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CSF > Block 6 > Flashcards

Block 6 Flashcards

1
Q

What are alleles?

A

Variations in DNA sequence found at a particular locus

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2
Q

How do you determine chances of both children inheriting a disorder?

A

(chance of one) X (chance of other)

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3
Q

Acrocentric chromosome

A

Centromere located at the end of the chromsome

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4
Q

Is the q arm the longer or shorter part of the chromosome?

A

Longer arm

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5
Q

What types of tissues are appropriate for analysis?

A

Lymphocytes from blood, cord blood, or BM. Fibroblasts from tissue, amniotic fluid, or chorionic villi

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6
Q

What is aneuploidy and how is it denoted?

A

Having a chromosome number not equal to a multiple of the haploid number.
Denoted: # chromosomes, sex chromosomes, additional or missing chromosome (47, XX, +21)

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7
Q

What is polyploidy and how is it denoted?

A 
Having an abnormal number of chromosomes equal to a multiple of the haploid number 
(triploidy = 3n=69)
# chromosomes, sex chromosomes
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8
Q

What are the two methods of triploidy?

A
  1. Dispermy -abnormal placenta with growth retarded fetus

3. Disomic egg- growth retarded fetus and small placenta

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9
Q

What is mosaicism?

A

Presence of two or more cell lines in an individual or tissue sample

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10
Q

What is dichytyotene?

A

Stage of oogenesis where oogonia remain halted in prophase I until ovulation.

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11
Q

When does chromosome nondisjunction occur?

A

During homolog pairing in meiosis I or sister chromatid separation in meiosis II

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12
Q

What are the most common trisomies that survive until birth?

A

Down syndrome, trisomies 13&16, Turner syndrome

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13
Q

What are the mechanisms of trisomy 21?

A

Maternal meiosis errors (85-90%)
Paternal meiosis errors (3-5%)
mitotic errors and robertsonian translocation (10%)

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14
Q

When do most of the maternal meiosis errors occur? Paternal?

A

Maternal: 75% meiosis I
Paternal: 75% meiosis II

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15
Q

What is Edwards syndrome and what are the clinical features?

A

Trisomy 18. DD/MR, dysmorphism, malformations

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16
Q

What is Patau syndrome and what are the clinical features?

A

Trisomy 13. Growth retardation, DD/ MR, Midline defects, clefting, microphtalmia, plydactyly, malformations

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17
Q

What is Turner syndrome and what are the clinical features?

A

Monosomy X. Short stature, broad chest, cubitus valgus, short webbed neck, congenital lymphedema, sensory-motor integration dysfunction, streak ovaries (infertility).
Can be mosaic with 46,XX or XY cells

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18
Q

What is Klinefelter syndrome and what are the clinical features?

A

47, XXY aneuploidy. Tall stature, long legs, delayed puberty, infertility, gynecomastia, learning disabilities

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19
Q

Are there phenotypic abnormalities with 47, XXX or 47, XYY?

A

No

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20
Q

What is the SRY region?

A

Sex-determining region on the Y. Conserved sequence = DNA binding domain. Can be deleted in XY females or present in XX males

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21
Q

What are Robertsonian translocations?

A

Rearrangements involving only acrocentric chromosomes and result in fusion of two long arms with loss of the short arm.

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22
Q

What are the acrocentric chromosomes?

A

13, 14, 15, 21, and 22

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23
Q

What is the nomenclature for Robertsonian translocations?

A

45, XY, derivative chromosome and breakpoint of chromosome

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24
Q

What are the issues with segregation of Robertsonian translocations?

A

Robertsonian chromosomes can form trivalents with freelying chromosomes. During separation can form monosomic and trisomic chromosomes.

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25
Q

Where are Robertsonian translocations found clinically?

A

Infertile couples (males more), female carriers more likely to have trisomic conception. More likely to have trisomy 21 than trisomy 13.

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26
Q

What are balanced translocations?

A

Involve two breakpoints on two chromosomes and material is rearranged

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27
Q

What is the nomenclature for balanced translocations?

