Flashcards in Abnormalities & Diseases Deck (192):
What is another name for Trisomy 21?
What is another name for Trisomy 13?
What is another name for Trisomy 18?
What is Klinefelter Syndrome?
What is the phenotype of Kinefelter Syndrome?
Tall stature, hypogonadism, gynecomastia, infertile, language impairment
What is the phenotype of 47,XYY Syndrome
Indistinguishable physically or mentally from normal males and are usually fertile; increased risk of behavioral and educational problems, delayed speech and language
What is Turner Syndrome?
What is the phenotype of Turner Syndrome?
Short stature, webbed neck, edema of hands and feet, broad shield chest, renal/cardio anomalies, failure in ovarian development
What is the event that leads to Velocardiofacial syndrome?
Deletion of a gene on chromosome 22
What is the event that leads to Velocardiofacial syndrome?
Deletion of a gene on chromosome 22
What causes Prader-Willi Syndrome, genetically?
A deletion in the paternal 15q11-13
What causes Angelman Syndrome, genetically?
A deletion in the maternal 15q11-13
Angelman syndrome is caused by defects in the expression of what? What does it do?
UBE3A; encodes a ubiquitin ligase involved in early brain development
Prader-Willi syndrome is caused by defects in the expression of what genes?
SNORD116 snoRNA genes
How can Prader-Willi Syndrome result from uniparental disomy?
If the maternal is disomic fro chromosome 15 and the father has a normal chromosome 15, this results in incompatible with life trisomy 15; but if there's mitotic disjunction early during development, fetus is rescued but if it has just the remaining two maternal chromosomes, it will have Prader-Willi.
Is Chediak-Higashi Syndrome autosomal recessive or dominant?
Chediak-Higashi Syndrome causes problems with what?
What is the phenotype of Chediak-Higashi Syndrome?
Partial oculocutaneous albinism, light hair, immunodeficiency, mild-bleeding tendency, variable cognitive impairment, neuropathy, ataxia, and parkinsonism
What is the expressivity of Chediak-Higashi Syndrome?
Variable severity of symptoms with neurological manifestations from childhood to early adulthood
In cancer, does low hypodiploidy indicate a poor or good prognosis?
In cancer, does high hypodiploidy indicate a poor or good prognosis?
Why does high hypodiploidy in cancer indicate a good prognosis?
A gain of chromosomes can mean more GFs --> Tumor Suppressor Genes are not lost
What tests can be used to diagnose Prader-Willi?
FISH or microarray
What specific opthalmologic problems are common in patients with Prader-Willi?
Strabismus & Nystagmus
What is a common treatment for Prader-Willi?
What is the phenotype of maternally inherited 15q interstitial duplication cause?
Autism, NOT dysmorphic, hypotonic, seizures
What does isodicentric isochromosome 15q (IDIC 15) cause?
Autism, NOT dysmorphic, hypotonic, seizures
What are supernumerary marker chromosomes?
Inverted duplicated isodicentric 15q
How can Angelman Syndrome be diagnosed?
FISH, UPD of 15q, or imprinting errors of 15q detected with methylation studies
What is the phenotype of Angelman Syndrome?
Mildly dysmorphic facial features, hypotonia, spasticity, intellectual disability, seizures, autism
What percentage of all DS cases is due to Trisomy 21?
What percentage of all DS cases is due to an unbalanced translocation between chromosome 21 and another acrocentric chromosome?
What percentage of all DS cases is due to mosaic trisomy 21?
How can a fetus be tested for DS during the first trimester?
Ultrasound measurement of nuchal folds + beta-hCG + PAPP-A
How can a fetus be tested for DS during the second trimester?
beta-hCG, aFP, unconjugated estriol, and inhibin levels
What are common medical issues associated with DS?
Cardiac, gastrointestinal, opthalmologic, EENT, endocrine, orthopedic, hematologic, developmental, neurologic, psychiatric
Approximately what percentage of patients with DS present with cardiac issues?
50% - atrioventricular canal is common
Approximately what percentage of patients with DS present with structural gastrointestinal anomalies?
10-15% - esophageal atresia, duodenal atresia, Hirschsprung's
What kind of functional GI issues do many children with DS present with?
Feeding problems, constipation, GERD, Celiac
What kind of opthalmologic problems do many children with DS present with?
