Diseases Flashcards
Kleinfelter Syndrome
47, XXY Phenotypes: learning disability delayed speech reduced body hair INFERTILITY hypospadias gynecomasiatia "female" body type
Jacobs Syndrome
47, XYY Phenotypes: learning disability speech delay developmental and behavioral delays Autism spectrum affects males
Triple X Syndrome
47, XXX Phenotypes: learning disabilities delayed speech and motor seizures kidney issues affects females
Turner Syndrome
45, X0
Phenotypes:
-Cardiac: coarctation of aorta, bicuspid aortic valve
-Eyes: epicanthal folds, blue sclera
-Ear, Nose, Mouth: low set ears, micronathia
-Neck: web neck, cystic hydroma
-Chest: pectus excavatum, widely spaced nipples
Skeleton: cubitus valgus, short stature, short 4th MCP
Learning: difficulty in math, poor spacial and verbal skills
Other: INFERTILITY, urinary, vision and hearing, hypothyroidism, gonadal dysgenesis (results in PRIMARY AMENOHHREA)
PKU
Phenylketonuria
- Defect in PAH liver enzyme (Phe –> Tyr)
- Unable to break down phenylalanine
- Affects CNS development
- Phenotypes: hyperactivity, seizures, microcephaly, mental impairment
- Treatment: low-phenylalanine diet, BH4 supplement (for those with defect in BH4 cofactor)
- Test in neonates
PKU Maternal Effect
PKU women have increased risk of congenital malformation and mental impairment in offspring - regardless of child’s genotype
ATD
alpha 1-antitrypsin deficiency
- Results in decreased elastin
- alpha 1-antitrypsin inhibits action of elastase
- Elastase breaks down elastin
- ATD results in lack of elastase inhibition –> degradation of elastin in lungs –> alveolar wall damage –> emphysema
- More common in N. Europeans
ATD Alleles
1) Z allele: results in low alpha 1-antitrypsin = cause for majority of ATD
- misfolded protein also accumulates in liver = liver damage and failure
2) S allele:
- S/S genotype has 50% mL activity
- usually don’t express phenotype
Tay-Sach Disease
- Fatal genetic disorder in kids
- More prevalent in Ashkenazie Jews
- Lysosomal Storage Disorder
- Mut in HEXA gene –> defective Alpha Hex A Enzyme subunity –> defect in HexA enzyme
- Phenotypes: neuro deteriation (3-6mo), die age 2-4, muscle weakness, seizures, vegetative state, mental impairment
Sandhoff Disease
- Mut in HEXB gene –> defective beta Hex A subunit
- Results in defect in HexA and HexB enzyme activity
AB Variant TS
- Defect in GM2 activator protein
- HexA and HexB enzymes nml
- GM2 accumulates
Gaucher Disease
- Lysosomal Storage Disease
- Autosomal Recessive
- Type 1: non-neuropathic, poor growth and development, bone disease
- Type 2: severe neuropathic, lethal age 2
- Type 3: later onset, mildly neuropathic, visceral complications
Trisomy 21 General Info
- Due to unbalanced translocation between Chr 21 and another ACROCENTRIC chromosome
- Due to error in nondisjunction
- Increased risk w/ maternal age
Trisomy 21 Phenotypes
- midfacial hypoplasia: small face
- mild hypotonia
- upslanting palpebral fissures
- small ears
- large appearing tongue
- clinodactyly (incurving 5th finger)
- Transverse palmar crease
- Increased space between 1st + 2nd toes
Medical Problems Associated
with Trisomy 21
- Cardiac: in approx 50% DS pts, atrioventricular canal
- GI: esophageal atresia, hirschsprung’s, feeding problems, constipation, GERD, celiac
- Developmental: delayed gross motor development (from hypotonia), spectrum of intellectual disability, speech problems
- Early onset Alzheimer’s Disease
Prader-Willi Syndrome (PWS)
- Missing PATERNAL Chr 15q11-13
- maternal allele is silenced like nml
- Causes: deletion of paternal 15q, Uniparental Disomy (have 2 copies of maternal 15q), imprinting issue (body thinks have 2 copies of maternal allele)
PWS Phenotypes
- Severe Hypotonia
- cryptorchidism (undescended testicles)
- Dysmorphic features
- Almond shaped eyes
- Lighter pigmentation than relatives
- Obese: from feeding issues
Medical Issues with PWS
- Eyes: stabismus (lazy eye), nystagmus
- Ortho: scoliosis
- Respiratory: obstructive sleep apnea (from obesity) (contraindication for placing pt on growth hormones)
- Motor: delays in motor development due to severe hypotonia
- Developmental: mild to moderate cognitive disabilities
- Behavioral: violent and aggressive
Testing for PWS
- Methylation testing
- FISH: only if PWS is due to deletion of paternal allele
- Microarry
IDIC 15
- Inverted Duplicated Isodicentric 15q
- Anomaly of maternal 15q (same region as PWS)
- Due to recombination in which new char has both centromeres and acrocentric ends
- Phenotypes: autism, seizures, NOT dysmophic, hypotonia
Interstitial 15q Duplication
- Can result in dup or partial Trisomy
- If maternally derived: show phenotype
- If paternally derived: no phenotype
- Phenotype: similar to IDIC 15 (autism, sz, hypotonia, Not dysmorphic)
Angelman Syndrome
-Deletion of maternal 15q11-3 allele
Phenotype: mild facial dysmorphia, mild hypotonia (less than PWS), severe intellectual disability, seizures, Autism
Ways to Develop AS
- -Deletion of Maternal allele
- Paternal Uniparental Disomy
- Imprinting Defect: think have 2 paternal
- Specific Mutation: similar to del (UBE3A)
Testing for AS
- Microarray: detects classic deletion of maternal allele
- Methylation: detects paternal uniparental disomy and imprinting errors
- FISH?