A

46, XX, t for translocation and breakpoints of corresponding chromosomes

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28
Q

What are unbalanced translocations?

A

Quadrivalent formed during meiosis and homologous recombination happens. Malsegregation can create unbalanced translocations.

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29
Q

What are derivative chromosomes?

A

Chromosomes containing material from more than one chromosome.

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30
Q

Are the chances for mental/ physical abnormalities greater if translocations are inherited or occur de novo?

A

De novo

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31
Q

What are the two types of deletions?

A

Terminal (occurs @ end) and interstitial (require 2 breaks)

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32
Q

What are paracentric inversions?

A

Inversions that Avoid the centromere with breakpoints in the same arm

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33
Q

What are pericentric inversions?

A

Inverstions that Include the centromere with breakpoints in each arm.

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34
Q

What is FISH used for?

A

Identification of chromosome material of unknown origin, detection of sub-microscopic chromosome alterations, detection of abnormalities in interphase cells,. Can detect specific gains, losses, and rearrangements depending on probe used

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35
Q

What is a polymorphism?

A

2 or more alleles for a given locus, each present in a population at a frequency of at least >1%

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36
Q

What is a compound heterozygote?

A

Genotype with two different alleles at the same locus where both alleles are different and both defective

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37
Q

What is the ratio of expression for dominant alleles?

A

3:1

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38
Q

What is the principle of segregation?

A

Organisms inherit two alleles for each trait and allele pairs separate during gamete formation.

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39
Q

What is the principle of independent assortment?

A

Genes at different loci are transmitted independently. Allele paris are randomly united at fertilization. An allele at one locus has no effect on an allele at another locus (NOT TRUE)

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40
Q

What are the characteristics of autosomal dominant inheritance?

A

Phenotype appears in every generation (vertical transmission), any child has 50% chance of inheritance, usually phenotypically normal family members don’t transmit. Males to females = equal likelihood and male-to-male transmission.

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41
Q

What is the inheritance pattern of incomplete dominant alleles?

A

If AB is an intermediate between AA and BB, then allele A is incompletely dominant to allele B

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42
Q

What is an example of incomplete dominant alleles?

A

Achondroplasia
dd: normal height
Dd: achondroplasia
DD: severe lethal achondroplasia

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43
Q

What is the inheritance pattern for co-dominant alleles?

A

If the phenotype of AB shows phenotypic features of alleles A and B then the alleles are co-dominant

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44
Q

What is an example of co-dominant alleles?

A

ABO blood groups where A & B are co-dominant and O is recessive

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45
Q

What are the recurrence risks of de novo mutations?

A

de novo (new) mutation:
parents of affected <1%
children of affected 50%

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46
Q

What is germline mosaicism?

A

Two or more children born with autosomal dominant disease where there’s no family history. Theoretically due to presence of more than one genetically distinct cell line in one parent (osteogenesis imperfecta)

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47
Q

Which diseases have delayed age of onset?

A

Huntington disease and breast cancer

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48
Q

What is penetrance?

A

Probability a gene will be expressed. Can be all or nothing or reduced.

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49
Q

What are two examples of penetrance?

A

HNPCC: 80% lifetime risk of colon cancer

Split-hand deformity ~70% penetrance

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50
Q

What is variable expression?

A

Penetrance is complete but the severity of disease can vary greatly both within and between families.

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51
Q

What is pleiotropy?

A

One gene produces multiple different effects on physiology or anatomy

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52
Q

What is an example of pleitropy?

A

Marfan syndrome

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53
Q

What is locus heterogenetiy?

A

single disorder caused by mutation in genes at different loci (hereditary breast cancer)

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54
Q

What is allelic heterogeneity?

A

Single disorder caused by different mutations in the same gene (cystic fibrosis)

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55
Q

What is phenotypic heterogeneity?

A

Different mutations in the same gene giving rise to different phenotypes (craniosynostosis syndromes)

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56
Q

What are the characteristics of autosomal recessive inheritance?

A

Clinical manifestation on in homozygous individuals. If phenotype occurs in more than one family member, it is usually seen in sibling of proband (not parents, offspring, and other relatives)

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57
Q

What is the recurrence risk if both parents are carriers?