Blocked tear ducts, myopia, lazy eye, nystagmus, cataracts
What kind of EENT problems do many children with DS present with?
Chronic ear infections, deafness, chronic nasal congestion, enlarged tonsils and adenoids (obstructive apnea)
What kind of endocrine problems do many children with DS present with?
Hypothyroidism, insulin dependent diabetes, alopecia areata, reduced fertility
What kind of orthopedic problems do many children with DS present with?
Hips, joint subluxation, atlantoaxial subluxation
What kind of hematologic problems do many children with DS present with?
Myeloproliferative disorder, leukemia risk, iron deficiency anemia
What kind of developmental problems do many children with DS present with?
Hypotonia, intellectual disability, speech problems
What kind of neurologic problems do many children with DS present with?
What kind of psychiatric problems do many children with DS present with?
Depression, early Alzheimer's, autism (10%)
What is the karyotype of patients with Turner Syndrome?
What are some abnormalities of the cardiovascular system in a patient with Turner Syndrome?
Bicuspid aortic valve, coarctation of the aorta, systemic hypertension, prolonged QTc Syndrome, partial anomalous pulmonary venous connection, persistent left SVC
What are some abnormalities of the eye in patients with Turner's syndrome?
Inner canthal folds, ptosis, blue sclera
What are some abnormalities of the skeletal system in patients with Turner's syndrome?
Cubitus valgus, short 4th metacarpal, short stature
What are some abnormalities of the neck in patients with Turner's syndrome?
Webbed neck, low hairline, cystic hygroma
What are some learning abnormalities in patients with Turner's syndrome?
Math difficulty, visual spatial skills, low non verbal scores
What is the disease classification of PKU (phenylketonuria)?
What are four phenotypes of PKU?
High phenylalanine in blood and phenylalanine metabolites in the urine, hyperactivity and epilepsy, mental retardation and microcephaly
PKU is a defect in what?
PAH (phenylalanine hydroxylase) (>98%) or defects in the PAH cofactor BH4 (tetrahydrobiopterin) (1-2%)
PAH converts what to what?
phenylalanine to tyrosine
How are newborns screened for PKU?
Tandem Mass Spectrometry (MS?MS) which sorts molecules in blood specimen by size, weight, and quantity. Fast detection and high sensitivity.
What is the main treatment of PKU?
Low phenylalanine diet. Other possibilities include BH4 supplementation, neutral amino acid supplementation, ERT, gene therapy.
What population is most at risk for α1-antitrypsin deficiency (ATD)?
people with Northern European ancestry
When is ATD usually diagnosed and what does it affect?
Later in life; lung & liver
What is α1-antitrypsin and what does it do?
A protease inhibitor of the serine protease elastase, which is released by activated neutrophils at the airway, destroying elastin in the connective tissues
Where is α1-antitrypsin made and where does it go?
Made in liver and travels to lungs through the blood.
Of two mutant alleles in α1-antitrypsin, Z & S, which genotypes causes the lowest amount of normal SERPINA1 levels?
Z/Z genotype has ~15% normal SERPINA1 level
S/S genotype has 50-60% normal SERPINA1 level
What is the treatment for ATD?
Treatment for lung disease (COPD): inhaled bronchodilators and inhaled steroids, vaccinations against flu/pneumonia, pulmonary rehab oxygen, lung transplant
Treatments in development: ERT, gene therapy, release of misfolded AAT protein from liver to blood
What is the disease classification of α1-antitrypsin deficiency?
What is the disease classification of Tay-Sachs Disease?
Tay-Sachs Disease (Gm2 gangliosidosis type I) causes the progressive destruction of what?
The central nervous system
What is the lifespan of a patient with Tay-Sachs?
~2-4 years of age
What is the biochemical defect of Tay-Sachs Disease?
A lysosomal storage disorder with >300xs accumulation of Gm2 ganglioside in the lysosome.
Tay-Sachs Disease is usually caused by a mutation in what gene? What is this gene responsible for?
Mutation in HEXA gene which makes the alpha subunit of teh enzyme hexosaminidase A which degrades Gm2 ganglioside.
Mutation in the HEXB gene causes which disease?
What enzyme is defected in Tay-Sachs?
What is the disease classification of Achondroplasia?
What is the disease classification of Huntington's Disease?
