Genetics Flashcards
Risk for Trisomy 21 with Robertsonian Translocation 14:21
Higher risk if inherited from an infant’s mother 10% to 15%, but only 1% to 2% if inherited from the father.
NOT affected by maternal age. That one is T21 resulting from meiotic nondisjunction
Maple Syrup Disease
- well for the first 1 to 2 days after birth, and then experience a rapid progression to an encephalopathic state.
Symptoms typically start with ketonuria, a maple syrup odor, poor feeding, and opisthotonus.
Neonates with classic MSUD will have elevated plasma concentrations of branched-chain amino acids (isoleucine, leucine, and valine) and alloleucine on plasma amino acid analysis.
Miscellaneous descriptions
Biotinidase levels screen for biotinidase deficiency. This disorder presents in young children with the slow evolution of neurologic abnormalities, including seizures, hypotonia, ataxia, developmental delays, vision problems, hearing loss, alopecia, and a skin rash.
Ceruloplasmin levels, in conjunction with copper levels, screen for Menkes disease. This disorder presents with a period of normal development in early infancy, followed by developmental regression, coarse, kinky hair (pili torti), and tortuosity of the carotid arteries and vasculature of the brain.
Mucopolysaccharidoses are identified through lysosomal enzyme screening and urine glycosaminoglycans. These disorders typically present with a slowly progressive coarsening of facial features, joint stiffness, and developmental regression.
Very-long-chain fatty acids screen for peroxisomal disorders, which present with a slow progression of hypotonia, poor feeding, dysmorphic facies, seizures, hepatic dysfunction, retinal dystrophy, and sensorineural hearing loss.
Prader-Willi Syndrome
Hypotonia, Hypogonadism, and poor feeding with FTT in infancy. Facial dysmorphology (bitemporal narrowing, thin upper lip, almond shaped eyes, hypogonadism and cryptorchidism)
Feeding pattern then transitions to excessive eating. Mild-moderate disability Short stature Behavioral difficulties Skin-picking behavior
Imprinted gene on CHR 15 - lacks paternal contributed region, inherited both from mom.
Fragile X
- X-linked autosomal dominant - loss of fxn mutation in FMR1 due to trinucleotide repeats (>200)
- Boys: mod-severe intellectual disability
- Girls: normal, mild ID, learning d/o
- 25% autism
- Facies: long face, protruding ears, prominent forehead, macrocephaly, large testes
Carriers: 55-200 repeats
- Males: tremor/ataxia syndrome
- Females: premature ovarian failure
X-linked dominant disorders can affect both males and females, but males are affected to a much greater degree because they have only one X chromosome. Affected men will pass the abnormal X to all of their daughters and none of their sons. Affected women will pass the affected X to 50% of their offspring of either sex.
Dx: FMR1 molecular analysis
All intellectually disabled pts should have chromosomal microarray and fragile X testing
Rett syndrome
GIRLS only
normal early growth/dev then microcephaly and DECLINE in dev skills, loss of purposeful hand movements, classic hand wringing, acquired microcephalus, and intellectual disability
abnormal regulation of autonomic nervous system leading to
- increased risk of sudden death from prolonged QT
- altered respirations and periods of apnea/hypo and hyperventilation
MECP2 molecular analysis - mutation of this gene on X chromosome
PKU
elevated serum phenylalanine levels
mousy body odor, developmental regression, light skin/hair, eczema, seizures, intellectual disability
What finding in neonate requires referral to genetist?
Congenital deafness
Congenital deafness as an isolated clinical finding warrants referral to a geneticist because up to 60% of cases` of congenital and early-onset hearing loss are caused by genetic factors.
Trisomy 18
Clenched fist with overriding fingers
Rocker bottom feet
Facial - micrognathia, ear anomalies, short palpebral fissures, small face
Hypotonia
Growth deficiency
Kidney anomalies - horseshoe kidneys
Cardiac anomalies
90% die within first month after birth.
