Diseases Second Test abridged

Question 1

Duchenne Muscular Dystrophy

Answer 1

Onset around 2 yrs, lose motor function, in wheelchair by 18 yrs, median age at death is 18 yrs.
Progressive myopathy, characterized by large calves (adipose tissue overcomes muscle tissue); Gowers Maneuver; median age of death 18 yrs;
abnormal gait; progressive myopathy; high creatine kinase levels (shows evidence of muscle damage)

Loss of Function: Large deletions in many exons in Xp21.2 (dystrophin gene); nonsense frameshift
High new mutation rate (alleles have 0 fitness because sons not living to reproduce)
Sometimes carrier females will demonstrate milder symptoms later in life (8%);
In-frame deletion or missense leads to milder Becker dystrophy

No treatment, just supportive care

Question 2

HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)

Answer 2

Autosomal dominant
Temporary (usually reversible) neuropathy when pressure is applied to various nerves; limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
First attack in 20-30 yrs old (usually recovery is complete, there is mild disability if not)

Loss of Function:
Deletion of PMP22 gene due to unequal crossing over (PMP22 is integral glycoprotein in nerves)

Question 3

Osteogenesis Imperfecta Type 1

Answer 3

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

Loss of Function: nonsense frameshift in COL1A1
Causes unstable mRNA that’s degraded, reducing COL1A1, which is important for collagen strength

Question 4

Charcot- Marie-Tooth Type 1A

Answer 4

Autosomal Dominant

Demyelinating motor and sensory neuropathy; lower extremity weakness and muscle atrophy and mild sensory loss; foot deformity known as hammertoes
Note: all versions of CMT affect peripheral nervous system, type 1A is dominant

Gain of Function: duplication of of PMP22 gene, 17p11.2
(PMP22 is integral glycoprotein in nerves)

Question 5

Osteogenesis Imperfect Types II, II, IV

Answer 5

Autosomal Dominant
Brittle bones, increased fractures, blue sclerae (Type II much more severe, usually lethal in perinatal period)

Novel Property Mutation: the COL1A2 protein has new property due to new/different folding, forming collagen trimers (much worse than Type I)
Classified as problem of assembly of monomers into homodimer

Question 6

Huntington’s Disease

Answer 6

Autosomal Dominant
(also can be auto recessive or X- linked as well)

Repeat CAG is in the Exon

Progressive neurodegenerative disorder with adult onset; chorea (child-like dance movement); death within 15 yrs of onset;
Gene anticipation (earlier onset in offspring and subsequent generations) most commonly occurs with paternal repeats

Polyglutamate disease; increased CAG repeats (>40 penetrant,

Question 7

Myotonic Dystrophy 1

Answer 7

Autosomal Dominant
Repeat in the 3’ End UTR

It is characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia.Droopy eyes, intellectual difficulty, hypotonia
Increased CTG repeats (in 3’ UTR) of DMPK gene

Question 8

PKU (Phenylketouria)

Answer 8

Autosomal Recessive

Epilepsy, mental retardation, hyperactivity
Newborn screen used to be Guthrie test (high phenylalanine overrides bacterial inhibitio, leading to bacterial growth), now by Tandem Mass Spectrometry
Screening timing is important because PAH is normal at birth because mom’s PAH is still in fetus, so test a few days later but still early enough to avoid CNS damage

Defect in PAH-phenylalanine hydroxylase enzyme (common) or BH4 cofactor (rare, also have high neurotransmitter imbalance because BH4 involved is involved in neurotransmitter synthesis)
High phenylalanine in blood, toxic to CNS

Side note: pregnant mothers advised to keep a low phenylalanine diet, irrespective of child genotype, because reduces risk of miscarriage and congenital malformations)

For PAH defects: keep low phenylalanine diet
For BH4 defects: low phenylalanine diet + drugs to supplement low neurotransmitter production

