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My M2M > Unit II Genetic Disorders > Flashcards

Unit II Genetic Disorders Flashcards

1
Q

Duchenne Muscular Dystrohpy: Inheritance

A

X- Linked Recessive

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2
Q

Duchenne Muscular Dystrohpy: Incidence

A

1/3000 males

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3
Q

Duchenne Muscular Dystrophy: clinical presentation

A

onset at 2 yrs, progressively lose motor function, wheelchair by 18 yrs. progressive myopathy, calf hypertrophy, + Gowers Maneuver, abnormal gait, high creatine kinase levels

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4
Q

Duchenne Muscular Dystrohpy: Mechanism

A

Deletion of multiple exons, Xp21.2 - dystrophin gene - loss-of-function

high mutation rate

in-frame deletion leads to Becker dystrophy

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5
Q

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP): Inheritance

A

Autosomal Dominant

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6
Q

HNPP: Clinical Presentation

A

temporary (usually reversible) neuropathy when pressure applied to various nerves (i.e. “arm going to sleep” for days etc) Onset at 20-30 yrs

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7
Q

HNPP: Mechanism

A

deletion of PMP22 gene (PMP22 is integral to glycoprotein in nerurons)

Loss-of-Function mutation

(reciprocal mutation to CMT1A that is a duplication of PMP22)

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8
Q

Osteogenesis Imperfecta Type I: Inheritance

A

Autosomal Dominant

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9
Q

Osteogenesis Imperfecta Type I: Incidence

A

1/30,000-50,000

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10
Q

Osteogenesis Imperfecta Type I: Clinical Presentation

A

Brittle bones and increased fractures, blue sclerae, normal stature, progressive hearing loss in adults

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11
Q

Osteogenesis Imperfecta Type I: mechanism

A

nonsense/frameshift mutation in the COL1A1 gene that leads to premature termination (mRNA is unstable and degraded) - assembly of multimeric protein COL1A1 is disrupted, normal ratio of protein subunits is disrupted and protein not produced in sufficient quantities

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12
Q

Charcot-Marie-Tooth Type 1A: Inheritance

A

Autosomal Dominant

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13
Q

Charcot-Marie-Tooth Type 1A: Clinical Presentation

A

Demyelinating motor and sensory neuropathy; lower extremitiy weakness and muscle atrophy along with mild sensory loss, foot deformity known as hammertoes

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14
Q

Charcot-Marie-Tooth Type 1A: Mechanism

A

Duplication of PMP22 gene (17p11.2)

Gain-of-Function mutation (reciprocal mutation to HNPP that is a deletion of PMP22)

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15
Q

Osteogenesis Imperfecta Type II, III, IV: Inheritance

A

Autosomal Dominant

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16
Q

Osteogenesis Imperfecta Type II, III, IV: Clinical Presentation

A

Brittle bones, increased fractures, blue sclerae (usually a more sever phenotype than Type I)

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17
Q

Osteogenesis Imperfecta Type II, III, IV: Mechanism

A

Novel property mutation of the COL1A2 protein that results in different folding of COL1A2 protein that forms collagen trimer (1/2 collagen being abnormal is worse than 1/2 being produced but is normal)

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18
Q

Huntington Disease: Inheritance

A

Autosomal Dominant

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19
Q

Huntington Disease: Incidence

A

1/10,000

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20
Q

Huntington Disease: Clinical Presentation

A

Progressie neurodegenerative disorder with adult onset - fatal within 15 yrs of onset

Gene anticipation (earlier onset/more severe phenotype in subsequent generations)

parental origin helps determine onset

paternal origin = early onset, maternal origin = later onset

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21
Q

Huntington Disease: Mechanism

A

trinucleotide repeat disorder in an exon of the HTT gene on 4p16.3 leads to increased polyglutamine residues in huntington protein

Novel Property Mutation

Number of repeats - <27 = normal, >40 = 100% penetrant disease, >60 = Juvenile onset

