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Flashcards in Genetic Diorders/Inborn Metabolism Deck (63):
1

Uniparental disomy

instead of inheriting one gene/chromo from each parent, both parts are from one parent

2

Genomic imprinting

gene defect expressed solely based on sex of parent passing on defective gene
ie, mother passes on 11q abnormality of chromo 15- Angelman, but w/ father, Prader-will. (Paternal prader willi)

3

Abnormal Morpho

Malformation- intrinsincally abnormal process forms abnormal tissue (bladder extrophy b/c infraumb mesenchyme doesn't migrate)
Deformation- mech forces on normal tissue => abnormal
Disruption- normal tissue becomes abnormal after destructive forces (ischemia, hypoxia)
Syndrome- unrelated abnormal features in a familiar patter

4

Maternal serum markers

AFP- elevated with NTDs, twins, underestimated GA, ab wall defect, fetal emise, fetal edema condictions. Low = overest GA, trisomy 21 and 18, IUGR
Triple marker = AFT, estriol, BHCG- all low= 18, low low high = downs

5

Genetic fetus eval

CVS- at 10-13weeks, can do karyotyping, DNA extract, enzyme analyses
Amnio- cells lsoughed off 16-18 weeks
PUBS- sample of fetal blood, look fo rmee abnormal, genetic disorders, infec, acidosis, or transfuse fetus

6

Marfans

Auto dom, Ocular, CV, skeletal, Chromos 15 for fibrillin
Clin- tall, elongated extremities/fingers, scoliosis/kyphosis, decreased upper to lower seg ratio (shorter torso)
Dx- clinical findings, but distinguish from homocystinuria w/ screening test. Upward lens sublux, retinal detach, aortic root dilatation, MV prolapse, mitral regurge
Compx- endocarditis, retinal detachment, sudden death from aortic dissection- HTN/chest trauma increase dissection risk, reduce w/ B block and avoid contact sports
Endocarditis prophylaxis + regular optho evals

7

Prader-Willi

Genomic imprinting, absence of a region on the paternally derived chromosome 15
Fx- almond eyes, fishlike mouth, FTT, feeding struggz in year 1, obesity from hyperphagia later, short stature/small hands/feet
Neuro- hypotonia in new born, mental retardation, learning disab, bheavioral problems, hypogonadism
Dx- FISH chormo deletion
Compx- poor sucking/feeding probs, then in childhood, OSA, in adulthood, cvd and t2dm + pscyh illness

8

Angelman

Happy puppet (puppety gait and smiling kid)
Imprtining- deletion on chromo 15 MATERNAL
Clin- jerky arm mvt, ataxia, inapropro laughing, mental retardation + speech delay. craniofac = small wide head, large mouth/wide spaced teeth, tongue protrusion, prognathia. blond hair/pale blue dep set eyes
Dx- FISH

9

Noonan

Sporadic or maybe auto dom, chromo 12. mainly males, but maybe females too!
Clin- short stature, shied chest, web neck, low hairline, hypertelorism (wide set eyes), epicanthal skin folds, downslant palpebral fissures, low ears.
RIGHT sided heart lesions, PUlm VALVE stenosis (turners has left)
Dx= clin features

10

DiGeorge

22q11 deletion- CATCH-22
Cardiac, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, gene defect 22. Sporadic and autodom
Digeorge = short palpebral fissures, small chin, ear anomalies, aortic arch anomalies, VSD, tet of fallot. thymus/parathyroid issue => immunodef + severe hypocalc
Dx w/ FISH
Compx- infections from cell med immunodef and seizures (hypocal)

11

Velocardiofacial

cleft palate, wide prom nose + squared nasal root, short chin, fish mouth, cardiac = VSD and R sided aortic arch, neonate hypotonia, learning disab, perseverative behaviors
Dx= fish probes

12

Ehlers Danlos

Defective type V collagen => hyperextensible joints + frag vessels + loose skin, auto dom
Clin = hyperextensible => joint disloc + scoiosis, velvety loose skin, paper thin scars, large wounds, mv prolapse, aortc root dil, frag blood vessels. GI = constipation, rectal prolapse, hernias
Dx clinically, compx = aortic dissection _ GI bleeds form blood fragility