What is the disease classification of Tuberous Sclerosis?
What is the disease classification of Marfan Syndrome?
What is the disease classification of Retinoblastoma?
What is the disease classification of Von Willebrand Disease?
What is the disease classification of Hereditary hemorrhagic telengiactasia?
What is the disease classification of Adult Polycystic kidney disease?
What is the disease classification of Neurofibromatosis?
What kind of penetrance does achondroplasia have?
What is the new mutation rate of achondroplasia?
What are the clinical manifestations of achondroplasia?
Short stature, rhizomelic limb shortening, short fingers, genu varum, large head/frontal bossing, midfacia retrusion, small foramen magnum
Where is the mutation in achondroplasia?
FGFR3 (fibroblast growth factor receptor 3)
Does parental age affect de novo autosomal dominant mutations rates?
Yes; paternal age effect (achondroplasia & more)
What is the mutation of Neurofibromatosis Type 1?
Mutation in NF1 (neurofibromin - tumor suppressor gene) on chromosome 17q11.2
What is the mutation of osteogenesis imperfecta type 1?
Mutation in COL1A1 (collagen type 1 alpha 1) on chromosome 7q21.3 - reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half
What is the new mutation rate of Marfan Syndrome?
What are the clinical manifestations of Marfan Syndrome?
Systemic disorder of connective tissue, ocular, skeletal, CV
What is the mutation of Marfan Syndrome?
FBN1 (fibrillin-extracellular matrix protein) on chromosome 15q21.1
What is the new mutation rate of Autosomal Dominant Polycystic Kidney Disease?
What is the mutation in Autosomal Dominant Polycystic Kidney Disease
PKD which makes polycystin 1 and 2; produces a truncated protein
What are the clinical manifestations of Autosomal Dominant Polycystic Kidney Disease?
Bilateral renal cysts, cysts in other organs, end stage kidney disease, vascular abnormalities
What is the new mutation rate of Familial Hypercholesterolemia?
What are the three genes whose mutations are known to cause Familial Hypercholesterolemia?
LDLK, APOB, PCSK9
What are the clinical manifestations of Familial Hypercholesterolemia?
High cholesterol and LDL levels, xanthomas, premature coronary artery disease and death
What are unique features of Trinucleotide Repeat Disorders?
Anticipation, expansion of a DNA segment consisting of 3+ nucleotides, slipped mispairing, parental transmission bias, AD, AR, and X-linked transmission
Define Huntingotn Disease
Trinucleotide repeat disorder of CAG - paternally transmitted with anticipation
What are the clinical manifestations of Huntington Disease?
Progressive neuronal degeneration causing motor, cognitive, and psychiatric disturbances.
What gene is mutated in Huntington Disease?
HTT which codes for Huntingtin protein on chromosome 4p16.3
How many CAG repeats are needed for full penetrance of Huntington Disease?
Define Myotonic Dystrophy Type 1
Autosomal dominant trinucleotide repeat disorder of CTG; anticipation & maternally transmitted
What are the clinical manifestations of Myotonic Dystrophy Type 1?
Adult onset muscular dystrophy, progressive muscle weakness and wasting, myotonia, cataracts, cardiac conduction defects
What is the mutation in Myotonic Dystrophy Type 1?
Mutation in DMPK gene which codes for myotonic dystrophy protein kinase on chromosome 19q13.3. Plays an important role in muscle, heart, and brain cells.
What are some examples of disease with multifactorial inheritance?
Pyloric stenosis, some cancers, type 1 & 2 diabetes, Alzheimer disease, inflammatory bowel disease, schizophrenia, cleft lip/palate, hypertension, rheumatoid arthritis, asthma
What is the clinical approach to disorders of sexual differentiation?
Obtain FISH studies for sex chromosomes and a karyotype. Order hormone studies. Consider ultrasound study. Surgical consult with urology.
