Genetic disorders and inborn errors of metabolism Flashcards
genomic imprinting
expressed solely based on sex of parent passing on defective gene ~ 11q of 15 -> angel man or trader-willi
maternal markers
alpha feto protein- incr with neural tube defects, multi gestation, fetal demise, underestimated gestational age, ventral abd wall defects
triple marker: nAFP, unconguated estriol, beta-HCG. down= low AFP, low estriol, high beta-hcg. all 3 low= trisomy 18
cvs
10-13wks. kayotype, DHA extration, enzym eanalysis
amniocentesis
16-18wks. sloughed fetal cells.
percutaneous umbilical blood sampling
hematologic abn, genetic d, infection, fetal acidosis. used to arm med or blood transufsion to fetus
common genetic D
marfan syndrome, prader willi, angelman, noonan, digeorge,ehler danlos, osteogenesis imperfecta, VACTERL association, CHARGE, Williams, Cornelia de Lange, Russell silver syndrome, pierre robin syndrome, cri du chat syndrome,
marfan syndrome
AD. CT D. C15-fibrillin
affect: ocular, CV, skeletal
P: tall, elongated extremitis/ fingers, j laxity, chest wall deformities (pectus excavatum), scoliosis or kyphosis. decr upper to lower segment ratio. upward lens subluxation and retinal detachemnt (need regulr ophthalmologic exam), aortic root diation, aortic dissection. aortic regurg
Dx: clinical. need r/o homocystinuria
C: endocarditis (prophylax), sudden death-dissection, HTN,
prader willi
P: almond eyes, fish like mouth. FFT, short, small feet. hypotonia, MR, hypogonadism
Dx: FISH
C: hypotonia- poor sucking. obesity- obstructive sleep apnea, cardiac disease, DM2, psych
angelman
C: jerky arm mV, ataxia. small wide head, large mouth, prognathic, blood hair blue eyes
noonan syndrome
= male turner. AD. C12
P: short, shield chest. short webbed neck and low hairline. right sided heart lesion~ pul valve stensis (turner has left sided heart lesion), MR in 25%
Dx: clinical
DiGeorge and celocardiofacial syndrome
AD or sporadic. C22q11 deletion. CATCH-22
Cardiac anomaly, abn facies, thymic hypoplasia, cleft palate, hypocalcemia (sz), C22.
digeorge: short palpebral issues, chin/ear anomalies, to, VSD, AA anomalies,
vekicaruifacuak: cleft palate, promiennt nose with square nasal root, fish mouth, short chin, VSD, right sided AA, hypotonia, learning D, preservative behavior.
Dx: FISH
ehlers-Danlos sydnrome
AD. defective type V collagen
Phyperextensible J -dislocation and scoliosis, loos/fragile skin (minor laceration = major wounds that heal poorly with broad atrophic tissue paper thin scars), MV prolapse, aortic root dilation, fragile vessels= bruise easily, constipation, real proposal hernia
dx- clinical
C: aortic dissection, GI bleeding
osteogenesis imperfecta
abn type I collagen
P: blue sclerae, fragile bones, yellow or gray-blue teeth, easy bruisability
dx: clinical and decr tpye I syn in fibroblast
C: early conductive hearing loss, skeletal deformity 2/2 fractures
VACTERL association
vertebral defects, anal atresia, cardiac anomalis -VSD, TE (tracheoesophageal fistula), renal, limb defects (hypoplasia, syndactyly),
dx- clinical
CHARGE
sporatic colobomas, heart defect-tog,, atresia of nasal choanae, retardation, genial anomalies, ear
williams
AD. C7- elastin.