A

1 in 4

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58
Q

What genetic disease are in higher frequencies in the Ashkenazi Jewish population?

A

Tay Sachs Disease and Gaucher Disease

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59
Q

What genetic disease occurs in higher frequencies in asian populations?

A

Alpha thalassemia

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60
Q

What genetic disease occurs in higher frequencies in greek/italian populations?

A

beta thalassemia

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61
Q

What is hemizygosity?

A

having only one member of a chromosome pair or chromosome segment rather than the usual two

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62
Q

What is the X-linked recessive inheritance pattern?

A

single dose mutant allele is a disease causing in males, two doses cause disease in females

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63
Q

What are some examples of X-linked recessive diseases?

A

Hemophilia A, duchenne muscular dystrophy, color blindness

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64
Q

When are females affected by X-linked recessive genes?

A

both copies in X, hemizygous female (45, X); translocation of X with preferential inactivation of normal X, skewed x-inactivation

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65
Q

What is the expression pattern for X-linked dominant conditions?

A

Occur in both males and females and phenotype is usually more severe in males

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66
Q

What is an example of an x-linked dominant disease?

A

hypophosphatemic rickets

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67
Q

Can X-linked traits be passed from father to son?

A

NO- dad only gives Y to son, but he will give affected X to all of his daughters

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68
Q

What are the features of X-linked dominant lethal traits?

A

No affected males seen because they die before term.

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69
Q

What is the recurrence risk for X-linked dominant lethal traits?

A

33%

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70
Q

What are two examples of X-linked dominant traits?

A

Goltz syndrome or incontinentia pigmenti

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71
Q

What are trinucleotide repeat disorders?

A

Disorders where trinucleotide repeats affect a segment of a gene and as they are passed, the number of trinucleotide repeats increases

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72
Q

What are some examples of trinucelotide repeat disorders?

A

Huntington’s disease, Fragile X, Myotonic dystrophy, Friedreich ataxia

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73
Q

What are contributing factors to trinucleotide diseases?

A

Repeat size (range in phenotype); parent of origin; anticipation = occurence of disease at earlier stages in successive generations

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74
Q

What are the characteristics of long expansions and fragile sites for trinucleotide repeat disorders?

A

Repeat 10X normal size, outside protein coding region, CCG/ CGG/ CTG motifs.

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75
Q

What are some examples of long expansion trinucleotide repeat disorders?

A

Fragile X, FXTAS, FRAXE, myotonic dystrophy, spinocerebellar ataxia type 8

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76
Q

What are the characteristics of Myotonic dystrophy type I?

A

Onset 20-40 yoa; muscular weakness/ wasting, cardiac arrhythmias, cataracts, male infertility, anticipation (esp from mom)

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77
Q

What is the recurrence risk for myotonic dystrophy type 1?

A

50% for children of affected parents to inherit gene

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78
Q

What causes myotonic dystrophy type I?

A

19q13 myotonin protein kinase CTG repeats in 3’ UTR. Affected at >50 repeats; congenital = 1000’s of repeats

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79
Q

What are the characteristics of congenital myotonic dystrophy?

A

Severe hypotonia, myopathic facies with tented mouth, absent suck, DD/MR, speech delay, club feet

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80
Q

What are the features of Fragile X syndrome?

A

FMR1 full mutation (>200) repeats. MR in males and mild retardation/ LD in females.
Males w/ characteristic features

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81
Q

What are the characteristic features of Fragile X syndrome?

A

macrocephaly, long face, prominent forehead and chin, protruding ears, connective tissue findings (laxity), and large testes.

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82
Q

What is fragile-x associated tremor/ ataxia syndrome?

A

In males with FMR1 premutation. Late-onset, progressive cerebellar ataxia and intention tremor

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83
Q

How common is FMR1-related premature ovarian failure?

A

Occurs in 20% of females with FMR1 premutation

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84
Q

Describe FMR1 pathogenesis

A

CGG repeats interrupted by AGG triplet every 9-10 repeats. AGG anchors segment against expansion. Uninterrupted repeats are methylated and causes decrease or complete absence of FMR1 transcript and protein. Expansion in oogenesis

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85
Q

What are the normal numbers of FMR1 repeats?