Question 9

ATD (alpha1- Antitrypsin Deficiency

Answer 9

Autosomal Recessive
More common in N. Europeans, 1/2500 affected, 1/25 carriers

Defective alpha1-AT protein (normally protease inhibitor of elastase; elastase recruited by neutrophil= increased elastase activity= increased emphysema and lung damage due to lack of alpha1-AT)
Smoking worsens it due to summoning more nuetrophils that will release elastase

Z allele (Glu342Lys) expresses misfolded protein that aggregates in the endoplasmic reticulum of liver cells, causing damage to the liver in addition to the lung. Is more common
S allele (Glu264Val) expresses an unstable protein that is less effective.
(M allele is wild-type)

Question 10

Tay-Sachs Disease

Answer 10

Autosomal Recessive
1/360,000 general
1/3,600 Ashkenazi Jew (100x more likely)

Progressive neurodegeneration of CNS. Onset at 3-6 months, with muscle weakness, decreased attentiveness, and increased startle response appear.
Later on: seizures, vision and hearing loss, diminishing mental function, and paralysis. An eye abnormality called “cherry-red spot” is a characteristic of T-S. Children of T-S usually live only till 3-4 years of age
Screen enzyme activity (at low temp, both enzymes active, at high temp HexA degrades and B still functions) test and DNA test (three mutant alleles account for 95% of cases)
Can screen carriers (have less HexA in blood)

Lysosomal storage disease; from defect in alpha subunit of HEXA (has alpha and beta subunits), which degrades GM2 ganglioside
Inability to degrade GM2 ganglioside, which aggregates in lysosomes in CNS neurons;

Over 100 HEXA mutations are known; most common mutant allele (~80%) in the Ashkenazi Jewish population is a 4 bp insertion in exon 11 of HEXA, causing a frameshift and a premature stop codon (null allele)
No treatment, supportive care

Question 11

Sandhoff Disease

Answer 11

Autosomal Recessive
Symptoms similar to Tay-Sachs
Screening enzyme activity shows that both HexA and HexB are inactive (just Hex A in Tay-Sachs)
Defects in both HexA (αβ) and HexB (homodimer of ββ) caused by a defective β subunit
No treatment, supportive care

Question 12

AB-Variant of Tay-Sachs

Answer 12

Autosomal Recessive
Resemble Tay-Sachs disease

Rare form where HexA and HexB are normal but GM2 accumulates due to defect in the GM2 activator protein (GM2AP), which facilitates interaction between the lipid substrate and the HexA enzyme

Question 13

Cystic Fibrosis

Answer 13

Autosomal Recessive

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
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

Question 14

Hereditary Hemochromatosis

Answer 14

Hepatic cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation.

Mutation in HFE gene on Chr. 6, important in iron regulation; defect causes iron overload

Question 15

Achondroplasia

Answer 15

Autosomal Dominant
1/40,000
Incomplete Dominance

Short stature, rhizomelic limb shortening (proximal limb shorter than distal limbs), large head with frontal bossing (prominent forehead); megalencephaly; “trident” hand; spinal cord compression (small cranial foramina); between 3-7% die suddenly in during first year

Gain of Function:Gly380Arg mutation in FGFR3 Gene (hot spot for mutation, fibroblast gene)
Receptor normally inhibits bone growth; defective receptor always on, causing shortening of limbs
De novo mutations occur almost exclusively in father’s germline and increase with paternal age
Homozygous state is lethal! Only see phenotype in heterozygotes (this is incomplete dominance)

Question 16

Neurofibrom atosis Type 1

Answer 16

Autosomal Dominant

Cafe au Lait spots, axillary and inguinal freckling; multiple neurofibromas; Lisch nodules (spots/bumbs on eye)
100% penetrance, variable expressivity
Mutation on chr. 17 on NF1 gene (codes for neurofibroma protein)

Question 17

Marfan Syndrome

Answer 17

Autosomal Dominant (1/5000)

Connective tissue disorder; ocular, skeletal and cardiovascular manifestations; risk of aortic aneurysm; appear tall and skinny (long- limbed); hypermobile joint, pectus excatum/carnatum
Mutation in FBN1 mutations (codes for fibrillin) on chromsome 15