Friedreich Ataxia
AR disorder with GAA repeat expansion
Frataxin gene on Chr 9
birth and early developmental milestones are normal
then gait and limb ataxia in childhood
areflexia, LE weakness, dysarthria, dysphagia
abnormal saccades of eyes
Medium Chain Acyl-Coenzyme A Dehydrogenase Deficiency
Elevated C8 with lesser elevations of C6 and C10 acylcarnitine
This enzyme is missing so you can’t oxidize medium and short chain fatty acids into glucose or ketones and there is reduced ureagenesis leading to hyperammonemia
Normal at birth.
3-24 months of age - episodes of hypoketotic hypoglycemia, vomiting, lethargy, usually triggered by minor illness
Liver dysfxn, Seizure, Coma, Death
Chart of lab abnormalities and met disorders
file:///Users/vicky/Downloads/C249.pdf
Hemihypertrophy is associated with what cancers?
Beckwith-Wiedemann
- macroglossia, global macrosomia, hemihypertrophy
- hepatoblastoma - AFP levels q3mo until 4 yrs
- nephroblastoma (Wilms) - ABd US q4 mo until 7-8
NOT associated with neuroblastoma
Proprionic Acidemia
Presents in neonates, with a brief symptom free period that progresses to feeding problems, vomiting, seizures, coma, and eventually death
Labs:
- metabolic acidosis with a high anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.
- elevated C3 (propionylcarnitine)
- urine organic acids: elevated 3-hydroxypropionate level and the presence of methylcitrate, tiglylglycine, and priopionylglycine
How to work up inborn error of metabolism
When a physician suspects an IEM, a basic metabolic workup should be undertaken, which typically includes:
A serum analysis for: Acylcarnitine panel Amino acids Ammonia Blood glucose Carnitine profile Electrolytes Lactate Pyruvate
Urinalysis for:
organic acids
ketones
It is very important to test for ketonuria because the absence or presence of ketonuria clues the diagnosis of the various types of metabolic disorders. Results can be obtained in an expedient manner, allowing for appropriate interventions to be initiated quickly. Genetic sequencing is appropriate, but the results would not be back in time to make life-saving decisions.
DiGeorge Syndrome -> hypoca -> what EKG changes
Prolonged QTc or ST intervals
Dilated Ao root is associated with what
Marfan’s
Alagille Syndrome
Autosomal Dominant = 20p12
Presents within first 4-6 months of life
Cholestatic jaundice, HSM, Pruritis (due to elevated bile acids)
Biopsy: Paucity of intrahepatic bile ducts
Elevated cholesterol, TAG, phospholipids.
ADEK deficiency
Prolonged PT and PTT time
Skeletal: Butterfly vertebrae, abnormalities of ribs/hands, shortening of ulna/radius/phalanges
CV: Pulm atresia, PPS, PDA
Increased risk of HCC as they age
Caffey Disease
Infantile Cortical Hyperostosis Proliferating bone disease - affects infants - irritability, fever, soft tissue swelling (without signs of infection) bc there is underlying cortical hyperostosis/thickening of the bone - MANDIBLE is most often affected. - Labs: leukocytosis, ESR, alk phos high
Autosom Dom or Sporadic
Dilated Ao root is associated with what
Marfan’s
NF1
Sporadic or AD mutation of NF1 gene
2 of the 7 criteria
- cafe au lait 6 or more >5mm prepubertal, > 15mm post
- axillary or inguinal freckling
- neurofibromas
- lisch nodules (hamartomas in iris)
- optic gliomas
- sphenoid dysplasia
- unilateral anterolateral angulation (bowing) of the tibia leading to thinning of the cortex and pathologic fracture (long bone pseudoarthrosis)
- 1st degree relative with NF1
Assoc with learning disorders, ADHD, speech disorders.
- hyperintense areas in the basal ganglia and cerebellum thought to represent localized areas of demyelination