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22
Q

Myotonic Dystrophy I: Inheritance

A

Autosomal Dominant

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23
Q

Myotonic Dystrophy I: Incidence

A

1/20,000

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24
Q

Myotonic Dystrophy I: Clinical Presentation

A

Adult-onset muscular dystophy (progressive muscle wasting and weakness), Droopy eyes, cataracts, intellectual disability, hypotonia, cardiac conduction defects

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25
Q

Myotonic Dystrophy I Mechanism

A

Tri-nucleotide repeat disorder: repeats in the 3’ UTR of the DMPK gene (19q13.3)

maternal expansion (leading to anticipation) more likely

Number of Repeats: 5-34 = normal, 34-49 = premutation range, >50 = 100% penetrance

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26
Q

Phenylketouria (PKU): Inheritance

A

Autosomal Recessive

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27
Q

PKU: Incidence (Northern Europeans) and degree of allelic heterogeneity

A

1/10,000 live births in Northern Europeans

High allelic heterogeneity - compound heterozygotes more likely = range of phenotypes observed

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28
Q

PKU: Clinical Presentation

A

Microcephaly, intellecutal disability if untreated in infancy. Seizures, tremor, gait disorders.

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29
Q

PKU: Screening

A

Use Tandem Mass Spectrometry

Timing is important because PAH normal at birth due to mothers PAH in circulation, must wait a few days after birth, but screen before CNS damage occurs

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30
Q

PKU: Mechanism

A

partial or complete loss-of-function mutations in PAH gene (12q22-24) - many patients compound heterozygotes (two different mutant alleles)

Defect in PAH (phenylalanine hydroxylase enzyme) or BH4 cofactor - leads to high levels of phenylalanine that damges CNS (exact mechanism unclear)

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31
Q

PKU: Treatment

A

low-phenylalanine diet recommended early, and maintained throughout life.

BH4 deficient patients supplemented with oral BH4.

Important for pregnant mothers to maintain diet throughout pregnancy to avoid miscarriage or congenital malformations, intellectual disability, growth impairment (circulating phenylalanine damages fetus regardless of phenotype).

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32
Q

alpha1-Antitrypsin Deficiency (ATD): Inheritance

A

Autosomal Recessive

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33
Q

ATD: Incidence (Northern Europeans)

A

1/2500 - carrier frequency 1/25

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34
Q

ATD: Clincal Presentation

A

late onset. 20X increased risk of emphysema (more severe for smokers - ecogenetics). liver cirrhosis.

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35
Q

ATD: Mechanism

A

SERPINA1 gene on 14q32.13.

Z (15% of SERPINA1 level) and S (50-60% of SERPINA1 level) alleles most common mutations

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36
Q

ATD: Treatment

A

Recombinant AT1 therapy (intravenous infusion, aerosol inhalation) is often used, may not be as effective as once believed

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37
Q

Tay-Sachs Disease: Inheritance

A

Autosomal Recessive

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38
Q

Tay-Sachs Disease: Incidence (whole population and Ashkenzai Jew)

A

1/360,000 general pop 1/3,600 Ashkenazi Jew

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39
Q

Tay-Sachs Disease: Clinical Presentation

A

Progressive neurodegeneration of the CNS. Onset at 3-6 months, muscle weakness, decreased attentiveness. characteristic “cherry-red spot” in eye

Later - seizures, vision/hearing loss, diminished mental function, paralysis. Fatal 3-4 yrs

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40
Q

Tay-Sachs Disease: Mechanism

A

Mutation of the HEXA gene leads to defective hexosaminidase- lysosomal storage disorder (accumulation of Gm2 ganglioside - primarily in the brain)

100 mutations known for HEXA

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41
Q

Tay-Sachs Disease: Screening

A

Enzymatic activity for HEXA/HEXB enzymes. can screen carriers for lower levels of HEXA - or prenatal screening