If a FISH study determines that a baby is 46, XY and that T & DHT levels are normal or elevated, what could the baby have? (2)
Androgen insensitivity syndrome or 5-alpha reductase deficiency
If a FISH study determines that a baby is 46, XY and that T & DHT levels are low, what could the baby have? (5)
Frasier syndrome, Denys-Drash, SRY mutations/deletions, DHH mutations, RSP01 mutations
If a FISH study determines that an ambiguous sex baby is 46, XX, what could the baby have? (6)
Congenital adrenal hyperplasia, ectopic SRY, WNT4 mutations, SOX3 duplications, RSP01 mutations, MALDMD1 mutations
Androgen insensitivity syndrome, previously called "testicular feminization," is caused by a mutation in what gene?
the X-linked androgen receptor (AR) gene
What is 5-alpha reductase deficiency? 46, XY
Causes decreased ability of the body to covert testosterone to dihydrotestosterone
What is the phenotype of a male with 5-alpha reductase deficiency?
Undervirilization until time of puberty
What is Denys-Drash and Frasier Syndrome?
Sex reversal with 46, XY; due to mutations in the WT1 gene which is a transcription factor for SRY gene
What kind of chronic diseases do Denys-Drash and Frasier Syndromes cause?
Diffuse mesangial sclerosis, focal segmental glomerulosclerosis
Describe the gene that encodes for the alpha subunit of hemoglobin.
Two copies of alpha gene on chromosome 16
Describe the gene that encodes for the beta subunit of hemoglobin.
One copy of beta gene on chromosome 11
Describe the levels of globin synthesis throughout fetal life and after birth.
Zeta globin converts to alpha globin at about 6 weeks posconceptual age. Alpha globin is made in high amounts throughout life. Epsilon globin converts to gamma globin about 6 weeks posconceptual age; gamma is made in abundance but then switches with beta about 6 months after birth.
What is a qualitative hemoglobinopathy versus a quantitative?
Qualitative has to do with normal synthesis of globin but altered properties or quality (solubility, stability, oxygen-affinity). Quantitative has to do with amount of synthesis of globin.
What is HbS?
Sickle cell anemia
What is the mutation in HbS?
Glutamine -> Valine (GAG->GTG)
What does HbC cause?
Lysis of RBCs
How can HbC, HbS, or HbA be tested?
Is the tense form of hemoglobin oxygenated or deoxygenated? The relaxed?
What is HbKempsey?
High oxygen affinity. Less oxygen to tissues and overproduction of RBCs. Polycythemia.
What is HbKansas
Low oxygen affinity. Cyanosis.
What is alpha-thalassemia?
low or zero alpha-globin; both fetal and postnatal defects
What is alpha-thalassemia usually caused by?
A deletion of the alpha-globin gene(s)
What is beta-thalassemia?
low or zero beta-globin; postnatal defects only
What is beta-thalassemia usually caused by?
Point mutations in the beta-globin gene; ocassionally caused by deletions in the LCR or the beta-gene cluster
What is the difference betweeen alpha-thalassemia 1 and 2?
1 means that one allele has both functioning genes, and the other has none. 2 means that both alleles have only one functioning gene.
What is hydrops fetalis?
A gamma tetramer -> fetal death
No alpha globin genes expressed whatsoever
What population is at higher risk for alpha-thalassemia 1?
What population is at higher risk for alpha-thalassemia 2?
Africa, Mediterranean, Asia
What is implied by simple thalassemia versus complex?
Simple means that only one gene is affected. Complex affects multiple genes in the cluster.
What cells makes globin first and where?
Megaloblasts make globin in the yolk sac
What cells make globin second and where and when?
Macrocytes make globin in the liver and spleen before birth
What cells make globin after birth and where?
Normocytes make globin in the bone marrow after birth and beyond
What is another name for Cooley's anemia?
Beta thalassemia major
When is Y Thalassemia significant?
Only at birth, usually over by 6 months of life
When is delta Thalassemia significant?
Not significant by itself but can be a problem if beta-deta thalassemia
What are some clinical features of Cooley's anemia?
Dense skull, marrow expansion, hepatosplenomegaly, osteopenia, iron overload, growth and endocrine failure.
What is the treatment for thalassemias?
Red cell transfusions, iron chelators, Vitamin C, splenectomy/cholecystectomy, bone marrow transplant
What is hemoglobin Barts?
A tetramer of gamma chains
What is the disease classification of Hypophosphatemic Rickets?
What is the disease classification of Fragile X Syndrome?
What is the disease classification of Charcot-Marie-Tooth?
What is the disease classification of Rett Syndrome?
What is the disease classification of Focal Dermal Hypoplasia?
What are the clinical manifestations of Hypophosphatemic Rickets?
