Repro Exam 1: Genetic Fact Sheets 8-13

Front 1

PKU is an ___ caused by significnatly ___ activity of the liver enzyme ___, resulting in increased blood levels of the amino acid ___.

Back 1

PKU is an INBORN ERROR OF METABOLISM caused by DECREASED activity of PHENYLALANINE HYDROXYLASE, resulting in increased blood levels of PHENYLALANINE

Front 2

true or false: hyperphenylalanemia = PKU

Back 2

false. ~1-2% of infants w/hyperphenylalanemia will have impaired synthesis or recycling of tetrahydobiopterin (BH4), a necessary cofactor for phenylalanine hydroxylase

Front 3

clinical features of PKU

Back 3

untreated --> severe MR, seizures, ++ irritability, musty odor, eczema

Front 4

if PKU is treated well early, then what?

Back 4

can be totally normal, BUT elevated phenylal levels in older children and adults w/PKU also put them at risk for behavioral and learning problems

Front 5

incidence of PKU

Back 5

1/15,000-1/20,000 in general US, more common in those of n. european ancestry

Front 6

inheritance of PKU

Back 6

autosomal recessive, variable expression (due to varying levels of enzyme activity and other stuff)

Front 7

what's the mutation in PKU?

Back 7

allelic heterogeneity (>500 mutations in phenylalanine hydroxylase gene), chromosome 12q23 is phenylal hydroxylase gene. most affected individuals are COMPOUND HETEROZYGOTES.

Front 8

lab tests for PKU

Back 8

blood phenylalanine levels from samples in newborn nursery (in all states) --> can be detected in blood obtained at least 24 h after birth, occasionally false +s are seen. carrier testing by molecular analysis when mutations have been identified in the proband. prenatal dx possible if mutations are known. in any neonate dx'ed w/hyperphenylalanemia, screen for BH4 deficiency

Front 9

management of PKU

Back 9

MR can be prevented if tx is initiated <4 wk.s of age w/special individualized diet low in phenylalanine --> lifelong diet w/metabolic formula and measured amounts of other stuff including low protein foods. blood phenylalanine levels obtained weekly (target: 120-480 micromoles/L). frequent adjustments necessary depending on growth, sickness, tolerance, etc.

Front 10

counseling issues

Back 10

it's imperative that women keep phenylalanine w/in strict limits (120-360 micromoles/L) during all of pregnancy --> very high risk for IUGR, microcephaly, MR, etc. b/c phenylalanine is potent teratogen. (maternal PKU is big problem for pregnancy)

Front 11

clinical features of MCAD deficiency

Back 11

presentation: hypoketotic hypoglycemia, vomiting and lethargy, triggered by prolonged fasting or intercurrent illness. most cases of decompensation occur by 5yo. episodes may be accompanied by hepatomegaly, acute liver dz, seizures. can progress to coma and death

Front 12

how do you treat MCAD deficiency acutely?

Back 12

IV glucose.

Front 13

MCAD deficiency is an ___ caused by significantly ___ activity of 1 of the enzymes involved in the pathway of ___, resulting in accumulation of ___.

Back 13

MCAD deficiency is an INBORN ERROR OF METABOLISM caused by DECREASED activity of an enzyme in the MITOCHONDRIAL FATTY ACID OXIDATION pathway, resulting in accumulation of MEDIUM CHAIN FATTY ACIDS

Front 14

incidence of MCAD deficiency

Back 14

1/10,000, N. european descent

Front 15

inheritance of MCAD deficiency

Back 15

autosomal recessive. variable age of onset (due to environmental factors)

Front 16

mutations in MCAD deficiency

Back 16

changes in the ACADM gene (acyl cyoenzyme A dehydrogenase) located on chr. 1p31. K304E most common mutation, >45 alleles identified

Front 17

lab tests for MCAD deficiency

Back 17

central newborn screening lab measures acylcarnitine species by tandem mass spectrometry. low false +, low false - on full term infants. carrier testing available if familial mutations known, prenatal dx possible if familial mutations known.

Front 18

management of MCAD def.

Back 18

prevention of symptoms --> avoid being in catabolic state (manage illness, no fasting, prompt hospitalization during acute metabolic decompensation). otherwise, prognosis is excellent. screen siblings.

Front 19

clinical features of marfan syndrome

Back 19

cardiovascular (aortic root dilation, dissection of ascending aorta, MVP, dilation of pulm art), ocular (dislocated lenses, myopia, detached retina, glaucoma, cataracts), skeletal (tall w/arachnodactyly, flat feet, joint laxity), typical facies, dental crowding, high arched palate...