DNA testing best for mutations known in Ashkenazi Jewish pop

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42
Q

AB - variant Tay-Sachs Disease

A

rare form when HEXA/B enzymes normal, but GM2 accumulates because of defect in GM2 activator protein that facilitates interaction with HEXA

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43
Q

Sandhoff Disease

A

Similar to Tay-Sachs, but there is a defect in both HEXA and HEXB due to defect in beta subunit that is used for both proteins

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44
Q

Cystic Fibrosis: Inheritance

A

Autosomal Recessive

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45
Q

Cystic Fibrosis: Clinical Presentation

A

Salty skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath

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46
Q

Cystic Fibrosis: Mechanism

A

Mutation of CFTR gene; CFTR protein needed to regulate components of sweat, digestive juices, and mucus by regulating movement of chloride and sodium ion across epithelial membranes

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47
Q

Achondroplasia: Inheritance

A

Autosomal Dominant

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48
Q

Achondroplasia: Incidence

A

1/40,000 newborns (80% new mutation rate, 100% penetrant)

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49
Q

Achondroplasia: Clinical Presentation

A

Short Stature, rhizomelic limb shortening (proximal limb shorter than distal), large head with frontal bossing, spinal cord compression, “trident” hand, brainstem compression - 3-7% die suddenly during 1st year of life

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50
Q

Achondroplasia: Mechanism

A

mutation in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene - 98% due to a specific Gain of Function mutation.

Receptor that normally inhibits bone growth turns on, shortening of limbs.

new mutations common, most often in paternal germline (higher risk with increasing age)

displays incomplete dominance - homozygous form is fatal pre-/perinatally

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51
Q

Neurofibromatosis Type I: Inheritance

A

Autosomal Dominant

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52
Q

Neurofibromatosis Type I: Incidence

A

1/3,000 births 50% new mutation rate

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53
Q

Neurofibromatosis Type I: Clinical Presentation

A

Cafe au Lait spots, axillary and inguinal freckling, multiple neurofibromas, Lisch nodules (eye)

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54
Q

Neurofibromatosis Type I: Mechanism

A

Loss of Function mutation in the NF1 gene (17q11.2) - 1000 mutations have been described. 100% penetrance but variable expressivity

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55
Q

Marfan Syndrome: Inheritance

A

Autosomal Dominant

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56
Q

Marfan Syndrome: Incidence

A

1/5,000

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57
Q

Marfan Syndrome: Clinical Presentation

A

Conective tissue disorder; ocular, skeletal and cardiovascular manifestations. risk of aortic aneurysm, apear tall and skinny, hypermobile joints, pectus excavatum/carnatum

Variable Expressivity

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58
Q

Marfan Syndrome: Mechanism

A

Mutation in FBN1 (15q21.1) gene that effects Fibrillin

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59
Q

Tuberous Sclerosis: Inheritance

A

Autosomal Dominant

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60
Q

Tuberous Sclerosis: Incidence

A

1/6,000

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61
Q

Tuberous Sclerosis: Clinical Presentation

A

hypopigmentation, angiofibroma, shagreen patch, renal cysts, Cardiac rhabdomyoma (infants) Variable Expressivity

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62
Q

Tuberous Sclerosis: Mechanism

A

Variable Expressivity Loss of function mutation in the TSC1 or TSC2 gene that encodes hamartin and tuberin proteins that regulate cell growth and proliferation

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63
Q

Fragile X Syndrome: Inheritance

A

X - linked dominant

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64
Q

Fragile X Syndrome: Incidence (males and females)

A

1/2,500-4,000 males 1/7,000-8,000 females

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65
Q

Fragile X Syndrome: Clinical Presentation

A

Childhood onset. Mental deficiency, enlarged testicles (macroorchidism), speech/language delay, autistic behaviors, social anxiety

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66
Q

Fragile X Syndrome: Mechanism

A

Trinucleotide repeat expansion in the 5’UTR of the FMR1 gene - results in hypermethylation and silencing of the gene.