P: cocktail party personality. elfin facies, MR, loquacious, supravalvular aortic stenosis, idiopathic hypercalcemia in infancy, CT abn- hoarse voice, hernia
dx- FISH
Cornelia de lange
sporatic> AD
P: single eyebrows (cynophrys), short, no skeletal abn, SGA. FFT, microcephaly, downturn upper lip, micrognathia, infantile hypertonia, MR, small hands/ft, cardiac defect, autistic behavior, no expression, self destructive
dx-clinical
Russell silver syndrome
short, skeet asylum, normocephalic, SGA
pierre robin syndrome
micrognathia, cleft lip and palate,
dx clinical
C: recurrent otitis media, upper airway obstruction
cri du chat syndrome
C5-arm delation. sporadc
catlike cry, microcephaly, MR.
dx-deletion, clincal
down syndrome
epicentral skin folds, brachycephaly, protruding tongue, hypotonia, clinodatyly, wide space btw 1st and 2nd tow, duodenal atresia, hischsprong, pyloric stenosis, cardiac-40%
C: atlantoaxial cervial spine instbaility, leukemia, celiac, alzheimer, obstructive sleep apnea, hearing loss, hypothyroidism, cataracts, glaucoma, refractive error
trisomy 18
F>M
MR, hypertonia, scissoring of LE, delicate small facial features, clenched hands, overlapping digits, rocker botton feet
95% die
trisomy 13
midline defect. holoprosencephaly, severe MR, microphthalmia, single eye, cleft let or palate.
die
turner
1X
P: short, webbed neck, shield chest, welling of dorm hands and ft, ovarian dysgenesis-delay puberty, cardiac defect-left sided, coarctation, hypothyroidism
fragile X
CGG
P: large ears, macrocephaly, blue irides, large testes, autistic / ADHD features
Klinefelter
XXY. most common male hypogonadism and infertility
P: tall, long extremities, hypogonadism, delay puberty bc lack testosterone, gynecomastia, variable IQ, behavioral findings
skeletal dysplasia
group of inherited disease with short stature caused by bone growth abn
achondroplasia- most common type
achondroplasia
AD. FGF-3R. incr with paternal age
rhizomelia= long bone abn= short humerus and four
AD.
megalencephaly, foramen magnum stneosis, frontal bossing, lumbar kyphosis in infant becoming lumbar lordosis, bow legs, trident shaped hands. otitis media, conductive hearing loss
C: foramen magnum stenosis lead to hydrocephalus or cord compression- SID
obstructiv esleep apnea
potter’s
severe oligohydramnios, fetal compression, limb abn, potter facies
amniotic band syndrome
rupture of amnionic sac, wrap around fetus cause scaring and amputation
fetal alcohol syndrome
SGA, microcephaly, FTT
phenytoin syndrome
MR, cardiac, growth retardation, nail abn, wide anterior fontanelle, low hairline,
inborn errors of metabolism
together 1:5000.
suspect if ill, non responsive to tx, unexplained sz, dev delay, FTT, persistent V, labs inconsistent with P
onset: acute severe neonatal illness (classic P). recurrent intermittent epi at times of stress, chronic progressivee sx (usually mito D)
Fx: neonatal death, parental consanguinity, MR
odor v IEM
mousey/musty- PKU
sweet maple syrup- maple syrup urine disease
sweaty feet- isovaleric or glutamic academy
rotten cabbage- hereditary tyrosinemia
AA metabolism defects
homocystinuria, PKU, hereditary tyrosinemia, maple syrup urin disease
homocystinuria
AR. cystathionine synthase def.
P: marfanoid body habits wo arachnodactyly, downward dens subluxation( marfan is upward), hypercoag, CV abn, scoliosis, dev delay
dx: incr methionine in urine and plasm. pos urine cyanide nitroprusside test
tx- methionine restricted diet, asprin decr TE, folic acid and B6 sup
transiet tyrosinemia of newborn
prematture infant on high protein diet
lethargic, asx
tx: vit C
self limited
PKU
AR
P: dev delay, hypotonia, mousy odor, MR
maple syrup urine disease
AR.