Front 20

incidence of marfan syndrome

Back 20

1/10,000

Front 21

inheritance of marfan

Back 21

autosomal dominant. variable expression. 25% new mutations

Front 22

mutations in marfan

Back 22

allelic heterogeneity. mutations w/in the FBN1 gene on chromosome 15q21 --> protein affected: fibrillin

Front 23

lab tests for marfan

Back 23

dx based on clinical features + family hx (highest weight given to aortic root dilation/dissection and/or ectopia lentis). genetic testing by mutation scanning and sequence analysis detects ~70-93%. note: a FBN1 mutation in itself does NOT confer dx --> need the phenotype

Front 24

management of marfan syndrome

Back 24

cardiac features are life-threatening --> lifelong follow up, often need surgery + pharm (e.g., beta-blockers). monitor skeletal abnormalities. annual ophtho exams

Front 25

counseling of marfan

Back 25

education. no contact sports/strenuous exercise. pregnant women need high risk OB and cardiac management b/c of risk of aortic dissection

Front 26

clinical features of congenital deafness

Back 26

defined by type (conductive/sensorineural/mixed), severity (mild: 26-40, mod: 41-55, severe: 56-90, profound: 90dB), unilat v. b/l, pre v. post lingual, frequencies affected, progressive v. stable

Front 27

incidence of congenital deafness

Back 27

1/500

Front 28

carrier frequency for GJB2 (connexin 26) mutation. what does this cause?

Back 28

1/33. leads to congenital deafness.

Front 29

inheritance of congen deafness

Back 29

environmental factors 40%, genetic causes 60%. of genetic causes, 30% are syndromic (>400 syndromes, all patterns of inheritance), 70% are non-syndromic (usually AR, can be AD, rarely X-linked or mt).

Front 30

what are the most common syndromic AD mutations (and genes) that cause congenital deafness?

Back 30

waardenburg syndrome --> PAX3, MITF. branchio-oto-renal (BOR) syndrome --> EYA1

Front 31

what are the most common syndromic AR mutations that cause congenital deafness?

Back 31

pendred syndrome (SLC26A4 mutations), Usher syndrome (heterogeneous)

Front 32

what is the most common non-syndromic causes of congenital deafness?

Back 32

DFNB1 (autosomal recessive, includes GJB2 and GJB6 genes, proteins connexin 26 and 30). other common non-syndromic mutations are DFNA (AD), DFN (x-linked), and A1555G mitochondrial mutation (predisposes to deafness w/exposure to aminoglycosides)

Front 33

waardenburg syndrome

Back 33

congen deafness, telecanthus and pigmentary dysplasia of irises, hair, and skin. (PAX3, MITF)

Front 34

BOR syndrome

Back 34

branchio-oto-renal --> congen deafness, branchial cysts, preauricular pits, abnormal ears, renal abnormalities (EYA1)

Front 35

pendred syndrome

Back 35

dysplastic cochlea, enlarged vestibular aqueducts, vestibular symptoms, euthyroid goiter (SLC26A4)

Front 36

usher syndrome

Back 36

retinitis pigmentosa, congen deafness

Front 37

lab tests for congen deafness

Back 37

newborn hearing screen, needs confirmation by ABR and audiometry. standard w/u includes testing for connexin mutations and CMV, EKG (look for long QT syndrome), temporal bone imaging, ophtho, renal US, genetic eval and counseling. specific gene testing if syndromic.

Front 38

if non-syndromic deafness is suspected w/o family hx, what should you test?

Back 38

blood spots for CMV and GJB2/6 testing. GJB2 testing best done by sequencing. if hx of IV aminoglycoside exposure, test for A1555G mitochondrial mutation

Front 39

management of congenital deafness

Back 39

confirm by ENT w/further assessment. talk about hearing aids, vibrotactile devices, cochlear implants. start speech tx. ? sign language. ? genetic eval of family. ? other specialties for syndromes. if enlarged vestib. aqueducts, need to be counseled about avoiding head trauma (i mean, you'd think everyone should avoid that, but...)