Number of repeats: 6-45 = normal, 55-200 = premutation, >200 = penetrant disease

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67
Q

Fragile X associated tremor/ataxia syndrome (FXTAS)

A

expressed when the 5’ UTR repeat number in the FMR1 gene (Fragile X) is in the premutation range.

Does not result in hypermethylation, but rather a gain of function mutation of the FMR1 gene.

Phenotype - adult onset with Ataxia, tremor, memory loss, peripheral neuropathy

68
Q

Premature Ovarian Failure

A

Occurs in women when the 5’ UTR repeats in the FMR1 gene are in the premutation range. Leads to cessation of menses before the age of 40.

69
Q

Hemophilia A: Inheritance

A

X-linked recessive

70
Q

Hemophilia A: Incidence

A

1/4,000 male births

71
Q

Hemophilia A: Clinical Presentation

A

blood clotting disorder. spontaneous bleeds into joints, muscle, intercranial. excessive bruising, prolonged bleeding after injury, delayed wound healing

72
Q

Hemophilia A: Mechanism

A

Mutation in F8 gene (Xp28) that leads to a deficiency in Factor VIII

73
Q

Hemophilia A: Treatment

A

Some success has been found introducing Factor VIII transgene into muscle tissue to secret transgeneic Factor VIII

74
Q

Turner Syndrome: Inheritance and Incidence

A

Sex Chromosome Disorder (45, XO) effects 1/2,000-5,000 live births. Often the result of Meiotic nondisjunction

75
Q

Turner Syndrome Presentation: Cardiovascular

A

bicuspid aortic valve, coarctation of aorta, systemic hypertension, prolonged QT syndrome, partial anomalous pulmonary venous connection, persistent left SVC

76
Q

Turner Syndrome Presentation: Eye

A

Inner epicanthal folds, ptosis, blue sclera

77
Q

Turner Syndrome Presentation: Skeletal

A

Cubitus valgus, short 4th metacarpal, short stature

78
Q

Turner Syndrome Presentation: Neck

A

Web Neck, low hairline, Cystic Hygroma (fetal)

79
Q

Turner Syndrome Presentation: Learning abnormalities

A

difficulty in math, visual spatial skills, and non-verbal scores

80
Q

Turner Syndrome Presentation: Chest, head/face

A

prominent auricles, low-set ears, high narrow palate, small mandible, shield chest, broad nipples, pectus excavatum, sensironeural hearing loss

81
Q

Turner Syndrome Presentation: Endocrine

A

Hypothyroidism, Gonadal dysgenesis

82
Q

Turner Syndrome: Challenges across the lifespan

A

Infertility, stature, sexual Development, and concerns regarding health and aging.

83
Q

Turner Syndrome: Pitfalls in medical culture

A

Secret keeping, difficulty in communicating infertility diagnosis, perceived negative experiences with physicians. Practice culturally effective medicine!!

84
Q

Kleinfelter Syndrome: Inheritance and Incidence

A

Sex Chromosome Disorder - occurs in 1/500-1,000 newborn boys (47, XXY)

85
Q

Kleinfelter Syndrome: Clinical Presentation

A

Learning disabilities, delayed speech and language, tall stature, small testis, reduced facial/body hair, infertility, hypospadias, gynecomastia

86
Q

Kleinfelter Syndrome: Mechanism

A

Meiotic nondisjunction - half of cases are due to pseudoautosomal recombination (15% of these mosaic)

87
Q

Jacobs (XYY) syndrome

A

Sex Chromosome disorder - 1/1,000 newborn boys learning disabilities, speech delays, developmental delays, behavioral/emotional difficulties, autism spectrum, tall. Not associated with criminal behavior!

