Genetic Diseases Flashcards
What is a genome vs chromosome mutation? Can these be seen via karyotyping?
Genome mutation - loss or gain of whole chromosome (i.e. trisomy)
Chromosome mutation - structural changes in a single chromosome which can be seen (translocations / deletions)
Both types can be seen via karyotyping
Are autosomal dominant or autosomal recessive disorders more uniformly expressed and why?
Autosomal recessive since both gene products will be knocked out, destroying whatever enzymatic function was there
Autosomal dominant inheritances can have variable expression of the unaffected allele between cells or individuals -> reduced penetrance and variable expressivity
How are acid hydrolases made and transported?
Made in the endoplasmic reticulum, and post-translationally modified in the Golgi apparatus with a mannose-6-phosphate residue.
Attaches to mannose-6-phosphate receptor in the Golgi and leaves via the Trans-Golgi network.
This vesicle of inactive acid hydrolases will fuse with acidic late endosomes to form lysosomes.
What are the only two lysosomal storage disease which are X-linked rather than autosomal recessive?
Fabry disease - for some reason you just remember this
Hunter syndrome - men are hunters, will affect men more
What are the four types of glycosphingolipids? Give the base, one sugar, with sulfates added, and with sialic acid added? Begin by saying what the backbone / functional groups are.
Backbone = sphingosine
C-C-N of serine, C2 will hold all the sugars.
Ceramide: C1 has palmitate, N has N-acetylated fatty acid
Cerebrosides: One sugar at C2, either glucose or galactose (i.e. glucocerebroside)
Sulfatides: Sulfate group attached to galactocerebroside
Globoside: Neutral, with extra sugars added to C2
Ganglioside: Includes sialic acid residues, which are charged (O or N-acetylneuraminic acid)
What is sphingomyelin? What is it similar to?
Ceramide + C2 = phosphocholine
It is a phosphosphingolipid, very similar to phosphatidylcholine which is the same but with glycerol backbone.
What are mucopolysaccharides primarily involved in and what happens when there is a lysosomal hydrolase deficiency in breaking them down?
Primarily involved in the extracellular matrix of different tissues
- > made of sugars including dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate, and hyaluronic acid
- > will accumulate in lysosomes and cause mucopolysaccharidoses
What are the clinical features shared by mucopolysaccharidoses?
- Organomegaly
- Abnormal facies
- Joint stiffness and deformity
- Cognitive impairment
When glycosaminoglycans (GAGs) (same as MPS) build up in the body, what two fluids do they tend to build up in so they are clinically detectable? What GAG is normal in urine?
- Urine (can be used for screening test as well as quantitative analysis up to 1 year) - some chondroitin sulfate is normal
- Amniotic fluid
What enzyme assays can test for MPS?
- Prenatal - culture cells from amniotic fluid (not CVS)
2. Postnatal - enzyme activity from skin fibroblasts, or leukocytes
What enzyme is deficient in Hurler syndrome and what accumulates in the urine?
alpha-iduronidase
(breaks one of the sugars in the dimers which form GAGs)
-> accumulation of dermatan and heparan sulfate
What are the common features of Hurler syndrome?
Airway destruction, dwarfing, coarse facial features, buildup of GAGs in heart, hepatosplenomegaly
- *corneal clouding**
- *Alder-Reilly anomaly**
What is the Alder-Reilly anomaly?
Accumulation of azurophilic granules in the cytoplasm of neutrophils and monocytes, seen in Hurler syndrome
What enzyme is deficient in Hunter syndrome and what accumulates in urine?
Iduronate sulfatase -> need to take sulfate groups off uronic acid sugars before they can be cleaved by alpha-iduronidase
Same accumulation as Hurler: heparan and dermatan sulfate
What are the clinical features of Hunter syndrome which distinguish it from Hurler?
Hunter has no corneal clouding
- > onset generally slightly later and milder as well, with aggressive behavior
- > both still have deafness, stiff joints, coarse facial features, etc
What is the general function of sphingomyelin?
Distributed throughout the body as a structural component of cell membranes
What are the two broad Types of Niemann-Pick disease and what causes it? Which group is overall most common?