A

5-44 repeats. Alleles still stably transmitted.

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86
Q

What are the intermediate FMR1 repeat sizes?

A

45-54 repeats in gray zone. Expansions may predispose to learning and/ or behavior problems

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87
Q

What are the sizes and associations with FMR1 premutation alleles?

A

55-200 repeats. Increases risk for FXTAS and POF but not MR. Usu normal intellect and appearance. May be subtle social anxiety or learning difficulties

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88
Q

What does a diagnosis of FXTAS require?

A

Presence of FMR1 gene premutation and white matter lesions on MRI w/ gait ataxia/ tremor

89
Q

What is the inheritance pattern for males with premutation FMR1?

A

Transmit to all of their daughters and none of their sons

90
Q

What is the general pattern of inheritance with FMR1 premutation?

A

Penetrance is age related and increases with age

91
Q

Describe the pathogenesis of FMR1 full mutation

A

> 200 repeats. 99% have increased repeats and abnormal methylation. All males with full mutation have fragile X. 50% of females have MR (only 50% inactivation)

92
Q

What are the characteristics of short expansions and neurodegenerative disorders?

A

Short expansions (<100 copies); repeat within protein coding region; CAG forms polyglutamine tracts - GAIN OF FUNCTION

93
Q

What are two examples of short expansion neurodegenerative disorders?

A

Huntington’s disease and Friedreich Ataxia

94
Q

What are the characteristics of Huntington disease?

A

Progressive neurodegenerative disorder. AOO- ~35 yoa. Survival ~15 years after dx. Dx= expansion of 36 or more CAG repeats in HTT

95
Q

What is the inheritance pattern for Huntington’s disease?

A

Autosomal dominant with 50% recurrence risk for children. Increased risk when inherited form father. Can have nonpenetrance.

96
Q

What are the symptoms of Friedreich Ataxia?

A

Dysarthria, muscle weakness, spasticity in lower limbs, scoliosis, bladder dysfunction, absent lower limb reflex, onset between 10-15 and before age 25

97
Q

What is the inheritance pattern for Friedreich Ataxia?

A

Autosomal recessive GAA repeat sequence on intron 1 of FXN. Full penetrance alleles: 66 to 1700

98
Q

What are the non-penetrant copy ranges for Friedreich Ataxia?

A

normal: 5-33
Mutable/ premuataion: 35-65
Borderline: 44-66

99
Q

What are continguous gene syndromes?

A

Deletion or duplication of a chromosome region involving few to hundreds of genes that can lead to variable phenotypes = microdeletion/dupl (ex Williams syndrome 7q11.23)

100
Q

Explain “dosage-sensitivity” in its relation to contiguous gene syndromes

A

Effects of disease are dependent on the relative doses of genes. Deletions/ duplications on same chromosome can cause different phenotypes

101
Q

What is the main mechanism causing continguous gene deletions/ duplications?

A

Non-allelic homologous recombination (NAHR)

102
Q

What is non-allelic homologous recombination?

A

Homologous repetitive DNA sequences flank gene regions on chromosomes and can cause misalignment of chromosomes. Recombination can result in chromosomes having reciprocal deletions/ duplications

103
Q

What are the clinical features of DiGeorge Syndrome?

A

Heart defects, narrow palpebral fissures, cleft palate, nasal speech, feeding difficulties, hypocalcemia, tymic aplasia, LD/ DD, increased risk for schizophrenia

104
Q

what are two methods of detecting deletion/dupl syndromes?

A

FISH and chromosome microarray

105
Q

What is epigenetics?

A

Study of changes in an organism due to modification of gene expression vs. altering the genetic code NOT mutations

106
Q

What are different epigenetic mechanisms of changing gene expression?

A

DNA methylation, chromatin remodeling/ histone modification, x-inactivation, RNAi

107
Q

True or false: methylation patterns can be inherited?