P: commit, hypotonia, coma, dev delay, hypoglycemia, acidosis,
dx: serum and urine branched chain aa
tx: dietary protein restriction- -if start w’in 2wks of life avert neuro damage
tyrosinemia type I
AR
P:peripheral neuropathy, liver disease, rotten fish or cabbage odor, renal tubular dysfunc
Dx: succinylacetone in urine
tx: restrict phenylalanine, tyrosisn, NTBC. liver transplant
die
membrane transport defects
cystinuria- AR, renal stones, UTI, dysuria, urinary freq
hartnup- AR, asx, ataxia, photosensitive rash, MR
urea cycle defect
ammonia >200. toxic to brain and liver. sx: poor feeding, hyper vent, behavioral changes,s sx, ataxia, coma
transient hyperammonemia of newborn- self limited, in premie, in 24-48hr of life, aggressive tx of hyperNH3 needed to prevent neuro sequelae
ornithine transcarbamylase def- most common urea cycle defect.t x-linked. begin at onset of protein ingestion= vomit, lethargy, coma, dx-elevated urine orotic acid, decr serum citrulline, incr ornithine, liver bx
tx- low protein diet and hyperammonemia,
carbohydrate meta
galactosemia hereditary fructose intolerance, glycogen storage disease
galactosemia
AR. galactose-1 phosphate uridyltransferase def.
suspected in any newborn with hepatomegaly and hypoglycemia
P: begin after cow’s milk –> V/D/FTT, hepatic dysfunction, cataracts, oil droplet appearance, renal tubular acidosis
dx: nonglucose reducing substance in urine. confirm enzyme def in RBC, prenatal screen
tx: galatose pree diet,
prog- normal IQ if tx early. ovarian failure, death in early infancy from e coli sepsis if not tx
hereditary fructose intolerance
fructose 1 p adolase B def. fruit
glycogen storage disease (GSD)
organomegaly and metabolic acidosis
1) von gierke’s disease (GSD type 1): G6P def. hypoglycemia, hepatomegaly, hypertriglyceridemia, enalrge kidney. need high complex carb diet. risk for HCC
1: pope’s disease (GSD type 2): alpha glycosides def: muscular weakness, cardiomegaly, preset in 2wk with flaccid weakness, poor feeding, hepatomegaly
fatty acid oxidative defect
present during acute illness or fasting when FA are used. nonketotic hypoglycemia, hyperammonenemia, myopathy, cardiomyopathy. medium chain acyl-CoA deH def= most common D
tx: high carb low fat diet, carnation sup
mitochondrial D
suspect in common disease has atypical presentation or disease involve 3+ organ systems. Kearns sayre syndrome (ophthlamoplegai, pig deign, hearing loss, heart block, neuro deign). MELAS. dx base on tissue bx- abn mito
lysosomal storage disease
gangliosidose (tay sachs, caucher’s, neimann pick, metachromatic leukodysptrophy), mucopolysaccharidoses (glycosaminoglycan accumulate in multi organ, short stature, mR, dysostosis multiplex, oar shaped ribs, breaklike vertebrae, hurler syndrome, hunter syndrome, sanfilippo, morquio),
tay sach
AR. hexosaminidase A def.
incr startle, hyperacusis, macrocepahly, cherry red macula, sever dev delay, blindness,
gaucher’s
glucocerebrosidase def- most common gangliosidosis. AR. erlenmeyer flask shape to distal femur. die by 4yo
niemann pick
sphingomyelinase def. neuro degen, atazia,sz, heptaosplenomegaly, cherry red macula. die by 4yo
hurler syndrome
most severe mucopolysaccharidosis. AR. progressive coarsened facial feature, corneal clouding,
dx: dermatan and heparan sulfate in urine,
tx- early bone marrow transplant
10-15y life
hunter syndorme
x-linked R.
P: hepatosplenomeglay, hearing loss, papule over shoulder, dy
hunter needs sharp eyes therefrore no corneal clouding
porphyrias
defect in heme pig biosynthesis
skin photosensitivity and neuro and abdominal sx.
personality change, emotion lability , weakness, colicky abd pain, autonomic instability, dark burgundy urine.
dx: incr serum and urine porphobilinogen
tx: IV glucose, correct electrolyte abn, avoid fasting and precipitating drugs
wilson’s disease
dx: decr serum ceruloplasmin. elevated serum and urine copper
menke kinky hair disease
x lined R. low serum copper, pare kinky friable hair,