Type I - Deficiency in spingomyelinase -> accumulation of sphingomyelin in reticuloendothelial system, among others
Type II - Defect in cholesterol esterification (NPC1 / NPC2), leading to lysosomal accumulation of unesterified cholesterol.
-> more common overall
What are the two subtypes of Type I Niemann-Pick (sphingomyelinase deficiency)? Give the clinical features overall, and the one thing that really distinguished type A from Type B.
- Type A - “severe infantile”, more common.
- > neurodegeneration (vacuolization / ballooning of neurons), hepatosplenomegaly, lipid-laden macrophages, “cherry-red” spot on macula like Tay-Sachs. - Type B - “chronic visceral”
- > organomegaly but NO CNS INVOLVEMENT
How will macrophages appear by LM and EM in both forms of Type I Niemann-Pick?
LM - foamy macrophages with “soap bubble” appearance
EM - Lamellated and whorled figures
What are the defining clinical characteristics of Type II Niemann-Pick and its two subtypes?
Type C: Presents in early childhood
Affects viscera (i.e. spleen, liver, bone marrow) and CNS
- > Neurovisceral presentation
- > Supranuclear palsy and mental deterioration is diagnostic
Type D: Less severe variant prominent in Nova Scotia
What is the primary function of gangliosides?
Normal component of cell membranes, especially neurons
What are the GM2 gangliosidoses? Why are the clinically similar? What enzymes are messed up?
Tay-Sachs disease - alpha-subunit of hexaminidase A
Sandhoff disease - beta-subunit of hexaminidase A
Activator deficiency - GM2 activator
All lead to accumulation of GM2
How do the subunits of these GM2 cleavage enzymes work?
Alpha-beta subunits meet and cleave GM2 with the help of activator for hexaminidase A
-> hexaminidase B is also deficient in Sandhoff because it is made from two beta-subunits.
Why is there a cherry-red spot in GM2 gangliosidoses, and what is the prognosis for these patients?
Because the macula is the lowest concentration of neurons -> has the lowest amount of glycosphingolipids accumulating as a result of enzyme deficiencies
Prognosis -> neurogenerative disease, blindness, and death by 2-3 years.
What will be seen on EM of the neurons and retina in Tay-Sachs / other GM2 gangliosidoses? What ethnic group is most effected?
Whorled material, very similar to Niemann-Pick.
Ashkenazi Jews are most affected
What enzyme is deficient in Metachromatic leukodystrophy and what will accumulate?
Arylsulfatase A - galactocerebroside sulfate will accumulate in Schwann cells / oligodendrocytes (a major component of myelin membranes)
What deficiency is phenotypically similar to metachromatic leukodystrophy?
Saposin B (SAP) which is an enzyme required for activity of arylsulfatase A, which solubilizes the hydrophobic lipid, making it accessible
When does metachromatic leukodystrophy most commonly begin and what are its major symptoms?
~2 years (late infancy)
- > Hypotonia, muscle weakness, and ataxia due to central and peripheral demyelination
- > Loss of white matter
- be aware that there are later forms (juvenile, adult)
How will the adult form of metachromatic leukodystrophy first present?
Likely as psychiatric symptoms first, then neurological symptoms (loss of white matter in brain)
How is metachromatic leukodystophy diagnosed / was classically diagnosed?
“metachromasia” in urine spot test due to presence of sulfatides in urine
Also from imaging scans showing demyelination.
Also, biopsy of sural nerve showing metachromatic granules
Where does material accumulate in metachromatic leukodystrophy and how does this appear when stained? EM?
Appears as metachromatic granules. On EM, has a herringbone pattern with pleomorphic / parallel lipid profiles.
-> mostly accumulates in oligodendrocytes / astrocytes / schwann, causing gliosis in brain. Some accumulation in gall bladder / kidney areas
What is multiple sulfatase deficiency? What disorders will it combine?
Deficiency in arylsulfatase A, B, and C, leading to accumulation of sulfatides (i.e. galactocerebroside sulfate), sulfated GAGs, and steroid sulfates
-> combines metachromatic leukodystrophy and mucopolysaccharidoses
What is the most common lysosomal storage disease and what is defective?