13

Osteogenesis Imperfecta

Abnormal type I collagen. Four types, here is type I
-blue sclerae, fragile bones => frequent fractures, genu valgum (knock knees), scoliosis/kyphosis, joint lax, osteoperosis/penia, yellow/gra/blue teeth, easy bruisng
Dx = clin fx + decreased type I collagen synth in fibroblasts
Compx = early conductive hearing loss, skeletal defomrities

14

VACTERL

Sporadic group of malform
Vertebral defects, anal atresia, Cards anomalies (VSD), TE (fistula0, Renal (and genital), limb defects (radial hypoplasia, syndactyly, polydactyly)
Dx on features

15

CHARGE association

Colobomas of retina, impaired vision
Heart defects (tet of fallot)
Atreasia (of nasal chonae)
Retardation of growth/cognition
Genital anomalies (hypoplasia)
Ear anomalies (cup shaped ears, hearing loss)
Dx on fx

16

Williams syndrome

Deletion on chromo 7, gene for elasti, auto dom
Cocktail party personality, elfin facies, short palpebral fissues, flat nasal bridge, round cheeks, mental retard, loquacious personality, supravalvular aortic stenosis, idiopathic hyperca, connective tissue abnormal (hoarse voice/hernias)
DX w/ FISH probes

17

Cornelia de Lange (Brachmann)

Single eyebrow, short stature, no skeletal abnormal, sporadic inheritance, maybe auto dom
Clin- SGA< FTT, synophrys, long curly eyelashes, microceph, thin down turned upper lip, micrognathia, HYPERtonia, mental retardation, small hands/feet, heart defects, autism, SELF-detructive, no facial expression
dx = clin fx

18

Russel Silver

Sporadic inheritance
Short stature/skel asymm/normal head circ
Clin fx- SGA, triangular face, prom forehead, downturned mouth, head looks large but isn't
Skel findings = short stature, limb asymm, cafe au lait, excessive sweat
On clin fx

19

Pierre Robin

Micrognathia, cleft lip/palate, large protruding tongue
Dx on clin fx
Compx = recurrent OM< upper airway obstruction needing tracheostomy

20

Cri du Chat

Partial deletion of short arm chromo 5
Clin fx = slwo growth, microceph, mental retardation, hypertelorism, downslanting palpebral fissures, catlike cry
Dx on chromo deletion/presence of clin fx

21

Down Syndrome

Trisomy 21, most common trisomy
AMA, increased nondisjunction in ovum
1:600 live births
Clin fx = brachyceph, epicantahl skin folds, upslant fissures, speckled irises, protruding tongue, hypotonia, mr, single palmar crease, flip flop spot, clinodactyly, duod atresia, hirschprung, omphalo, pyloric sten, endocardial cushion
Compx- atlanto axial cervical spine instab, leukemia, celiac disease (IgA/anti-endomysium antibody), early alzhemier's, OSA< conductive hearing oss, hypothyroidism, cataracts, glaucoma, refrac errors :(

22

Trisomy 18

Second most common, 3x more common in females
Clin fx- MR, hypertonia, scissoring lower extremities, delicate small face, clenched hands, overlapping digits, ROCKER bottom feet, dorsiflexed big toes
Dx- chromo analysis
prog- 95% die in first year :(

23

Trisomy 13

MIdline defects- holopropsencephaly, microceph, seizure, severe MR
Microphthalmia, retinal dysplasia, colobomas, Single ey, cleft lip palate
Dx- chromo analysis, prog - death in first months of life

24

Turners

Only one X- 1;2000
Clin- short stature, web neck, shield chest (scoliosis/kyphosis), swelling dorsum hands/feet, ovarian dysgenesis- pubertal delay, L sided heart lesions, coarctation of the aorta, bicuspid aortic valve, hypoplastic L heart, hypothyroidism
Dx- clin features, chromo analysis

25

Fragile X

X-linked disorder on X chromo, CGG repeats, anticipation
More severe in males, MR in females (1;1.25K males, , i in 2.5K females)
MOST COMMON FORM OF INHERITED MR
Clin- severe to mild mr, large ears, macrocephaly, thickened nasal bridge, blue irises, large testes in puberty
Behavioral 0- emotional instability, autistic, ADHD
Dx- chromo