Question 18

AD Polycystic Kidney Disease

Answer 18

Autosomal Dominant (1/1000)
Enlarged kidneys with multiple cysts, end stage renal disease, extra-renal cysts (i.e. in pancreas), intracranial aneurysms
Mutation in ADPKD-1 (85%; chr. 16) or ADPKD-1 (14.5%; chr. 4); Locus heterogeneity (mutation in more than one locus can the same clinical condition

Question 19

Fragile X syndrome

Answer 19

X-linked Dominant

Repeat at 5’ UTR

Onset at childhood, mental deficiency, dysmorphic facies, male postpubertal macroorchidism (enlarged testicles); speech/language delay, autism-like syndromes, large ears/prominent jaws
Fragile X-associated tremor/ataxia syndrome (FXTAS): from premutation, Parkinsonian- like features, adult onset, ataxia, tremor, memory loss, peripheral neuropathy
Premature Ovarian failure in women (20% of women with permutation)

Trinucleotide CGG expansion (>200 penetrant, 6-45 normal, grey zone/premutation in between) in 5’ UTR causing hypermethylation, and thus silencing of gene at fragile site of X chromosome
Maternal gene anticipation

Premutation is 59

Question 20

Hemophilia A

Answer 20

X-linked Recessive
Bleed complications (decreased clotting)
Factor VIII deficiency
(Note: Hemophilia B is Factor IX)
Can supplement with Factor VIII

Question 21

Turner Syndrome

Answer 21

Sex Chromosome Disorder (45X)
Affects 1/2000- 5000 liveborns
Gonadal dysgenesis, short stature, heart defects, fused kidneys, webbed neck, brown nevi, widely spaced nipple, infertility, social difficulty etc.
Meiotic nondisjunction

Question 22

Klinefelter Syndrome

Answer 22

Sex Chromosome Disorder (47XXY)
Affect 1/1000

Gonadal dysgenesis/hypogonadism, infertility, tall stature, gynecomastea, high frequency of sterility, language impairment
Meiotic Nondisjunction
Half of cases due to failure of pseudoautosomal recombination (15% are result of mosaicism)

Question 23

XYY Syndrome “Jacob’s Syndrome”

Answer 23

Sex Chromosome Disorder (47XYY)
Affects 1/900-1000
Indistinguishable physically or mentally from normal males and are usually fertile (a little taller); increased risk of behavioral and educational problems, delayed speech and language skills
NOT associated with criminal behavior
Meiotic Nondisjunction
Results from errors in paternal meiosis II, producing YY sperm.

Question 24

Androgen Insensitivity Syndrome

Answer 24

X-linked recessive
Feminine features (due to end-organ unresponsiveness to testosterone)
Absence or abnormality of cytosolic androgen receptor protein; similar to androgen insensitivity syndrome, mutations androgen receptor gene.

Question 25

Congenital adrenal hyperplasia

Answer 25

Autosomal recessive
1/25,000 births

Ambiguous genitalia, masculization of females
ACTH secretion increased (b/c lack of negative feedback via cortisol to pituitary), such that adrenals are hyperplastic, overproducing androgens

Question 26

5α reductase deficiency

Answer 26

Autosomal recessive
Incomplete phallic development, severe hypospadias (pseudovaginal perineal hypospadius); ambigous external genitalia in 46 XY males

Failure of end organs to activate testosterone to dihydrotestosterone (DHT) in 46, XY individuals; 5- alpha reductase needed to covert tetosterone to active DHT

Question 27

Smith-Lemli- Opitz Syndrom

Answer 27

Autosomal Recessive
Feminization of males
Cholesterol synthesis disorder, decreasing testosterone production

Question 28

Nonsyndromic

Deafness

Answer 28

Autosomal Dominant (progressive childhood deafness) Autosomal Recessive 
1/500-1000 are deaf (further broken down into syndromic, nonsyndromic, etc)
1⁄2 of children with clinical presentation are genetic/congenial (recessive); of those, 3⁄4 are non syndromic (occur in isolation)