A

True: can be inherited in germ cells (imprinting and inheritance)

108
Q

What happens if there are mutations in the MECP2 gene?

A

Methyl-CpG binding protein 2 fx in silencing and regulating other genes. Can cause Rett syndrome

109
Q

What is the Lyon hypothesis?

A

Only one X chromosome in females is transcriptionally active; the other is inactive and is a Barr body

110
Q

When does X inactivation occur?

A

Early in embryogenesis and is randomly determined. All daughter cells have same X inactivated

111
Q

Explain the mechanism of X chromosome inactivation

A

X inactivation center @ Xq13 contains XIST gene

112
Q

What does the XIST gene encode?

A

X inactive specific transcript = functional non-coding RNA that helps silence X chromosome by binding to chromosome and causing methylation

113
Q

How many X-chromosomes escape inactivation?

A

About 15%

114
Q

What are some instances in which the X-chromosome inactivation is preferentially inactivated?

A

Large X chromosome deletions and translocations involving the X chromosome. Or if monozygotic twins split before Xi

115
Q

What is the clinical effect of having skewed X inactivation?

A

Females can show symptoms of SLR genes if some chromosomes are not inactivated even if carrier

116
Q

What is genomic imprinting?

A

Heritable epigenetic changes affecting patterns of gene expression that can depend on if maternally or paternally inherited.

117
Q

When does genomic imprinting take place?

A

During gametogenesis

118
Q

Define maternally imprinted

A

maternally-inherited gene is silenced

119
Q

Define paternally imprinted

A

paternally-inherited gene is silenced

120
Q

Define non-imprinted gene

A

gene is always expressed, regardless of inheritence

121
Q

What two diseases are dependent on paternal or maternal inheritance of chromosome 15q11.2

A

Prader-Willi (paternal) and Angelman syndrome (maternal)

122
Q

What are the clinical features of prader-willi syndrome?

A

neonatal hypotonia, DD/LD/ID, feeding difficulties, early childhood hyperphagia/ insatiable appetite

123
Q

What are the clinical features of angelman syndrome?

A

DD/ID, microcephaly, speech impairment, seizures, ataxia, happy, excitable demeanor with hand flapping/ repetitive movements

124
Q

What are the causes of Prader-Willi?

A

Large deletion of paternal 15q11.2 (75%); uniparental disomy of maternal chromosome (25%); imprinting center defect

125
Q

What are the causes of Angelman syndrome?

A

large deletion of maternal 15q11.2 (60-70%); uniparental disomy of paternal chromosome 15 (5%); imprinting center defect; mutation in UBE3A gene in 15q11.2 region

126
Q

What is uniparental disomy?

A

Both copies of a chromosome originate from a single parent

127
Q

What are the mechanisms of uniparental disomy?

A

Trisomy rescue; monosomy resuce; gametic complementation

128
Q

What is trisomic zygotic rescue in UPDs?

A

Start with a disomic gamete from one parent and norm from another. Join in fertilization but undergo nondisjunction so daugther cells can have some normal and some w/ trisomic

129
Q

What is gemete complementation in UPDs?

A

One gamete doesn’t have genes and the other gamete is disomic, so inherit both from one parent

130
Q

What is monosomy rescue in UPDs?

A

One gamete normal w/ one copy and other doesn’t have it. Gamete with both copies from one parent.

131
Q

Why does the genotype-phenotype correlation matter?

A

Helps with determining natural history/ prognosis. Can be differences between deletion and UPD

132
Q

Is the recurrence risk higher for UPDs/deletions or imprinting center mutations?

A

Imprinting center mutations

133
Q

What is a hydatidiform mole?

A

Complete mole- non viable egg has lost its DNA is fertilized = no contribution from maternal genome

134
Q

What is a partial mole?

A

monospermic/ dispermic fertilization of a viable egg cell leading to triploid or tetraploid embryo

135
Q

What is a molar pregnancy?

A

Pregnancy with little to no fetal tissues but overgrown/ dysplastic placenta

136
Q

What happens if an embryo only has a maternal genome?