Gaucher disease - defect in glucocerebrosidase, with different abnormal alleles for the enzyme giving rise to three clinical subtypes
What type of cell is present histologically in Gaucher’s disease and why does it exist?
Gaucher cell - lipid-laden macrophages which appear like “crumpled tissue paper”
-> exist because glucocerebrosides from senescent WBCs/RBCs are not broken down, and eaten by monocytes / macrophages
What are the features of the most common type of Gaucher disease, and how is it distinguished from the other two types? Who is it common in?
Type 1 -> most common in Ashkenazi Jews
Hepatosplenomegaly
Pancytopenia
Bone disease - avascular necrosis, osteoporosis, bone crises
NO primary neurological disease versus the two other types (no Gaucher cells in brain)
What bone finding is common in Type 1 gaucher disease?
“Erlenmeyer flash deformity” -> flattened ends of femurs
What are the findings in Type 2 gaucher disease and what is special about the amount of glucocerebrosidase?
Type 2 - primary CNS involvement, hepatosplenomegaly and cytopenias, but NO BONE INVOLVEMENT
-> glucocerebrosidase is completely ABSENT
What is Type 3 Gaucher disease?
Juvenile form,
involves hepatosplenomegaly, cytopenias, as well as CNS AND Bone involvement
-> more slowly progressive
How is Gaucher disease treated?
Replacement therapy w/ recombinant enzymes or bone marrow transplant
What enzyme is defective in Fabry disease and what substrate accumulates?
alpha-galactosidase A
-> accumulates Gb3 or ceramide trihexose
How will presentation in Fabry disease differ between the sexes?
X-linked disease so
Males have most severe disease and will have full spectrum of manifestations
Females will be asymptomatic or have variable manifestations / later onset because of lyonization (random X inactivation)
What is the triad of early symptoms to remember as early manifestations of Fabry disease?
- Angiokeratomas - spotty skin lesions (red, punctate) due to dilation of capillaries
- Hypohidrosis - decreased sweating ability
- Acroparesthesia - peripheral neuropathy causing pain in hands / feet
What is cornea verticillata?
Corneal spiral streaks also sometimes seen in Fabry disease
-> due to re-duplication of the corneal basement membrane
What are the late symptoms of Fabry disease?
- Progressive renal failure (podocytes accumulate Gb3, leading to proteinuria)
- Cardiovascular disease
- Cerebrovascular disease (strokes)
- > vascular damage.
What enzyme is deficient in classic galactosemia?
Galactose-1-phosphate uridyltransferase
Remember: Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT)
What are the major clinical features of classic galactosemia?
Liver problems: hepatomegaly
CNS problems: failure to thrive and intellectual disability
Eye problems: Cataracts within a few days (accumulation of galactitol, toxic substance)
** Infection susceptibility: E. coli sepsis in neonates
What are the pathologic findings of galactosemia?
Steatosis of hepatocytes w/eventual cirrhosis
Brain: edema, gliosis, neuronal necrosis
How is galactosemia diagnosed? How is it managed?
Newborn screening test generally via galactosuria
Managed by avoiding lactose or galactose (definitely no breastfeeding)
What are two non-classical forms of galactosemia?
- Galactokinase deficiency (can’t attach 1-phosphate to galactose for processing by uridyl-transferase)
- UDP-gal-4-epimerase (can’t convert galactose to glucose)
What should happen physiologically in the hepatic vs myopathic forms of glycogen storage diseases?
Hepatic forms - accumulation of glycogen in the liver + low blood glucose
Myopathic forms - accumulation of glycogen in muscle and muscle weakness (unable to generate ATP thru glycolysis)
What type of GSD is von Gierke disease and what enzyme is absent?
von Gierke disease = Glucose-6-phosphatase, can’t do that last step in breaking down glycogen to glucose so it accumulates in sites of glycogen storage (cannot be let out into the blood as free glucose)
- > if G6P were accumulating in skeletal muscles, would just be used for glycolysis
- > this is a HEPATIC form
What are the clinical features of von Gierke disease?
Hepatomegaly and renomegaly (from glycogen accumulation)
Severe fasting hypoglycemia
Increased blood lactate -> glucose accumulates and is pushed to lactate
Marked lipidemia / ketosis, can cause eruptive xanthomas in face and buttocks
How do von Gierke’s babies look and why?