Congenital Deafness in recessive form
Progressive Childhood Deafness in dominant form

Allelic heterogeneity
GJB2 most commonly mutated (DFBN1 protein); responsible for 50% of nonsyndromic deafness

Do newborn screening
Hearing aids, cochlear implants, speech and sign language therapy

Question 29

Syndromic Deafness

Answer 29

Deafness with associated syndroms
General: Intellectual!disability, seizures, dysmorphic syndromes Specific
• With!retinitis pigmentosa suggests!Usher (AR)syndrome
• With!thyroid!goiter!suggests Pendred (AR)!syndrome
• With!arrhythmia!or!sudden!death suggests!Jervell and!Lange”Nielson!(AR)!syndrome
• With!white!forelock!suggests!Waardenburg (#1 AD)syndrome
• With!8th nerve!schwannomas suggests Neurofibromatosis!type!II

Question 30

Fabry Disease

Answer 30

X-linked Recessive

Neurologic pain crises in childhood; reduced sweating, risk of heat stroke; progressive renal failure (cause of death prior to renal transplanation); risk of heart attacks and stroke; hypertrophy of cardiac tissue also seen
Due to deficiency of alpha-galactosidase (protein misfolding); Accumulation of glycosphingolipids causes widespread microvascular damage
One particular mutation (25% of disease)
Chaperone-based therapy, helps alpha-galactosidase A fold correctly
Approved in the United States#annual cost $150- 200,000 / patient (lifelong)
Recombinant enzyme replacement therapy appears to mitigate parts of disease

Question 31

Down’ s Syndrome

Answer 31

Chromosomal Abnormality
(Trisomy 21) Affects 1/900

Mid-face hypoplasia, short stature, hypotonia, moderate intellectual disability
Congenital malformations (endocardial cushion defects, duodenal atresia, GI anomalies, Hirschprung disease)

95% of Trisomy 21 cases are result of non- disjunction in maternal meiosis I
3-4% Robertsonian Translocation (usually extra 21 is fused with chromosome 14, resulting in 45 chromosomes)
1-2% of Mosaic Down’s Syndrome (47,XX+21/46XX)

Question 32

Trisomy 13 (Patau’s Syndrome)

Answer 32

Chromosomal Abnormality
(Trisomy 13)
Characteristic facies, severe intellectual disabilities
Congenital malformations (fusion of brain lobes, facial clefts, polydactyly, renal defects)
Trisomy 13

Question 33

Trisomy 18 (Edward’ s Syndrome)

Answer 33

Chromosomal Abnormality
(Trisomy 18)

Intrauterine growth retardation, characteristic facies, severe intellectual disabilities, characteristic hand positioning, hypertonicity, rocker feet
Congenital malformations (valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal defects, seizures)

Trisomy 18
Usually due to translocation der(14, 18)

Question 34

Cri-du-Chat

Answer 34

Autosomal contiguous gene syndrome
Microcephaly
Characteristic cry
Seizures, intellectual disability
Del(5p15.2)

Question 35

Prader-Willi Syndrome

Answer 35

Autosomal contiguous gene syndrome
Hypotonia, hypopigmentation, hypogenitalism, obesity, excessive eating, short stature, small hands and feet, hypogonadism, intellectual disabilities
Paternal Del(15q11-q13) accounts for 70% of cases
Uniparental disomy and imprinting error account for remaining cases

Question 36

Angelman Syndrome

Answer 36

Autosomal contiguous gene syndrome
Seizures, intellectual disability, unusual facial appearance, short stature, severe intellectual disabilities, prominent chin
Maternal Del(15q11-q13)
Increased incidence in infertile couples using advanced reproductive therapy to conceive (may be related to imprinting erasure and resetting malfunctions)

Question 37

WAGR Syndrome

Answer 37

Autosomal contiguous gene syndrome
Wilms tumor
Aniridia
Genitourinary anomalies Intellectual disability
Del(11p13)
Interstitial deletion of 11p13 (large enough to see at chromosome level)

