally) followed by hyperphagia.
¢ Hypothalamic hypogonadism, short stature, hypopigmentation, small hands and feet, skin picking, behavioral problems.
Angelman Syndrome
¢ This disorder is often studied along with Prader-Willi syndrome and represents a microdeletion disorder and an imprinting disorder.
¢ The gene responsible is UBE3A on Chromosome 15.
¢ Patients are severely mentally retarded and often mute with inappropriate laughter.
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