88
Q

Androgen Insensitivity Syndrome (AIS)

A

X-linked recessive varies from mild under-virilization to full sex reversal mutation causes abnormality of androgen receptor, tissue cannot respond to androgen

89
Q

Congenital Adrenal Hyperplasia

A

Autosomal Recessive, 1/25,000 births Ambiguous genetalia due to deficieny of 21-hydroxylase

90
Q

5 - Alpha Reductase Deficiency

A

Autosomal Recessive disorder causing a failure to convert testosterone to dihydrotestosterone that leads to incomplete phallic development and under virilization that may be reversed naturally at the onset of puberty

(“Middlesex” example)

91
Q

Nonsyndromic Deafness: Inheritance (progressive childhood and congenital varieties)

A

Progressive childhood type - Autosomal dominant

Congenital type - Autosomal recessive

Genetic causes account for 1/4 of congenital deafness, 3/4 of genetic causes are nonsyndromic

92
Q

Nonsyndromic Deafness: Clincial Presentation

A

Deafness (duh)

93
Q

Nonsyndromic Deafness: Mechanism

A

50% of nonsyndromic cases are due to a mutation in the GJB2 - typically a loss of function mutation

94
Q

Syndromic deafness: Clinical Presentation and different types

A

Deafness along with generally intellectual disability, seizures, dysmorphic syndromes

Reinitis pigmentosa - Usher Syndrome (AR)

thyroid goiter - Pendred (AR)

arrythmia or sudden death - Jervell and Lange-Nielson syndrome (AR)

white forelock - Waardenburg syndrome (AD)

8th nerve schwannomas - Neurofibromatosis type II

95
Q

Fabry Disease: Inheritance

A

X-linked recessive

96
Q

Fabry Disease: Clinical Presentation

A

Microvascular disease, neuropathy, cardiomyopathy, reduced sweating, progressive renal failure

97
Q

Fabry Disease: Mechanism

A

deficiency of alpha-galactosidase leads to accumulation of glycosphingolipids that causes widespread damage

98
Q

Fabry Disease: Treatment

A

Chaperone-based therapy may help to fold the protein correctly and increase enzymatic activity. Recombinant enzyme therapy has also been used to mitigate progression of the disease

99
Q

Downs Syndrome: Inheritance

A

Chromosomal Abnormality due to Trisomy 21 - most often associated with advnaced maternal age

100
Q

Down Syndrome: Screening

A

1st trimester screening - ultrasound measurement of nuchal folds + beta-hCG + PAPP-A

2nd trimester - beta-hCG, AFP, unconjugated estriol, and inhibin Detection rate of 95% for 1st and 2nd trimester

101
Q

Down Syndrome: Clinical Presentation

A

normal growth parameters, midfacial hypoplasia, upslanting palpebral fissures, epicanthal folds, small ears, large-appearing tongue, low muscle tone (hypotonia), increased joint mobility, short fingers, transverse palmar crease, Vth finger incurving, increased space between toes 1 and 2

102
Q

Down Syndrome Common Medical Issues: GI

A

10-15% have structural abnormalities esophageal atresia, duodenal atresia, Hirschsprung’s

Feeding problems, constipation, GERD, Celiac Disease

103
Q

Down Syndrome Common Medical Issues: Cardiac

A

50% of patients all types of anomalies, atrioventricular canal is common

104
Q

Down Syndrome Common Medical Issues: Ophthalmologic

A

blocked tear ducts, myopia, lazy eye, Nystagmus, Cataracts

105
Q

Down Syndrome Common Medical Issues: ENT

A

chronic ear infections, deafness, chronic nasal congestion, enlarged tonsils and adenoids (obstructive apnea)

106
Q

Down Syndrome Common Medical Issues: Orthopedic

A

hips, joint sublexation - especially of the atlantoaxial subluxation

107
Q

Down Syndrome Common Medical Issues: Endocrine

A

Thyroid disease, Insulin Dependent Diabetes, Alopecia areata, reduced fertility

108
Q

Down Syndrome Common Medical Issues: Hematologic issues

A

increased risk of leukemia, iron deficiency anemia

109
Q

Down Syndrome Common Medical Issues: Developmental

A

hypotonia effects gross motor development.