A

egg deveops unfertilized with two copies of the maternal genome has poor fetal growth w/ fibrotic placental tissue = ovarian tetroma

137
Q

What effects can histone hyperacetylation have on development.

A

Can cause NT defects. Agents like valproate

138
Q

What effect can assisted reproductive technologies have on gene expression?

A

Increased risk of imprinting errors in offspring

139
Q

What information should be included in a pedigree?

A

Three generations, miscarriages, still births, birth defects, DD/ID, age of onset, ethnic background, consanguinity

140
Q

What is the typical occurence of x-linked recessive diseases?

A

50% for boys to be affected; 50 % for girls to be carriers

141
Q

What does the Hardy -Weinberg Equilibrium predict?

A

Genotype frequencies in population at a particular locus based on gene frequencies

142
Q

What does the HW equilibrium assume?

A

Genetic variation in a population will remain constant as long as there’s no disturbance?

143
Q

What things can disturb HW equilibrium?

A

new mutations, natural selection, non-random mating, migration of populations

144
Q

What is the HW equation?

A

genotype AA; Aa; aa = frequency p2; 2pq; q2 where p2+2pq+q2 =1

145
Q

What are the applications of the HW equilibrium?

A

Can be used to calculate allele frequencies and heterozygote/ carrier frequencies when incidence known

146
Q

What is special about the HW equilibrium for autosomal dominant traits?

A

Incidence of affected homozygotes is very low and can be ignored, so incidence of disease is equal to number of heterozygotes

147
Q

How is the HW equation used for autosomal recessive traits?

A

For an autosomal recessive trait the incidence of the disease is equal to the number of affected homozygotes. The frequency of the disease gene (q) is calculated by taking the square root of the incidence of the disease (q2). q can then be used to calculate the carrier frequency 2pq.

148
Q

What is the coefficient of relationship (R)?

A

The degree of consanguinity or the proportion of genes shared

149
Q

What is the coefficient of inbreeding (F)?

A

Chance of homozygosity by descent or the probability that an individual has received both alleles of a pair from a single ancestor

150
Q

What are the consanguinity coefficients for parent-child/

A

R: 1/2
F: 1/4

151
Q

What are the consanguinity coefficients for brother-sister?

A

R: 1/2
F:1/4

152
Q

What are the consanguinity coefficients for uncle-niece?

A

R: 1/4
F: 1/8

153
Q

What are the consanguinity coefficients for first cousins?

A

R: 1/8
F: 1/16

154
Q

What are the consanguinity coefficients for second cousins?

A

R: 1/32
F: 1/64

155
Q

What is an easy way to calculate carrier frequencies in consanguinous relationships for AR diseases?

A

Draw family tree and draw arrows of relatedness. Each arrow = 1/2 chance carrier is passed

156
Q

What is the shortcut for calculating early onset recessive carrier status in an unaffected individual for AR disease?

A

2/3 because can rule out being homozygous affected

157
Q

What are multifactorial traits?

A

Traits in which variation is thought to be caused by the combined effects of multiple genes and environmental factors

158
Q

Explain traits with continuous variation

A

Traits where phenotypes are distributed from one extreme to another in a continuous overlapping pattern.

159
Q

Do individual genes underlying a polygenic or multifactorial trait follow Mendelian principles?

A

YES

160
Q

Explain the additive model of multifactorial traits

A

Each gene adds an incremental amount to the phenotype and more genes involved, greater number of different phenotypic cases = bell-shaped curve

161
Q

Explain mutifactorial threshold traits

A

trait does not show a continuous distribution (affected or unaffected).
Does not follow pattern of single gene inheritance.

162
Q

What is gene liability?

A

Only certain gene types are liable to express phenotypes and liability is due to the influence of multiple gene.

163
Q

What sorts of things increase recurrence risk for threshold genes?

A
  1. As severity of disorder increases
  2. Number of affected family members increases.
  3. If at risk child is of affected sex
  4. If the pro band is of the less frequently affected sex
164
Q

Pyloric stenosis is an example of what kind of mutlifactorial trait?

A

Threshold model- affected females are more likely to have affected offspring (bc females less likely)

165
Q

What is anticipation?

