Genetic Diorders/Inborn Metabolism

Question 1

Uniparental disomy

Answer 1

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

Question 2

Genomic imprinting

Answer 2

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)

Question 3

Abnormal Morpho

Answer 3

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

Question 4

Maternal serum markers

Answer 4

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

Question 5

Genetic fetus eval

Answer 5

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

Question 6

Marfans

Answer 6

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

Question 7

Prader-Willi

Answer 7

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

Question 8

Angelman

Answer 8

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

Question 9

Noonan

Answer 9

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

Question 10

DiGeorge

Answer 10

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)

Question 11

Velocardiofacial

Answer 11

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

Question 12

Ehlers Danlos

Answer 12

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

Question 13

Osteogenesis Imperfecta

Answer 13

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

Question 14

VACTERL

Answer 14

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

Question 15

CHARGE association

Answer 15

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

Question 16

Williams syndrome

Answer 16

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

Question 17

Cornelia de Lange (Brachmann)

Answer 17

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

Question 18

Russel Silver

Answer 18

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

Question 19

Pierre Robin

Answer 19

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

Question 20

Cri du Chat

Answer 20

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

Question 21

Down Syndrome

Answer 21

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 :(

Question 22

Trisomy 18

Answer 22

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 :(

Question 23

Trisomy 13

Answer 23

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

Question 24

Turners

Answer 24

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

Question 25

Fragile X

Answer 25

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

Question 26

Klinefelter

Answer 26

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

Question 27

Skeletal dysplasia classification

Answer 27

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

Question 28

Achondroplasia

Answer 28

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)

Question 29

Potter syndrome

Answer 29

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

Question 30

Amniotic band syndrome/rupture sequence

Answer 30

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

Question 31

Fetal Alcohol Syndrome

Answer 31

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

Question 32

Teratogens!

Answer 32

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

Question 33

Fetal phenytoin syndrome

Answer 33

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

Question 34

Why an NTD?

Answer 34

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

Question 35

Congenital Heart disease

Answer 35

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

Question 36

IEM

Answer 36

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!!!

Question 37

MGMT of IEM

Answer 37

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!

Question 38

Clin fx of IEM generally

Answer 38

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

Question 39

Homocystinuria

Answer 39

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

Question 40

Transient tyrosinemia of newborn

Answer 40

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

Question 41

PKU

Answer 41

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

Question 42

MSUD

Answer 42

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

Question 43

Tyrosinemia Type I

Answer 43

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

Question 44

Cystinuria

Answer 44

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

Question 45

Hartnup disease

Answer 45

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

Question 46

Urea cycle defect

Answer 46

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

Question 47

OTC deficiency

Answer 47

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

Question 48

Galactosemia

Answer 48

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

Question 49

Hereditary Fructose Intolerance

Answer 49

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

Question 50

Glycogen Storage Diseases

Answer 50

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

Question 51

Fatty Acid Ox Defects

Answer 51

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

Question 52

Mito disorders

Answer 52

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

Question 53

Tay-Sachs

Answer 53

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

Question 54

Gaucher

Answer 54

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

Question 55

Niemann Pick

Answer 55

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

Question 56

Metachromatic leukodystrophy

Answer 56

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

Question 57

Mucopolysaccharidoses

Answer 57

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)

Question 58

Hurler

Answer 58

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

Question 59

Hunter

Answer 59

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

Question 60

Other weirdos

Answer 60

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

Question 61

Porphyrias

Answer 61

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

Question 62

Wilson's

Answer 62

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

Question 63

Menkes kinky-hair disease

Answer 63

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