Front 40

counseling of congen deafness

Back 40

diagnostic/carrier testing offered if mutations known. if no specific dx or inheritance pattern can be est'd, couple may still have ++ risk of recurrence. (est. to be ~14% even if neg. for GJB2/6 mutations). be sensitive about Deaf culture, even w/hearing parents

Front 41

diagnosis of neurofibromatosis type 1 requires at least 2 of these sx:

Back 41

6+ cafe au lait spots, 2+ neurofibromas/1 plexiform neurofibroma, axillary or groin freckling, optic glioma, 2+ lisch nodules, distinctive bony lesion (e.g., sphenoid dysplasia), 1st degree relative w/NF1 by independent diagnostic criteria

Front 42

clinical features of NF1

Back 42

progresses w/age. children may only have cafe au lait spots. lisch nodules and cutaneous fibromas develop late childhood-adulthood. plexiform neurofibromas are congenital. increased risk for learning problems (40-60%), seizures, HTN (renal artery stenosis, pheochromocytoma), malignant neoplasms

Front 43

incidence of NF1

Back 43

1/3000

Front 44

inheritance of NF1

Back 44

autosomal dominant, variable expression, nearly complete penetrance. 50% are new mutations

Front 45

mutations in NF1

Back 45

allelic heterogeneity, NF1 gene chromosome 17q, protein is neurofibromin

Front 46

lab tests for NF1

Back 46

dx depends on clinical features and family hx. NF1 mutation analysis has multi-step protocol including protein truncation testing, sequencing, FISH, southern blotting --> combined, detects up to 95% of mutations in patients that meet clinical criteria. (sequencing alone detects up to 89%).

Front 47

management of neurofibromatosis 1

Back 47

complications increase w/age. severe MR is evident early, opic gliomas and progressive scoliosis occur in childhood (if ever), plexiform neurofibromas before adulthood. need developmental assessment, ophtho, HTN monitoring, pain and h/a monitoring.

Front 48

true or false: generally, surgical removal of neurofibromas are not recommended

Back 48

TRUE. (exception: compromising essential organ - duh)

Front 49

counseling of NF1

Back 49

genetic risks (AD). ~50% have mild manifestations, 30% have severe complications. intrafamilial variability is common. 1st degree relatives should be examined. prenatal dx possible but does not predict severity (poor phenotype-genotype correlation). puberty and pregnancy assoc. w/increase in size and # of neurofibromas

Front 50

clinical features of mitochondrial disorders

Back 50

heterogeneous, characterized by multi-system disease. preferentially affects tissues w/high energy requirements (brain, nerves, cardiac, special senses, GI, endocrine, renal...). think mitochondrial if an individual has 3 systems involved. can present at any age (infancy-adulthood). d/os are typically progressive, course often unpredictable

Front 51

incidence of mitochondrial disorders

Back 51

1/5000-1/10,000. may be underdiagnosed (variability in presentation, difficult to dx)

Front 52

inheritance of mitochondrial d/o

Back 52

can be caused by defects of nuclear DNA (can be AR, AD, or X-linked) or of mitochondrial DNA (maternal inheritance)

Front 53

what is complicated about mitochondrial inheritance?

Back 53

maternal inheritance can be complicated by heteroplasmy --> presence of >1 type of mitochondrial DNA in mitochondria of an individual. also see the threshold effect --> level of mutated mtDNA required before function is compromised and clinical sx become apparent can vary b/w individuals, tissue types, and specific mtDNA mutations

Front 54

what is the most common way to inherit a mitochondrial d/o?

Back 54

nuclear gene defects inherited through autosomal recessive pattern

Front 55

mutations in mitochondrial d/o

Back 55

~1500 genes involved in mt function, but only 37 are coded by mdDNA. the most common nuclear DNA gene affected is POLG1

Front 56

what are the usual types of mutations in mitochondrial DNA? (e.g., SNPs, deletions...)

Back 56

deletions are typically de novo. duplications and point mutations of mtDNA are more commonly maternally inherited

Front 57

lab tests of mitochondrial d/o

Back 57

if clinical picture is characteristic of a specific mitochondrial d/o, the dx can be confirmed by molecular genetic testing. if mitochondrial dz is suspected, you may need family hx, blood and/or CSF lactate levels, neuroimaging, cardiac evals, muscle bx, molecular genetic testing to confirm dx

Front 58

counseling issues for mitochondrial d/os

Back 58

sx amont family members are variable. mitochondrial genetic bottleneck causes variability in siblings

Front 59

mitochondrial genetic bottleneck

Back 59

reduction of mtDNA molecules w/in developing oocytes before subsequent amplification of mitochondrial seen in mature oocytes --> can affect the % of mutant v. normal mitochondria