spectrum of intellectual disability, average is mild-moderate disability

speech delay (sign language taught early on)

110
Q

Down Syndrome Common Medical Issues: Psychiatric

A

depression, early Alzheimer’s, Autism (10% of patients)

111
Q

Down Syndrome Common Medical Issues: Neurologic

A

Hypotonia, seizures

112
Q

Down Syndrome: Mechanism

A

95% of cases are due to nondisjunction error associated with advanced maternal age 3-4% of patients due to unbalnced translocation of chromosome 21 and another acrocentric chromosomes (13, 14, 15, 22) 1-2 % of patients are mosaic Down Syndrome - loss of 3rd chromosome early in fetal development leads to different karyotype in different cells - milder phenotype

113
Q

Trisomy 13 (Patau’s): Inheritance

A

Chromosomal abnormality

114
Q

Trisomy 13 (Patau’s): Clinical Presentation

A

facial dysmorphism, severe intellectual disability, holoprosencephaly, facial celfts, polydactyly, renal anomalies Often fatal by 1st year of life

115
Q

Trisomy 13 (Patau’s): Mechanism

A

Due to nondisjunction error. 20% of cases due to a Robertsonian translocation (chromosome 14 has and extra 13 tacked onto the end of it)

116
Q

Trisomy 18 (Edward’s): Inheritance

A

Chromosomal Abnormality

117
Q

Trisomy 18 (Edward’s): Clinical Presentation

A

Intrauterine growth retardation, characteristic face, severe intellectual disability, clenched fingers, rocker-bottom feet Congential malformations: heart, NS, renal) Often fatal by 1st year of life

118
Q

Trisomy 18 (Edward’s): Mechanism

A

Often due to translocation der(14, 18)

119
Q

Cri-du-Chat

A

microdeletion of 5p15.2 (microcephaly, characteristic cry, seizures, disability)

120
Q

Prader-Willi Syndrome: Inheritance

A

Autosomal contiguous gene syndrome

121
Q

Prader-Willi Syndrome: Clinical Presentation

A

Hypotonia, hypopigmentation, hypogenitalism, obesity, excessive eating, short stature, small hands and feet, hypogonadism, intellectual disability

122
Q

Prader-Willi Syndrome: Mechanism

A

70% due to deletion of 15q11-13 region on paternal gene (imprinting does not allow for expression of this gene on the maternal chromosome) 28% due to Uniparental Disomy (maternal) 2% due to imprinting center mutation (paternal copy imprinting same as maternal copy)

123
Q

Angelman Syndrome: Inheritance

A

Autosomal contiguous gene syndrome

124
Q

Angelman Syndrome: Clinical Presentation

A

mildly dysmorphic facial features, hypotonia in infancy, intellectual disability, seizures, autism

125
Q

Angelman Syndrome: Mechanism

A

complement to Prader-Willi - deletion of 15q region on maternal chromosome of UBE3A which is turned off by imprinting on the paternal copy of chromosome 15 Can also be caused by (paternal) uniparental disomy or imprinting center mutations

126
Q

IDIC 15

A

Inverted duplicated isodicentric 15q Due to a supernumerary marker chromosome 15 Phenotype - Autism, not dysmorphic, often hypotonic, seizures

127
Q

15q interstitial duplication

A

Only results in a phenotype if the duplication is inherited from the mother, not the father Phenotype - autism, not dysmorphic, seizures common, hypotonia common (similar to IDIC 15) related to GABA protein

128
Q

WAGR Syndrome

A

Autosomal contiguous gene syndrome Phenotype - WIlms Tumor, Aniridia, Genitourinary anomalies, (retardation) intellectual disability interstitial del 11p13 - large enough to see on karyotype

129
Q

DiGeorge Syndrome

A

Autosomal contiguous gene syndrome Phenotype - absent or hypoplastic thymus and parathyroid, congenital heart disease deletion of 22q11.2