26

Klinefelter

Most common cause of male hypogonadism/infert, 1 in 500, XXY, AMA risk
Tall, long extremeities,, hypogonad, delayed puberty (lack of testosterone), gynecomastia, variable intelligence, antisocial, excessive shy/agressive
Dx- chromosomal analysis

27

Skeletal dysplasia classification

Location of bone!
Rhizomelia- prox long bone abnormal (short humerus/femur)
Mesomelia (medial long bone abnormal)
Aromelia (distal abnormal/small hands/feet)
Spondylodysplasia = abnormal spine, w/wout limb issues

28

Achondroplasia

Most common, rhizomelia, autosomal dom or sporadic
Fibroblast growth factor receptor gene 3
Cin- megalencephaly, foramen mag stenosis, frontal bossing, midface hypoplasia, low nasal brige
Skel- lumbar kyphosis, lumbar lordosis later in childhood/adulthood. Rhizomelic limb shortening/bowed legs/joint hyperextensibility, trident shaped hands
Recurrent otitis media
COMPX- hydrocephalus/cord compression, monitor head circ closely. SIDS from cord compression. OSA from FM narrow, ortho problems (genu varum/back pain)

29

Potter syndrome

Severe oligohydramnios => lung hypoplasia/fetal compression w/ limb abnormal + Potter facies
Why? chronic AF leak or IU renal failure or bilat renal agenesis, PCKD, obstructive uropathy

30

Amniotic band syndrome/rupture sequence

Fluid leaks due to intrauterine constraint, small strands from amnion wrap around fetus => limb scarring/amputation

31

Fetal Alcohol Syndrome

Most common teratogen, if woman binges in prego
SGA, FTT, microceph, long smooth philtrum, thin smooth upper lip, MR, ADHD, cardiac defect (VSD)

32

Teratogens!

cigarettes- SGA, polycythemia
cocaine- IUGR, microceph, GU tract
DES- cervical carcinoma, GU anomalies
Isotretonin- CNS malform, microtia, cardiac defect, small thymus
Propylthiouracil- hypothy and goiter
Thalidomide- phocomelia (malformed flipper appendages)
Valproid acid- narrow head, high forehad, mid face hypoplasia, spina bifida, cardiac defects, convex nails
Warfarin- hypoplastic nose, deep groove beween nasal alae and tip, stippled epiphyses, hypoplastic nails

33

Fetal phenytoin syndrome

Mild/mod MR, cardiac, GR, nail/digit weird, facial features
Pregnant women w/ seizure- do i take anticonvulsants or have a seizure?

34

Why an NTD?

Most common congen anomaluy of CNS
multifactorial, includes nutrition, genetic predispo, drugs radiation exposure
GIve folic acid 400-800 ug/day

35

Congenital Heart disease

Recurrence risk increases w/ each child affected from 1% gen pop rate
Why ? syndromes, drugs, maternal disease, genetic inheritance

36

IEM

overall incidence 1:5K births, most autosomal recessive, some x-linked, some spont
Suspect if- acutely ill kid dnr to tx, unexplained seizures, developmental delay, prog neuro degen, recurrent/persistent vom, FTT, wierd lab values
Onset- acute severe neonatal illness = CLASSIC, or recurrent intermittent episodes @ stressful times, or chronic/progressive if mitochondrial
Fam hx suspicious if neonatal deaths, related parents, MR, weird diet preferences. SEPSIS is more common!!!

37

MGMT of IEM

Assess for mets acidosis/ammonia
then provide energy w/ IV glucose, prevent exposure to offending substance (give lipids if a protein issue, etc)
then correct acidosis w/ bicarb
give sodium benzoate/sodium phenylacetate increase ammonia excretion
Oral neosporin/lactulose = no ammonia production in colon
Dialysis if other interventions fail!