Question 38

DiGeorge Syndrome

Answer 38

Autosomal continous gene

Absent or hypoplastic thymus and contiguous gene parathyroid’s, congenital heart disease
syndrome
Del(22q11.2)

Question 39

Acute Lymphomatic Leukemia

ALL

Answer 39

Hypo-diploidy

less than 46 chromosomes

Question 40

Chronic Myelogenous Leukemia (CML)

Answer 40

Translocation (in bone marrow)
Enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising

Bcr-Abl translocation (9;22) is diagnostic
Can be detected by FISH fusion probe
Treat with Gleevec (tyrosine kinase inhibitor)

Question 41

Acute Promyeloid Leukemia (APL/PML)

Answer 41

Translocation (in bone marrow)

Enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising

PML-RARA translocation (15;17) is diagnostic
Viewing Auer rods (cytosolic precipitation) is diagnostic
Can be detected by FISH fusion probe
Treat with retinoic acid

Question 42

Gaucher Disease

Answer 42

Autosomal recessive
1/50,000 general
1/450 Ashkenazi Jews
Hepatosplenomegaly, thrombocytopenia, anemia, join pain, CNS issues
Three types (Type 1 most common, does not have CNS issues, affects 6-80 yrs, GCase activity

Question 43

Pompe Disease

Answer 43

Autosomal Recessive

Progressive muscle failure, cardiomegaly, hypotonia, cardiomyopathy, respiratory distress, muscle weakness, feeding difficulties, and failure to thrive (used to die by 1 yr)
Accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme

Drug given every 2 weeks by IV → hundreds of thousands of dollars per year for just drug (not including home care, doctor’s visits, etc)

Question 44

Progeria

Answer 44

De novo dominant trait
Premature aging syndrome

Point mutation in LMNA/C gene yielding abnormal progerin protein
Progerin targeted to nuclear membrane by Farnesyl group→ pathological effects at membrane
o Farnesyl transferase inhibitors appear to reduce progerin sequestration at the nuclear membrane

Question 45

Hb Kempsey

Answer 45

Altered Hb binding affinity
Increased erythropoietin production and a resultant polycythemia

Gain of Function: Asp99Asn missense mutation Binds oxygen too tightly

Question 46

Hb Kansas

Answer 46

Altered Hb binding affinity
Anemia

Weak binding of oxygen

Question 47

Sickle Cell (HbS)

Answer 47

Autosomal Recessive
Common in African population (carrier frequency ~10%)

Novel Property Mutation: Single base mutation at codon#6 in the β-globin gene changes glutamate to valine. HbS is 80% less soluble than HbA when not bound to O2, and polymerizes into long fibers that distort the RBC into a characteristic sickle shape. These sickled cells become lodged in the micro-capillaries and further exacerbate the sickling crisis.

Question 48

Hemoglobin C (HbCC)

Answer 48

Autosomal Recessive
Milder form of hemolytic anemia than sickle cell anemia
Can also have HbCA (heterozygote) trait or Cβ- thalassemia (HbC syndromes)

Single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine. HbC is less soluble than HbA and tends to form crystals, reducing the deformability of RBC

Question 49

HbS or HbC Trait

Answer 49

Carrier of HbS or HbC (heterozygote)
They are clinically normal except when under severe low pO2 stress.