A

The increase in severity of a disease in successive generations. It is a hallmark trait of trinucleotide repeat disorders.

166
Q

What type of inheritance patterns do all metabolic diseases have?

A

Autosomal recessive

167
Q

What are two types of organic acidurias?

A

PA, MMA

168
Q

Describe Phenylalanine Hydroxylase deficiency

A

Enzyme deficiency that leads to build-up of phenylalanine (neurotoxic) and leads to microcephaly and severe cognitive impairment.

169
Q

What are the treatments for PAH (PKU)?

A

Phe-restricted diet. Formula feeds.

170
Q

What are some general effects of disorders of amino acid metabolism?

A

Acidosis, ketosis, metabolic decompensation with catabolism.

171
Q

What are some general cures for amino acid disorders?

A

Restricted diets, AA specific formulas, +/- additional medications

172
Q

Methylmalonic aciduria is a disorder of what enzyme?

A

Methylmalonyl CoA mutase (Vitamin B12 cofactor)

173
Q

Proprionic aciduria (PA) is a disorder of what enzyme?

A

Proponyl CoA carboxylase (Biotin cofactor)

174
Q

What do PA and MMA both result in?

A

Defects in succinyl CoA and the citric acid cycle

175
Q

How do PA and MMA present?

A

Acidosis during catabolism with severe neonatal presentation.

176
Q

What are treatments for PA/ MMA?

A

Restricted diet/ propimex

177
Q

What are some predispositions associated with PA/ MMA?

A

Cardiomyopathy (PA), pancreatitis, neutropenia, seizures, DD

178
Q

Maple syrup urine disease is a deficiency in what substance?

A

BCKDH (branched chain ketodehydrogenase) = build up in Leucine

179
Q

CoA Lyase/ Synthase 3MCC are diseases in what pathway?

A

Leucine degredation pathway

180
Q

What are some clinical presentations of Glutaric Aciduria Type 1?

A

Lack of neonatal encephalopathy, large head circumference, Subdural hemorrhage/ illness before metabolic crisis. Dystonia, chorea, delays.
Can be mistaken for child abuse

181
Q

What are urea cycle disorders disrupting?

A

Disorders in the pathway of nitrogen excretion and the build up of ammonia

182
Q

How can urea cycle disorders present?

A

Catastrophic neonatal illness or illness during childhood/ teen, pregnancy. Tx= lifelong protein restriction

183
Q

What is the unusual inheritance pattern of ornithine transcarbamoylase deficiency?

A

X-linked and women can be affected. Neonatal presentation is lethal.

184
Q

What is galactosemia?

A

Defect in GALT (galactose 1 phosphate uridyltransferase) that prevents proper breakdown of galactose into glucose.

185
Q

What are glycogen storage disorders a result of?

A

Defects in glycogen degradation leads to glycogen build-up. Can be seen in the tongue and liver (Pompe disease)

186
Q

What are GLUT 1 disorders caused by?

A

Deficiency of transporter responsible for sending glucose into the brain. Presentation w/ DD, seizures, CSF glue <40, microcephaly

187
Q

What are fatty acid oxidation disorders caused by?

A

Inability to process fatty acids through mitochondria that can predispose to hypoglycemia during fasting.

188
Q

What is MCADD?

A

Most common fatty acid oxidation disorder where illness is caused by prolonged fasting. Thought to cause SIDS.

189
Q

What is VLCADD?

A

FAOD with longer chain fatty acids. Can cause cardiomyopathy and requires diet restriction.

190
Q

What are some general characteristics of carnitine deficiencies?

A

Involve the transport of fatty acids into mitochondria.

191
Q

What is the first line testing for suspected biochemical disorders?

A

Biochemical profiles (plasma AA, etc). Then enzyme analysis and measurement of product/ build-up. Finally molecular analysis of gene.

192
Q

How many of the complexes involved in electron transport are partially encoded on mitochondrial DNA?

A

4/5 Complex II does not have any protein subunits encoded by mitochondrial DNA

193
Q

The inheritance of maternal mitochondria in the zygote is an example of what kind of inheritance?