130
Q

Acute Lymphoblastic Leukemia (ALL)

A

chromosome or FISH analysis of bone marrow can reveal prognosis

hyperdiploidy (55 chromosomes) is a favorable prognosis, hypodiploidy (<38 chromosomes) is unfavorable

131
Q

Chronic Myelogenous Leukemia (CML)

A

Presentation: night seats, fatigue, weight loss, anemia (enlarged spleen, anemia, thrombocytopenia)

Due to a translocation t(9;22) of BCR/ABL genes that cause a fusion protein product - evaluated via FISH

Treatment with Gleevac (Imantinib) that inhibits tyrosine kinase activity of fusion protein (competitive inhibitor of ATP)

132
Q

Acute Promyeloid Leukemia (PML)

A

due to a translocation of PML/RARA genes t(15;17) that causes fusion protein product that represses gene expression, Can be diagnosed via FISH probe, or visualizaton of AUER rods Treated with retinoic acid (change confirmation of protein so that it recruites coactivator machinery - transcribes gene)

133
Q

Gaucher Disease: Inheritance and Incidence

A

Autosomal Recessive 1/50,000 in general pop 1/450 in Ashkenazi Jew

134
Q

Gaucher Disease: Clinical Presentation

A

Hepatosplenomegaly, thrombocytopenia, anemia, joint pain, may have neurological involvement, osteopenia, fatigue

Type I - most common, least severe phenotype (no neurologic symptoms

Type II - rare, severe and fatal in infants

Type III - intermediate, presents after infancy, nerological component present

135
Q

Gaucher Disease: Mechanism

A

Many mutations identified for the GBA gene (allelic heterogenetiy) deficiency in the glucocerbrosidase enzyme that breaks down glucocerebroside (membrane protein). Ends up accumulating in the macrophage lysosomes in liver and spleen leading to enlargement (Gaucher cells)

136
Q

Gaucher Disease: Treatment

A

Enzyme Replacement Therapy has been found to alleviate symptoms, but is costly (infusions 2X per month for life). Can be supplemented with substrate reduction therapy (SRT).

137
Q

Pompe Disease

A

Shit is expensive yo

138
Q

Pompe Disease

A

Autosomal Recessive progressive muscle failure, respiratory distress caused by accumulation of glycogen in lysosome due to deficiency in alpha-glucodidase enzyme

ERT treatment IV every 2 weeks for life

139
Q

Progeria

A

de novo dominant trait premature aging syndrome caused by a point mutation in the LMNA/C gene yielding abnormal progerin protein Treatment with farnesyl transferse inhibitors to help reduce progerin sequestration at the nuclear membrane

140
Q

Hb Kempsey

A

qualitative hemoglobinopathy altered Hb that results from a gain of function missense mutation. Causes hemoglobin to bind O2 at a higher rate - results in increased erthropoeitin production and polycythemia.

141
Q

Hb Kansas

A

Qualitative hemoglobinopathy altered Hb binding that leads to decreased function of hemoglobin (binds oxygen worse)

142
Q

Sickle Cell Anemia: Classification and inheritance

A

Qualitative hemoglobinopathy Autosomal recessive (more frequent in African populations due to association with heterozygote malaria resistance)

143
Q

Sickle Cell Anemia: Mechanism and Treatment

A

Due to a single base mutation in beta-globin gene (allelic homozygosity) Hbs is 80% less soluble when in relaxed state, polymerizes and forms sickle shaped cells - lodge into micro-capillaries to cause issue treatment with butyrate which increasing expression of fetal hemoglobin, can reduce polymerization of HbS

144
Q

Hemoglobin C: Classification and inheritance

A

Qualitative hemoglobinopathy Autosomal recessive

145
Q

Hemoglobin C: Presentation and Mechanism

A

milder form of hemolytic anemia - HbC is less soluble then HbA and tends to form crystals caused by single base mutation of beta globin gene

146
Q

Hemoglobin SC

A

Presence of multiple common mutant alleles on the same gene can lead to a compound heterozygote that has a more severe phenotype than a normal heterozygote. Example is HbC and HbS mutations in same individual

147
Q

Hemoglobin E

A

Qualitative Hemoglobinopathy Most common in Southeast Asia, results from single mutation in beta chain. mild hemolytic anemia and splenomegaly.