Elevated triglyceride levels to compensate for hypoglycemia -> excessive fat in face / buttocks (doll-like appearance)
How will the liver appear pathologically in von Gierke’s?
Very pale grossly (accumulation of glycogen)
Clear glycogen inclusions histologically
Liver adenomas may develop to try to cope with increased glycogen load
What type of disease is McArdle and why? What enzyme is missing?
Myopathic GSD
- Glycogen phosphorylase in (M)uscle is absent, which breaks off alpha 1-4 bonds until down to the last 4 sugars on the branch
- Only affects muscle because the liver glycogen phosphorylase is present
- glycogen accumulates in muscle cells which cannot be broken down into glucose-1-phosphate
How will patients present clinically with McArdle?
Muscle cramps due to lack of energy in muscles working. There will be no rise in blood lactate with exercise (no glucose available)
Leads to Myoglobinuria -> use of protein as energy source
- > possible rhabdomyolysis and acute renal failure
- > will have a second burst of energy during exercise due to increased blood flow and increased glucose delivery to muscles
What will be seen pathologically in McArdle disease?
Subsarcolemmal accumulation of glycogen in skeletal muscles
What is the best characterized systemic form of glycogen storage diseases and what enzyme is deficient?
Pompe disease (deficiency of alpha-1,4-glucosidase (acid alpha-glucosidase / acid maltase), also has 1-6 activity can totally break down glycogen into glucose) think of Pompeii's volcanic acid
-> lysosomal breakdown of glycogen is deficient
What are the clinical findings in Pompe disease?
Cardiomegaly is major issue, along with hepatomegaly, hypotonia, and muscle wasting
-> death occurs early due to heart failure
What is Type IV GSD and what enzyme is deficient? What form of disease is it?
Anderson disease
Branching enzyme is deficient
It is a systemic disease
What are the clinical features of Anderson disease?
Hepatosplenomegaly and failure to thrive
- > cirrhosis and ascites
- > abnormal glycogen deposits in brain, heart, skeletal muscle
How can Anderson and Pompe disease be clinically distinguished?
Anderson’s disease will have accumulation of abnormal glycogen -> cannot be broken down by diastase
What three deficiencies can cause PKU?
Types:
1. Phenylalanine hydroxylase (converts phenyalanine to tyrosine)
- Tetrahydrobiopterin (BH4) -> cofactor for PAH
- Dihydropteridine reductase (re-reduces BH2 to BH4 following PAH activity)
Why are the second and third types of PKU called malignant PKU?
Because they lack BH4 or BH4 reduction, which is also required to metabolize tyrosine and tryptophan
-> high tyrosine and low phenylalanine diet will not save them
What are the clinical features of PKU and why?
Severe intellectual disability, seizures, eczema, fair skin and hair color. This is because Tyrosine is needed to make T3/T4, NE / E / Dopamine, and melanin pigment
How is PKU detected in newborns?
Phenylpyruvic acid in newborn urine (urinary excretion by minor pathways)
What happens if moms with PKU don’t restrict their diets during pregnancy?
Can lead to Maternal PKU
-> microcephaly, growth retardation, and intellectual disability in baby
What is the most common lethal genetic disease in the Caucasion population and what is the mutation?
Cystic fibrosis
Mutation in CTFR gene on chromosome 7, delta F508 mutation (3 bp deletion of phenylalanine at position 508)
-> autosomal recessive
What are the functions of CFTR in lungs, GI tract, and sweat glands?
Lungs / GI tract: ATP-gated Cl- channel which secretes Cl- into lumen.
If absent: extra sodium and water are drawn in, and luminal secretions become very thick.
Sweat glands: Cl- channel normally reabsorbs Cl-. If blocked, Na+ is not reabsorbed as well, sweat becomes very high in Cl- / Na (diagnostic).
What is seen in the lungs, pancreas, intestines, and vas deferens in CF?
Lungs - bronchial secretions are thick - recurrent respiratory infections
Pancreas - thick secretions cause blockage of ducts with pancreatic insufficiency / autodigestion of pancreas. Also leads to malnutrition
Intestines - blocked by secretions, can lead to atresia in utero as well.