38

Clin fx of IEM generally

Lethargy/coma, FTT, poor feeding, intractable hiccups,
Odors- Mousey/musty = PKU, maple syrup, rotten cabbage = tyrosinemia, sweaty feed = isovaleric/glutaric acidemia
Neuro- hyper/hyptonia, ? developmental delay/seizuresEyes - cherry red macula, cataracts, or corneal clouding
GI- vom w/ mets acidosis to raise suspicion b/c excessive vom causes mets alk. hepatomeg
Mets- hypoglycemia w/ ketosis, high urea, urinary ketones always BAD
Plasma NH3 for urea cycle defects

39

Homocystinuria

cystathionine synthase deficiency- auto recessive
Kinda like marfans but normal length fingers (no arachnodactyly), and DOWNward lens sublux, hyperocag state (more stroke/MI/dvt), CV issues w/ mitral/aortic regurg, NO aortic dilation, scoliosis/large stiff joins, dd, milkd MR, psych illness
dx- increased methionine in urine/plasma or positive urine Cyanide NP test
MGMT = methionine restricted diet, aspiring for thromboembo risk, folic acid/vit B supplementation

40

Transient tyrosinemia of newborn

In babies getting high protein diets
Clin fx- first 2 weeks of life, poor feeding/lethargy, maybe asx
dx- elevated serum tyrosine/phenylalanine
mgmt- decrease protein in acute episode, vitamin c to elim tyrosine
Prog- self-lim disease, resolves in 1 month

41

PKU

auto recessive
dd, hypotonia, musty/mousy odor, progressive MR, eczema, light eyes/hair, milk PKU w/ hyperactivity
dx- phenlyal: tyrosine ration high
MGMt- restrict diet
prog- near normal if diet restriction at less than one month

42

MSUD

maple syrup odor in urine
auto receissve
prog vom/poor feeding
lethargy/coma, hypotonia, evelopmental delay
Increased serum/urine branched-chain AAs
do dietary protein restriction, if before 2 WOL, avert neuro damage

43

Tyrosinemia Type I

Autosomoal recessive
Episodes of periph neuro, chronic liver disease, odor of rotten fish/cabbage odor, renal tub disfunction
Dx- succinylacetone in urine
Dietary restric phenylalnine, tyrosine, NTBC, liver trans
Prog- death by one year if disease in infancy, up risk HCC/cirrhosis

44

Cystinuria

Recessive, defect in renal reabsorb of cystine/lysine/arginine/ornithin => renal stones
Back pain, UTI, dysuria, urgency/frequency

45

Hartnup disease

Autosomal recessive- defect in transport of neutral AAs
most asx, some w/ intermittent ataxia, photosensitive rash, MR, emotional lability

46

Urea cycle defect

Defect manifested w/ elevated Ammonia > 200 uM,
toxic to brain/liver, sx of poor feeding, hypervent, behavioral change, seizures, ataxia, coma
Transient hyperammon = self-lim in first 24-48 hrs, nonspecific resp distress, alk, vom, lethargy, coma, aggressive TX

47

OTC deficiency

MOST COMMON UREA CYCLE DEFECT
x-linked recessive, males severely affected
clin fx- onset of protein ingestion/include vom/lethargy => coma
Females may have cyclic vom and intermittent ataxia
Dx = based on elevated urine orotic acid, down serum citrulline, increased orntihine, livr biopsy
MGMT - low pro diet, mgmt hyperammon, mayb need liver transplant :(
prog- dep on neur sequelae of hyperammonemic episode,recurrent common

48

Galactosemia

Recessive, galactose-1-phosph ut def- any baby w/ hepatomeg + hypogly
clin = after newborn starts drinking formula or breastfeeds, vom/diarrhea, FTT, hepatic dysfn/hepatomeg, oily cataracts, RTA
Dx- nonglucose reducing substance in urine, Clinitest, confirm enzyme def in RBCs, prenatal/newb screen
MGMT - galactose free diet (soy/elemental formula)
Prog = good if treated early, MR if late, ALL females w/ ovarian failure, death in infancy from E. coli sepsis if untreated

49

Hereditary Fructose Intolerance

Fructose-1-phosphate aldolase B deficiency
Begins in infancy after introducing fruit/fruit juice Sx- severe hypogly, vom, diarrhea, FTT, seizures
MGMT = avoid fructose, scurose, sorbitol

50

Glycogen Storage Diseases

GSD- organomegaly + mets acidosis
GSD1= von gierke's- G6pD deficiency, pres w/ persistent hypogly, hepatomeg, mets acid, hyperTG, big kidneys
mgmt w/ frequent feeding high complex carb diet, risk of HCC
GSD2 = pompe's- alpha glucosidase def- infant w/ musc weakness + cardiomeg, first 2 weeks of life, flaccid weakness, poor feed, prog big heart, hepatomeg, acidosis