A

Matrilinear inheritance

194
Q

What are some ways paternal mitochondria are removed in the zygote?

A

autophagy/ lysosomal degredation, ubiquitin-proteasome degredation pathway

195
Q

What is a human mitochondrial DNA haplogroup?

A

Differences in mitochondrial DNA sequences among mitochondria

196
Q

What is the term used to describe mitochondrial containing only one type of mtDNA?

A

Homoplasmic

197
Q

What term is used to describe mitochondria containing mixtures of mutant and normal mtDNA?

A

Heteroplasmic

198
Q

Describe mitochondrial random segregation

A

During cytokinesis, cytoplasm divides daughter cells and location of mitochondria determines which cell receives which mitochondria

199
Q

Describe the tissue threshold effect in terms of mitochondrial genetics

A

Variability of energy demands in different tissues determines disease phenotypes and the OXPHOS capacity of certain tissues decreases as tissues age.

200
Q

Does mtDNA have a higher or lower mutation rate than nDNA?

A

Higher- about 6-17x more rapidly

201
Q

What is Leber’s Hereditary Optic Neuropathy and what type of genetic disease is it?

A

Rapid bilateral loss of central vision due to optic nerve death. Due to G-A point mutation in NADH dehydrogenase in mitochondria

202
Q

What is Kearns-Sayre Syndrome and what kind of genetic disease is it?

A

Variety of neuromuscular disorders caused by a cumulative damage and deletion of mtDNA. Can present with ptosis

203
Q

What are some characteristics of myoclonic epilepsy and ragged red fibers (MERRF)?

A

Mitochondrial disorder w/ epilepsy, hearing loss, ataxia. Onset from late childhood and adolescence to adulthood.

204
Q

How do the prognosis for mitochondrial myopathies relate to metabolism?

A

Progression of disorders depends largely on metabolism, which varies greatly among patients.

205
Q

Are there any specific treatments for mitochondrial myopathies?

A

No but can do OT/PT, Coenzyme Q10, B vitamins, L-carnitine for fat transport, DCA to reduce acidosis, etc.

206
Q

How are mitochondria myopathies tested?

A

Transmitochondrial cell lines (hybrids) used. If they have poor function = defective mtDNA.

207
Q

What is the “three parent baby” approach?

A

Approach to overcome mtDNA related diseases

208
Q

What are 3 general characteristics of complex traits?

A
  1. DO NOT follow Mendel’s laws (still inheritable)
  2. Polygenic (affected by multiple genes)
  3. Multifactorial- polygenic and environmental factors
209
Q

DM1 and DM2 are examples of what kind of genetic disease and what can they cause?

A

Multifactorial genetic trait. Combined with environment, they can predispose to diabetes

210
Q

What are some characteristics of MODY?

A

Mature onset diabetes of the young. Onset of diabetes in the 20s NOT associated with obesity. Autosomal dominant

211
Q

Which 3 genes are involved in Mendelian Alzheimers?

A

Presenillin-1, presenillin-2, amyloid precursor protein

212
Q

What is the inheritance pattern of Mendelian Alzheimers?

A

AD with 100% penetrance

213
Q

Which gene is related to multifactorial inheritance of Alzheimers?

A

APOE e4 (e2 is protective). Older females are in a higher risk group

214
Q

What is concordance?

A

Measured in twin studies. If twins share the same trait.

215
Q

How do you determine the heritability of a trait (twin studies)?

A

H= 2 (cMZ-cDZ) (c=concordance)

216
Q

What does it mean if concordance in MZ > DZ?

A

Genetics plays a bigger factor

217
Q

What are the three hallmark examples of X-linked recessive disorders?

A

Hemophilia A, Duchenne Muscular dystrophy, color blindness

218
Q

Hypophosphatemic rickets is an example of what type of inheritance?

A

X-linked dominant. Affects both males and females, but is more severe in males.

219
Q

Goltz syndrome and incontinentia pigment are examples of what type of genetic inheritance?

A

X-linked lethal= NO AFFECTED MALES (they die).

CSF (3 decks)

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