Diseases Flashcards
Wilson’s Disease
Autosomal recessive condition caused by mutation in ATP7B gene; ATP7B protein transfers excess copper into the blood stream
Results in liver cirrhosis & neurological deficiency
Suspected by Kayser-Fleischer rings
Kayser-Fleischer rings
Corneal deposits of copper visible on eye exam
+ sign of Wilson’s Disease
Trisomies Compatible with Life
Trisomy 13 (Patau Syndrome) Trisomy 18 (Edward's Syndrome) Trisomy 21 (Down's Syndrome)
Patau Syndrome
Trisomy 13; characterized by severe intellectual disabilities, failure of the embryonic forebrain to divide properly (holoprosencephaly), facial clefts, polydactyly, renal anomalies, congenital heart and urogenital defects
Edward’s Syndrome
Trisomy 18; characterized by dysmorphic facial features (receding jaw, low-set ears), intrauterine growth retardation, clenched fists, valvular heart disease, diaphragmatic hernia, renal anomalies
Hirschprung disease
Often seen in Trisomy 21; results from lack of embryonic migration of nervous tissue to the colon, leading to inability of the colon to relax and pass stool, creating obstruction; entire colon, stomach, and esophagus may be affected in rare cases
Klinefelter Syndrome
47 XXY as a result of errors in either maternal meiosis (I or II) or paternal Meiosis I; characterized by tall stature, hypogonadism, gynecomastia, sterility, and learning disabilities
Turner Syndrome
XO, most often resulting from loss of the paternal X chromosome; characterized by short stature, webbed neck, broad chest, ammenorrhea, renal & cardiovascular anomalies (bicuspid aortic valve, aortic coarctation)
15% mosaicism
*Loss of function mutation
Hemophilia A
X-linked disorder of coagulation caused by mutation in the F8 gene which codes for Factor VIII, an enzymatic cofactor involved in clotting combination; characterized by spontaneous bleeding into joints, muscles, or intracranial & excessive bruising
Hemophilia B
X-linked disorder of coagulation caused by mutation in the F9 gene which codes for Factor IX, a protease involved in clotting
No common F9 mutation is known; Hemophilia B Leyden results from point mutations in the F9 promoter and resolves at puberty
Chromosomal abnormalities underlying Down Syndrome
Trisomy 21, usually as a result of nondisjunction in maternal meiosis (95%)
Robertsonian translocation between 21q and the long arm of one of the other acrocentric chromosomes; 46 chromosomes, effectively trisomic for genes on 21q (4%, risk unrelated to maternal age)
Isochromosome 21 - results from a 21q21q translocation in which 21p is deleted and 21q is duplicated in a mirror-like fashion; all gametes are either monosomic (lethal) or trisomic (Down)
Mosaic Down Syndrome - cell populations have both normal and Trisomy 21 karyotype (1-2%)
Neurofibromatosis (NF1)
Autosomal dominant condition resulting from loss of function mutation in NF1 gene, which codes for neurofibromin tumor suppressor
Example of pleiotropy: Characterized by growth of benign fleshy tumors (neurofibromas), cafe au lait spots, small benign tumors on the iris (Lisch nodules), & freckling of the axillary/inguinal region
*Loss of function mutational mechanism
Cri du Chat Syndrome
Results from deletion of part of 5p15; characterized by microcephaly, epicanthal folds, low-set ears with preauricular tags, moderate to severe intellectual disability, and heart defects
XYY Syndrome
Results from paternal nondisjunction at meiosis II, producing YY sperm; generally indistinguishable from XY males except for mild learning disability
Trisomy X
XXX resulting from errors in maternal meiosis I, two of the X chromosomes are inactivated; phenotypically normal, may exhibit some intellectual/learning disability and behavioral problems
Tetrasomy X and Pentasomy X are possible and associated with increasingly impaired physical and mental development
Charcot-Marie-Tooth (CMT-1A)