Achondroplasia
- 100% penetrant!!
- Autosomal Dominant
- Mut in FGFR3 (regulates bone growth)
- Chr 4p
- Missense mut (aa substitution)
- Mut increases activity of FGFR3 so less bone production
- Paternal Age Effect
Phenotypes of Achondroplasia
- Small stature
- Proximal limb shortening
- short fingers
- Genu varum (bow legged)
- Trident hands
- Large head/frontal bossing
- Midfacial retrusion
- Small foramen magnum
Neurofibromatosis Type 1
- Autosomal Dominant
- Variable Expressivity
- Loss of Function mutation of NF1 (Neurofibromin Tumor suppressor Gene)
- On Chr 17q
- Phenotypes: cafe-au-lait spots, neurofibromas, plexiform neurofibromas, lisch nodules (eye freckles)
Tuberous Sclerosis
- Autosomal Dominant
- Variable Expressivity
- 1/3 inherited, 2/3 de novo
- 100% penetrant
- Locus heterogeneity
- Loss of Function Mutation
- Mut in TSC1 + 2 on Chr 9 + 16
- Regulates cell growth and development
- Phenotypes: lots
Osteogenesis Imperfecta Type 1
- AD
- Variable Expressivity
- Mut in COL1A1 on Chr 7
- Reduces collagen production (by 1/2)
- loss of function mutation
- Phenotypes: multiple fx, Blue Sclera, mild short stature, adult onset hearing loss
Marfan Syndrome
- AD
- Variable Expressivity
- Systemic connective tissue disorder
- Mut in FBN1 on Chr 15q
- Fribrilin misfolding (protein) - weakened extracellular matrix - decreased systemic structural integrity
- Phenotypes: aortic root enlargement, wrist and thumb sign, precuts excavatum
Huntington Disease
- AD
- Trinucleotide Repeate Disorder - CAG
- Anticipation
- Mut in HTT gene on Chr 4p
- Phenotype: progressive neurological degeneration, motor, cognitive, and psych disturbances
- 100% penetrant over certain # of trinucleotide repeats (>40)
Fragile X Syndrome
X-linked
- FMR1 gene mutation leads to hypermethylated FMR protein promoter
- TNR disorder - CGG
- Anticipation
- Maternal Transmission Bias: unstable when female w/ expansion has offspring, but not males
- Phenotype: intellectual disabilities, dysmorphic features, aggression, social anxiety, hand flapping/biting
Duchenne Muscular Dystrophy (DMD)
X-linked recessive
- Mut in DMD on Xp
- Large deletions
- nonsense (stop), framshift, deletions - cause truncated protein + loss of function
- Causes absence of dystrophin
- Males only
- Phenotype: proximal to distal progressive muscular weakness, calf hypertrophy, cardiomyopathy
- Onset prior age 5
- Wheelchair prior age 13
- Death in 30s
- Screening test: lying to standing
Hemophilia A
X-linked recessive
-Decreased blood clotting from deficiency in Factor 8
-Mut in F8 gene on Chr Xq
-Majority from 22A inversion
Phenotype: spontaneous bleeding, prolonged bleeding, delayed wound healing, excessive bruising
-Royal family
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
- Loss of function mutation
- AD
- Deletion of PMP22 gene
Nonsyndromic Deafness
- does not involve other systems
- Typically AR
- Mut in GJB2 gene - most common
Syndromic Deafness
- Includes other systems (than just ears)
- Intellectual disability, seizures, dysmorphic syndromes
Trisomy 18
- Edwards Syndrome
- Small gestational age, small head, clenched fingers, rocker-bottom feet, heart/brain abnormalities
- Tolerated aneuploidy - viable birth
Trisomy 13
- Patau Syndrome
- Characteristic faces, severe intellectual disabilities, congenital malformations, polydactyly, facial clefts, renal issues