Vas deferens - infertility due to thickened tube. Males commonly sterile.
What causes Marfan syndrome and what is the inheritance?
Autosomal dominant mutation in fibrillin-1 gene on chromosome 15
-> defective elastic connective tissue due to lack of glycoprotein organizing the connective tissue elastin rich in desmosine / isodesmosine linkages
What are the clinical features of Marfan syndrome?
Hyperextensible joints, skeletal deformities, lens dislocation, mitral valve prolapse, pectus excavatum, dilation of aorta / dissection of aorta, arachnodactyly
What are the clinical findings of NF-1?
Multiple cafe au lait spots Axillary / inguinal freckling Multiple cutaneous neurofibromas or plexiform neurofibroma (tortuous structure) Iris Lisch nodules Optic glioma
What is the function of the NF-1 gene?
Encodes neurofibromin, a tumor suppressor gene that acts as a GTPase, inactivating Ras
What is a Lisch nodule?
A pigmented hamartoma of the iris
What malignant tumor are patients with NF-1 more susceptible to?
Malignant peripheral nerve sheath tumors (MPNST)
What protein is dysfunctional in NF-2?
Merlin - NF2 located on chromosome 22
-> tumor suppressor gene involved in communication between ECM and cytoplasm
What are the tumors which typically result from NF-2?
Think of “2”
2 eyes = bilateral cataracts
2 ears = bilateral acoustic schwannomas
2 brains = meningiomas and ependymomas (ependymal cells line the ventricles and spinal cords)
What are the most important clinical signs of Down syndrome?
- Hypotonia (at birth) with IUGR**
- Single transverse palmar crease (only 5% chance in a normal person)
- Oblique palpebral fissues
- Clinodactyly - short, curved 5th finger
- Intellectual disability
- Hearing and heart defects
Why are Alzheimer’s patients at increased risk for Alzheimer’s disease?
Amyloid precursor protein is encoded on chromosome 21
What GI abnormalities are trisomy 21 patients at risk for?
Duodenal atresia (double bubble sign) and Hirschsprung disease
What cancers are Down syndrome patients at increased risk for?
ALL and AML
lymphoblastic and myeloid
What is the mneumonic for Edward syndrome?
PRINCE Edward (trisomy 18) = election age
P = prominent occiput R = Rocker-bottom feet I = intellectual disability N = nondisjunction C = Clenched fists (overlapping fingers) E = Low-set ears
Remember also microcephaly with micrognathia and congenital heart disease
What is the mneumonic for Patau syndrome? What trisomy is it?
Patau = Trisomy 13 = Puberty
6 P’s:
- cleft Palate / lip
- holoProsencephaly
- Polydactyly
- cutis aPlasia - missing skin on scalp
- Polycystic kidney
- microPhthalmia w/ possible proboscis (due to holoprosencephaly)
What are the clinical features of Velocardiofacial syndrome?
One possible 22q11 syndrome
Velopharyngeal incompetence = cleft palate (not cleft lip)
Cardio = cardiac defects
Facial = facial dysmorphism, prominent nose, upslanted palpebral fissues, small, abnormal ears.
What are the DiGeorge 22q11 anomalies?
Thymic aplasia -> T cell deficiency Parathyroid asplasia -> hypocalcemia Cardiac defects (3rd and 4th pouch defects)
How are 22q11 abnormalities diagnosed?
FISH
What is the most common cause of hypogonadism in the male and its karyotype most often?
Klinefelter syndrome
47,XXY most often
Associated with small testes and penis
Other than hypogonadism, what are some of the other important features of Klinefelter syndrome?
Tall stature / elongated body
Gynecomastia
Renal abnormalities
-> ratio of estrogens to testosterone determines degree of feminization
Why do Turner syndrome patients have residual puffiness of dorsum of hands and feet?
Overflow of lymph, relates to puffy hands/feet + webbed neck. Even when the edema subsides, the webbing of the neck remains, commonly from cystic hygroma blocking lymph flow
Are Turner syndrome babies easily born?
No - fetal mortality is high (up to 99%) - XO babies
What gonadal and cardiac defects are common in turner syndrome?