Hypophosphatemia, short stature, bone deformity
What is the mutation of Hypophosphatemic Rickets?
PHEX which regulates fibroblast growth factor and inhibits the kidney's ability to reabsorb phosphate into the blood stream.
What causes Fragile X Syndrome and what are some of its characteristics?
Trinucleotide repeat disorder of CGG. Anticipation & maternal transmission bias.
What are the clinical manifestations of Fragile X Syndrome?
Intellectual disability, dysmorphic features, autistic behavior, social anxiety, hand flapping/biting, aggression
What is the mutation of Fragile X Syndrome? What is the defect?
FMR1 & FMRP on chromosome Xq27.3. Protein is essential for normal cognitive development and female reproductive function
What is the minimum number of CGG repeats needed for full mutation leading to Fragile X Syndrome?
What is the new mutation rate of Rett Syndrome?
What are the clinical manifestations of Rett Syndrome?
Loss of normal movement and coordination, loss of communication skills, failure to thrive, seizures, abnormal hand movements
What is the mutation of Rett Syndrome? What is the defect?
Mutation in MECP2 (methyl CpG binding protein). Essential for the normal function of neurons.
What is the disease characteristic of Colorblindness?
What is the disease characteristic of Lesch-Nyhan Syndrome?
What is the disease characteristic of Hunter's Disease?
What is the disease characteristic of Menkes Disease?
What is the disease characteristic of Hemophilia A & B?
What is the disease characteristic of Wiscott Aldrich Syndrome?
What is the disease characteristic of Glucose 6 phosphate dehydrogenase deficiency?
What is the disease characteristic of Dystrophinopathies?
What are the clinical manifestations of Lesch-Nyhan Syndrome?
Neurological and behavioral abnormalities, overproduction of uric acid, self injury
What is the mutation in Lesch-Nyhan Syndrome? What is the defect?
Mutation in HPRT1 (hypoxanthine phosphoribosyltransferase 1) which is responsible for recycling purines
What is the mutation in dystrophinopathies?
Mutation in DMD dystrophin on chromosome Xp21-21.1
What are the clinical manifestations of Duchenne Muscular Dystrophy?
Progressive muscular weakness from proximal to distal, calf hypertrophy, dilated cardiomyopathy, CK levels 10x, death in 30s, absence of dystrophin
What is the difference between Duchenne and Becker Muscular Dystrophy?
Becker Muscular Dystrophy is an abnormal quantity or quality of dystrophin while Duchenne is a complete absence.
What percentage of female carriers of Hemophilia A are affected?
What are the clinical manifestations of Hemophilia A?
Spontaneous bleeds into joints, muscles, or intracranial, excessive bruising, prolonged bleeding after injury or incision, delayed wound healing
What is the mutation in Hemophilia A and what is the deficiency?
Mutation and deficiency in Factor VIII, chromosome Xq28
Define mitochondrial disease
Group of disorders caused by dysfunction of the respiratory chain; tend to affect tissues that rely heavily on oxidative phosphorylation: brain, retina, skeletal muscle, heart
What is the disease classification of Kearns-Sayre?
What is the disease classification of MELAS?
What is the disease classification of MERRF?
What is the disease classification of Leber Hereditary Optic Neuropathy?
What are the clinical manifestations of Kearns-Sayre?
Eyes affected, cardiac conduction defects, ataxia, deafness, kidney problems
What is the mutation in Kearns-Sayre?
Single large deletion of mtDNA (most commonly removes 12 genes)
What are the clinical manifestations of MELAS?
Muscle weakness, seizures, repetitive stroke-like episodes, elevated lactic acidosis
What are the clinical manifestations of MERRF?
Muscle symptoms, seizures, ataxia, dementia, ragged-red fibers
What is the mutation in MELAS?
Mitochondrial genes (lots of them)
What is the mutation in MERRF?
Mitochondrial genes MT-TK
What are the clinical manifestations of Leber Hereditary Optic Neuropathy?
What is the mutation in Leber Hereditary Optic Neuropathy
Mitochondrial genes (lots of them)
Describe Fabry Disease
X-linked disorder, deficiency of alpha-galactosidase A activity
What are the symptoms of Fabry Disease?
Microvascular Disease, neuropathy, nephropathy, cardiomyopathy
What is the treatment for Fabry Disease?
Protein replacement: Recombinant alpha-galactose