Heterozygous:
HbS Trait: HbS/HbA HbC
Trait: HbC/HbA

Question 50

Hemoglobin SC Disease (HbSC)

Answer 50

Compound heterozygote
Milder anemia compared to sickle cell

Compound heterozygote HbS/HbC

Question 51

β -Thalassemias

Answer 51

Wide range of severity; caused by virtually every possible type of mutation in the β-globin gene
High allelic heterogeneity means most patients with β-thalassemia are compound heterozygotes
Simple: Mutations of β-globin gene ONLY
Complex: large deletions that remove the β-globin gene plus other genes in the β-cluster, or the LCR. Note that some deletions within β-cluster cause HPFH

Question 52

β-thalassemia major (Cooley’ s anemia

Answer 52

Autosomal recessive
Severe anemia; RBCs are destroyed before released into blood.
Thin bone cortex (osteopenia), hepatosplenomegaly from massive effort to produce blood.
MCV (circumference of RBC) is low

2 severely abnormal or absent genes

Always treat temporarily with blood transfusions; iron accumulation from repeated transfusion leads to organ failure so iron chelation therapy (e.g. desferrioxamine)
Also can do bone marrow transplant, splenectomy, or cholecystectomy

Question 53

β-thalassemia intermediate

Answer 53

Auto Recessive
Mild to moderate anemia Low MCV
Homozygous: 2 mildly mutated genes

Sometimes need’s transfusions

Question 54

β+-thalassemia

Answer 54

Autosomal Recessive
Most common form of β-thalassemia (90% of the cases)
Caused by mutations affecting transcription, RNA processing, or protein stability
Some β-globin is made so some HbA present

Question 55

β0-thalassemia

Answer 55

Autosomal Recessive
Zero β-globin synthesis so that no HbA is present. [Hb] is ~5% of normal level (of which 95% is α2γ2 with 5% α2δ2), which is not enough for good survival.

Caused by deletion of the β-globin gene, nonsense or frameshift mutations at the 5’ of the coding region that lead to an early stop codon, or mutations that result in no RNA synthesis. BAAAAD

Question 56

β-thalassemia trait/minor

Answer 56

Heterozygous
Almost no clinical presentation (very mild anemia)
Normal or low MCV
One mutated beta-globin gene, one normal

No transfusion

Question 57

HPFH Autosomal (Hereditary Recessive Persistence of
Fetal
Hemoglobin)

Answer 57

Symptom free b/c adequate levels of γ chains still made due to the disruption of the perinatal globin switch from γ to β. 100% of hemoglobin is HbF (α2γ2). HPFH individuals have higher HbF (17- 35%) level than δβ0-thalassemia individuals (5-18%).

Heterochronic expression; still make fetal HbF as adult (alters expression of timing)
No δ or β synthesis because of deletions of both genes. Increased γ-globin expression (1) extended deletion brings cis-acting enhancer element closer to γ-globin gene (2) destroy binding site of a repressor, thereby relieving postnatal repression of γ.

Question 58

α -Thalassemias

Answer 58

Deletions in one or both α genes in cluster, thus, γ- and β-globin are in excess. Affects the formation of both fetal and adult hemoglobins.

Question 59

Hydrops Fetalis (–/–)

Answer 59

Homozygous for α-thal-1-allele (–)
This allele most common in Southeast Asia
Stillborn
There is enough ζ2γ2 (Hb Portland) to sustain fetal development, but most fetal hemoglobin is γ4 (Hb Bart’s) and incompatible with life
Homozygous for α-thal-1-allele (–)

Question 60

α-thallasemia-1 trait

αα/–

Answer 60

Heterozygous for α-thal-1-allele
Mild anemia
Homozygous for α-thal-1-allele (–)

Question 61

α-thallasemia-2 trait

α-/α-

Answer 61

Homozygous for α-thal-2-allele (α-)
This allele is most common in Africa, Asia Mediterranean

Mild Anemia
Homozygous for α-thal-2-allele (α-/α-)
Note: heterozygote is fine (αα/α-) and is silent carrier

Question 62

HbH disease

Answer 62

Compound heterozygote (α-/--)
Severe Anemia

Compound heterozygote (α-/--)
About 5-30% of their hemoglobin is β4 (HbH), which precipitates

Question 63

Where the 3 repeats are located in the trinucleotide diseases

Answer 63

Mytonic Dystrophy–>Increased CTG repeats (in 3’ UTR) of DMPK gene

Fragile X syndome–> Repeat at 5’ UTR

Hunnington Disease–> Repeat of CAG in the exons