148
Q

Hydrops Fetalis: Genotype

A

Homozygous for α-thal-1 allele mutation (–/–)

149
Q

Hydrops Fetalis: Mechanism / Presentation

A

4 gene deletion - most severe form, results in still born no alpha subunit is produced, fetal hemoglobin Hb Barts is not sufficient for life after development

150
Q

Hemoglobin H disease: Genotype

A

compound heterozygote ( α-/–)

151
Q

Hemoglobin H disease: Mechanism / Presentation

A

moderate to severe anemia - only produce enough α subunit to make 25% of normal hemoglobin, 5-30% of hemoglobin is β4 (HbH) which precipitates . Sometimes transfusion dependent

152
Q

α-thalassemia 1 trait: Genotype

A

heterozygote for α-thal-1 allele (αα/–)

153
Q

α-thalassemia 2 trait: Genotype

A

homozygous for α-thal-2 allele (α-/α-)

154
Q

α-thalassemia trait: Mechanism / Presentation

A

none to mild anemia

155
Q

Distribution of α-thalassemia alleles

A

α-thal-1 (–) allele is more common in Southeast Asia, whereas α-thal-2 (α-) is more common in Africa, Mediterranean, Asia. α-thal-1 can lead to more potent forms of the disease (HbH, Hydrops Fetalis)

156
Q

β-thalassemia: Inheritance

A

Autosomal recessive Many different possible mutations of the β-globin gene - high allelic heterogeneity means many patients with disease are compound heterozygotes

157
Q

β-thalassemia molecular classifications: Simple β-thalassemia

A

caused by mutations or deletions that impair the production of β-globin chain alone, no other gene involvement.

158
Q

β-thalassemia molecular classifications: Complex β-thalassemia

A

caused by large deletions that remove the β-globin gene plus other genes in the β-cluster on the locus control region. Ex - Hispanic (episilon gamma delta beta) thalassemia

159
Q

clinical classifications: β-thalassemia major (Cooley’s anemia)

A

2 severly abnormal or absent genes leads to severe anemia, most RBCs are destroyed before being released into circulation. Thinning of bone cortex, enlarged liver/spleen. MCV low. Need to treat with blood transfusions and iron chelation therapy to avoid iron overload

160
Q

clinical classifications: β-thalssemia intermediate

A

homozygous for 2 mildly mutated genes - mild to moderate anemia, low MCV. Sometimes need transfusion

161
Q

clinical classifications: β-thalssemia minor

A

heterozygous for β-globin gene mutation - little to no clinical presentation

162
Q

β+ thalassemia

A

most common form (90%) - some β-globin is made, so some HbA present.

163
Q

β0 thalassemia

A

zero β-globin synthesis so no HbA present - deletion of β-globin gene, or nonsense/frameshift mutation. fatal.

164
Q

δβ0 thalassemia

A

milder than β0 thalassemia. remaining γ gene is active and can therefore form HbF (α2,γ2)

165
Q

Hereditary Persistence of Fetal Hemoglobin

A

symptom free - adequate levels of γ mean that despite lack of β-globin deficieincy HbF is the main hemoglobin, present at 17-35% the normal level of hemoglobin.

166
Q

Rec(8)

A

pericentric inversion of chromosome 8 carriers are at risk for recombination errors that lead to a trisomy of 8q22.1 and monosomy for 8p23.1 presents as VSD, Hypertelorism, thin upper lip, wide face concentrated in Hispanic populati in SW USA

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