Gonadal - ovarian dysgenesis (streak gonads / made of fibrous tissue)
Cardiac - coarctation of the aorta (narrowing, around ligamentum arteriosum)
What is the second most common cause of intellectual disability after Down syndrome? How does it get this name?
Fragile X syndrome - region on chromosome appears broken when cells are cultured on FOLATE-DEFICIENT MEDIA
What are the clinical features of Fragile X?
Prominent, square jaw, macroorchidism (large testes), intellectual disability, macrocephaly, behavioral problems
What sequence is repeated in Fragile X? What gene is this in?
Trinucleotide repeat CGG
C = chin
G = giant
G = gonads
giant chin and gonads
Gene is in FMR1 = familial mental retardation 1, >200 will have disease
What pre-mutation state of Fragile X affects males mostly? How is it detected?
Fragile X Tremor Ataxia Syndrome (FXTAS) - late onset, progressive cerebellar ataxia and intention tremor affecting males
Detected via white matter lesions to middle cerebellar peduncles on MRI
What pre-mutation state of Fragile X affects females?
Premature Ovarian Insufficiency (POI) - cessation of menses in 20% of premutation carrier females. Premature menopause before age 40.
When do the number of trinucleotide repeats in Fragile X become worse?
During oogenesis -> males can’t increase the number of repeats. They will have the disease, but if they pass to their daughters it will be the same amount.
Females can be carriers and pass the full mutation to their daughters.
Are all mitochondrial diseases encoded by mitochondrial DNA? How are they inherited?
No, actually about 85% are mitochondrial genes encoded by nuclear DNA, rest by mitochondrial DNA
Mitochondrial DNA disorders are variably inherited thought the mother only (ova contain many mitochondria, sperm contain few if any)
What types of proteins are encoded by mitochondrial DNA? What organs will be affected by their dysfunction?
Respiratory chain enzymes, ribosomal RNA, and translational RNA
- > mutations can lead to inefficient ATP production and accumulation of free radicals / excess metabolites
- > organs most dependent on oxidative phosphorylation will be affected (CNS, eyes, SM, liver, kidneys)
What is the “threshold effect” in mitochondrial diseases?
Mitochondria is distributed variably during mitosis, and there can be wild type and abnormal mitochondria within a single cell (heteroplasmy).
High enough proportion of mitochondria in daughter cell must be affected to see clinically outcomes (threshold effect)
What is MERRF? How is it clinically identified?
Myoclonic Epilepsy associated with Ragged Red Fibers
Myoclonus, seizures, cerebellar ataxia, and lactic acidosis
How is muscle with MERRF pathologically identified?
Ragged red fibers on muscle biopsy due to replication of mitochondria in an attempt to compensate (seen with trichrome stain)
Succinate dehydrogenase stains highlight the extra mitochondria (complex 2 encoded by nuclear enzymes)
Subsarcolemmal mitochondria with paracrystalline inclusions by EM
When does imprinting occur? What does it do?
During gametogenesis
Silences that gene via methylation.
What chromosomal mutation leads to Prader-Willi, and how can UPD (uniparental disomy) cause this?
15q11, a defect in the Paternal gene (which is normally expressed)
If you have maternal UPD, both of these will have this gene region silenced, functionally knocking out what would be the father’s gene, leading to Prader-Willi Syndrome
What chromosomal mutation leads to AngelMan Syndrome, and how can UPD (uniparental disomy) cause this?
M = need maternal genes expressed
15q11, a defect in the maternal gene
If you have paternal UPD, both of these chromosomes will have this gene region silenced, functionally knocking out what would be the mother’s gene, leading to Angelman Syndrome
What are the clinical features of Prader-Willi syndrome?
Hypotonia at birth (extreme)
Intellectual disability
Obesity due to hyperphagia
Hypogonadism
What are the clinical features of Angelman syndrome?
Inappropriate laughter “happy puppets”
Seizures
Gait ataxia (child needing to be held up)
Severe speech impairment / intellectual disability
How does gonadal mosaicism occur? What does it explain?
In a future parent, there is a germ cell mutation which occurs in early-embryonic development (post-zygotically)
- > mutation only affects germ cells
- > explains how some parents who are normal will keep having children with an autosomal dominant defect