Autosomal dominant disorder caused by a duplication of the PMP22 gene on chromosome 17; characterized by muscle atrophy of the foot, lower leg, and hand muscles, and hammertoes, due to peripheral nerve demyelating neuropathy
*Gain of function mutation
Hereditary Neuropathy with Predisposition to Pressure Palsy (HNPP)
Autosomal dominant condition resulting from deletion of PMP22 gene on Chromosome 17, coding for PMP22 protein which is an integral membrane glycoprotein in nerves; presents as focal pressure neuropathy in 20s-30s
*Loss of function mutation
An example of contiguous gene syndromes
Velocardiofacial Syndrome and DiGeorge syndrome, both caused by del 22q11, a common cause of cardiac defect
Prader-Willi Syndrome
Caused by deletion of 15q11-13 on the paternal homolog (or uniparental disomy of the maternal chromosome); characterized by almond-shaped eyes, excessive & indiscriminate eating, obesity, short stature, strabismus & nystagmus, hypotonicity, mild-moderate cognitive disability
Angelman Syndrome
Caused by deletion of 15q11-13 on the maternal homolog; characterized by short stature, spasticity, seizures, autism, and intellectual disability
Acute Promyelocytic leukemia (PML)
Characterized by translocation involving the retinoic acid receptor-alpha (RARA) gene on 17 and the promyelocytic leukemia (PML) gene on 15; the translocation produces a PML-RARa fusion protein that binds to the RAR element in the promoters of certain genes necessary for proper myeloid differentiation, blocking transcription
Treatment with retinoic acid (vitamin A) (differentiation therapy)
Chronic Myeloid Leukemia (CML)
Characterized by translocation between the breakpoint cluster region (BCR) gene on 22 with the ABL gene 9 - the “Philadelphia chromosome; this translocation produces the BCR-ABL fusion protein, a constituively active tyrosine kinase, leading to myeloproliferative disease
Treatment: Gleevec (a tyrosine kinase inhibitor)
DiGeorge Syndrome
Caused by a deletion on 22q; characterized by developmental delay, ADHD, and aortic defects
Down Syndrome phenotypic features
Flattened facial features Upslanting palpebral fissures Epicanthal folds Small ears Low muscle tone/increased joint mobility Transverse Palmar Crease
Medical Issues associated with Down Syndrome
Cardiac anomalies (30-50%), especially atrioventricular septum defects
Esophageal/duodenal atresia
Hirschprung Disease
GERD
Nystagmus
Cataracts
Chronic ear infections & nasal congestion
Obstructive apnea
Thyroid disease, most commonly hypothyroidism
Increased risk of leukemia (12-20x)
Early onset Alzheimer’s
IDIC 15
Characterized by presence of an extra, inverted duplicated isodicentric chromosome 15q, in addition to the 2 normal copies, resulting in partial trisomy of this region; characterized by Autism & seizures, NOT dysmorphic
Maternally inherited interstition duplication of 15q
Interstitial duplication of a region of 15q leads to partial trisomy for these genes; presentation is similar to IDIC 15 including autism and seizures, NOT dysmorphic
Paternal duplication of 15q show normal phenotype
Fragile X Syndrome
Caused by an expansion in the number (>200) of CGG repeats in the 5’ UTR of the FMR1 gene, causing excessive methylation of the promoter and failure to express the FMR1 protein; characterized by intellectual disability, dysmorphic features, autistic behavior
Demonstrates genetic anticipation through the maternal germ line
Acute Lymphoblastic Leukemia (ALL)
Caused by translocation between the TCF3 gene on chromosome 1 and the PBX1 gene on chromosome 19
Hyperdiploidy (>51 chromosomes) is associated with a good prognosis
Children with TPMT enzyme deficiency must be given 10% standard dose
Recurrence Risk for Down Syndrome caused by maternal nondisjunction
1/100 + age-related risk
Maturity onset diabetes of the young (MODY)
Beta cell destruction (characteristic of Type I) with later-onset presentation (characteristic of Type II)
Example of variable expressivity: Many individuals with mutations in the same codon exhibit widely varying age of diagnosis