51

Fatty Acid Ox Defects

Present during acute illness/fasting when fatty acids normally used as energy source
Get nonketotic hypogly, hyperammon, myopathy, cardiomyo
Middle chain acyl-coadh def (MDH) most common
do mass spec, see high plasma MCFA
Feed high carb low fat diet + carnitine supplemnt

52

Mito disorders

If atypical presentation or disease w/ 3+ organ systems
Kearns-Sayre = opthalmoplegia, pig degen of retina, hearing loss, hart block, neuro degen
MELAS- mitochon enceph, lactic acidosis, strokelike episodes
need tissue biopsy revealing abnormal mitochondira

53

Tay-Sachs

Autosomal recessive, hexosaminidase A- Jewish
Infantile = early infancy, down eye contact, hypotonia, mild motor weakness, increased startle (hyperacusis), macroceph, cherry red macula, severe dd, prog blind/seizures
Juvenile = after 2 years, ataxia, dysarthria, chereoathetosis, (normal eye)
prog- infantile, untx, death by age 4, jevinle/adult = poor prog to chronic debil state

54

Gaucher

Glucocerebrosidase deficiency- MOST COMMON gangliosidosis
autosomal recessive
HSM, TCP, Erlenmyer flask shaped distal femur
mortality by age 4 if in infancy. give enzyme replacement

55

Niemann Pick

Sphingomyelinase deficiency, by 6 mo age presents w/ prog neurodegn, ataxia, seziures, HSM, cherry red macula, death by age 4 too

56

Metachromatic leukodystrophy

Neurdegen from arylsulfatase A deficiency
Presenting feature s= ataxia/seizure/progressive MR
Death by 10-20 years :(

57

Mucopolysaccharidoses

Lysosomal storage disorder glucosaminoglycans acumulate
Organomegaly, short stature, MR, skel issue (dysostosis multiplex, bony thick cranium, J sella turcica, beaky vertebrae, thick clav, oar ribs)

58

Hurler

aLiduronidase def = most severe, autosomal recessive
After 1 year of age, see dd, HSM, kyphosis, coarsening facial fx, frontal boss, corneal clouding, stiff joints, wide nose bridge
dx= dermatam/heparan sulfates in urine + decrease enzyme activity in leuko/fibroblasts
Mgmt = early bone marrow transplant (prevent nuerodegen)
poor prognosis, death by 10-15 yo

59

Hunter

x-linked recessive, no corneal clouding

instead- HSM, hearing loss, progressively contracted joints, small papules over shoulder, scapula, lower back, dysotosis multiplex
Hunter needs sharp eyes, NO CLOUDING
dx= same, no tx, mortality by 20

60

Other weirdos

Sanfilippo- recessive, rapid/severe mental/motor retardation
MOrquio- MR absent!!! Severe scoliosis + cor pulmonale, death by 40

61

Porphyrias

Elevated serum porphyrins, lead to photosensitivty + neuro/ab sx, AIP = classic
Clin fx- episodic, precip by drugs (etoh, sulfa, ocp),, hormones, poor nutrition
Neuro = personality changes, emotional lability, paresthesias, weakness
GI = colicky ab pain, vom, constipation, like acute ab
Autonomic instab => tachy, htn, sweat, fever
Dark burgundy urine
Dx = increased erum/urine prophobilinogen
MGMT = IV glucose/correction of electrolyte abnormalities/avoid fasting/drugs

62

Wilson's

Autorecessive defect in copper excretion, stuck in liver, brain, eyes, heart
Clin fx- kayser-fleiscer rings in cornea, neuro = behavior change, dystonia, dysarthria, tremors, atax, seizures
Liver dysfn
Dx- decreased serum ceruloplasmin = screening, elevated serum/urine copper, liver biopsy w/ copper deposition in hepatos
MGMT = avoid nuts, liver, shellfish, chocolate, chelate w/ oral peniciliamine/zinc salts/liver transplant

63

Menkes kinky-hair disease

x-linked recessive, abnormal copper transport
affected pts = lower serum copper (opp of wilsons)
Clin fx in first few months- myoclonic seizures, pale kinky firable hair, optive nerve atrophy, severe MR, early death, degen neuro
Dx - hair and low serum ceruloplasmin/copper