ABP Content Specs #2 D&E Biological Mechanisms in Dev & Beh

Question 1

Type of inheritance pattern for Huntington’s disease, NF-1, achondroplasia, familial hypercholesterolemia?

Answer 1

Autosomal dominant

each affected person usually has an affected parent; happens in every generation

Question 2

Type of inheritance pattern for Tay-Sachs disease, sickle cell anemia, cystic fibrosis, phenylketonuria (PKU)?

Answer 2

Autosomal recessive

both parents of an affected person are carriers; not usually seen in every generation

Question 3

Type of inheritance for Hypophosphatemic rickets (vitamin D resistant rickets), ornithine tanscarbamylase deficiency?

Answer 3

X-linked dominant

Females more frequently affected b/c all daughters and no sons of an affected man will be affected. Can have affected males and females in same generation if mom is affected.

Question 4

Type of inheritance pattern for Hemophilia A, Duchenne muscular dystrophy?

Answer 4

X-linked recessive

Males more frequently affected. Affected males often present in each generation.

Question 5

Genomic imprinting?

Answer 5

process by which maternally & paternally derived chromosomes are uniquely modified (usually by methylation) –> leading to different expression of a certain gene or genes on these chromosomes depending on their parental origin.

If genes are inactivated/silenced in the female line then it is maternally imprinted (ie. only the paternally derived allele is expressed/active).

If genes are inactivated/silence in the male line then it is paternally imprinted (ie. only the maternally derived allele is expressed/active).

Question 6

Example of condition that is caused by loss of paternal copy of 15q11?

Answer 6

Prader-Willi syndrome (paternal copy loss or paternal imprinting).

Have loss of paternal copy of PWS critical region on ch 15q11.2-13

Question 7

Example of condition that is caused by loss of maternal copy of 15q11?

Answer 7

Angelman syndrome due to loss of maternal copy of 15q11.2-13.3

Question 8

Mitochondrial conditions are inherited maternally or paternally?

Answer 8

maternally b/c mitochondria are transmitted by ova and not sperm

Question 9

Inheritance pattern of mutations in mitochondrial DNA?

Answer 9

1. both males and females affected
2. condition is transmitted through the female to her offspring
3. if a male has the trait and his spouse doesn’t then their offspring won’t have the trait

I.e. an affected woman can pass the defective mitochondria ch to all of her children. But an affected man has little risk of passing the mutation to his child.

Question 10

Tendency of certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations?

Answer 10

Anticipation

Usually seen in conditions resulting from expression of a nucleotide repeat expansion that increases in size and have a more significant effect when passed from one generation to the next.

Question 11

Most common X-linked disorder with triplet repeat instability and expansion?

Answer 11

Fragile X syndrome

Question 12

Examples of diseases with anticipation?

Answer 12

Huntington’s disease
Myotonic dystrophy
Friedrich’s ataxia

Question 13

Conditions that are contiguous gene disorders (i.e. clinical constellation of symptoms caused by deletion of a chromosome segment that has two or more adjacent genes)?

Answer 13

Williams syndrome
Smith-Magenis syndrome
22q11.2 deletion syndrome

Question 14

Features of Williams syndrome?

Answer 14

-contiguous gene disorder that deletes gene for elastin & other neighboring genes on 7q11.23
-coarse, elf-like facies with upturned nose, full lips
-short stature
-congenital heart disease (supra-valvular aortic stenosis)
-hypercalcemia
-GDD, mostly have ID but STRONG language skills
-cocktail party personality/friendly
-attention problems
-anxiety

Question 15

Features of Smith-Magenis syndrome?

Answer 15

-contiguous gene disorder with deletion on chromosome 17p11
-prominent forehead, deep-set eyes, cupid-shaped upper lip
-ID
-self-mutilating behaviors (head banging, wrist biting, onychotillomania - pulling out fingernails and toenails, polyembolokoilamania - inserting foreign body into orifices)
-sleep issues

Question 16

Features of 22q11.2 deletion (Velocardiofacial syndrome or DiGeorge syndrome)?

Answer 16

-contiguous gene disorder
-hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies
-cleft palate
-heart defects (conotruncal cardiac defects like Tetralogy of Fallot)
-thymus hypoplasia leading to immune issues
-parathyroid hypoplasia leading to low calcium

Question 17

What is Malformation?

Answer 17

morphological abnormality due to innate genetic defect (e.g. cleft lip)

Question 18

What is Deformation?

Answer 18

distortion of bodily structures due to external physical force (e.g. oligohydramnios leading to micrognathia, talipes)

Question 19

What is Disruption?

Answer 19

destruction of bodily structure due to external factor (e.g. amniotic bands leading to digit or limb amputation)

Question 20

What is aneuploidy?

Answer 20

The occurrence of one or more extra or missing chromosomes in a cell or organism

ex. Trisomy 21/Down syndrome

Question 21

What conditions are due to micro-deletion in chromosomes?

Answer 21

1. prader-willi syndrome/Angelman syndrome in chromosome 15q11-13
2. Smith-magenis syndrome (deletion of chromsome 17p11.2)
3. DiGeorge/velo-cardio-facial syndrome: hemizygous deletion of chromosome 22q11.2
4. Williams-Beuren syndrome: deletion of chromosomal region 7q11.2
5. ATR-X syndrome: mutation in the ATR-X gene on the X-chromosome

Question 22

What conditions are due to single gene defects?

Answer 22

1. Barth syndrome (X-linked cardioskeletal myopathy and neutropenia): mitochondrial function impairments due to the TAZ gene on chromosome Xq28
2. Fragile X syndrome: CCG repeat expanion on FMR1 gene
3. ICF syndrome: mutation in the DNA methyltransferase 3B 9DNMT3B) gene on chromosome 20
4. Neurofibromatosis: mutations or deletions in neurofibromin gene on ch 17q11.2
5. Rett syndrome: mutations in the MECP2 gene on the X-chromosome
6. Smith-Lemli-Opitz syndrome: mutations in the gene encoding sterol delta-7-reductase on chr 11q12-13

Question 23

Trisomy 13 features?

Answer 23

-associated with advanced maternal age
-midline defects including cleft palate and holoprosencephaly
-cutis aplasia (don’t have extra layer of skin, just thin membrane esp scalp)
-microcephaly
-micro-opthalmia, ear anomalies
-IUGR/severe growth issues
-45% die in 1st month, 85% in first year

Question 24

Trisomy 18 features?

Answer 24

-associated with AMA
-rocker bottom feet
-hypoplastic nails, clenched fists, overlap fingers
-microcephaly, prominent occiput
-micro-opthalmia, micrognathia, ear anomalies
-heart malformations
-horseshoe kidneys
-IUGR
-50% die in first week, 95% in first year

Question 25

Trisomy 21:

Answer 25

-small head circumference -brachycephaly (short head width - from front to back) -low set, folded ears -upslanting palpebral fissures -epicanthal folds -brushfield spots (speckled iris) -flat nasal bridge -small mouth, protruding tongue -excess skin at nape of neck -short neck -single transverse palmar crease -5th finger clinodactylyl with hypoplastic mid phalanx -wide space between 1st and 2nd toes (sandal gap) -hyper-extensible joints -short stature -hypotonia -abnormal moro response -duodenal atresia, Hirschsprung disease -need formal eye exam by 6 months to check strabismus, cataracts, nystagmus -40-50% have congenital heart defect; most common AV canal defect; others VSD, TOF, ASD, PDA -check CBC for leukemoid reactions, polycythemia, rare leukemia -check hearing every 6 months for up to 3 years if can't see TM of ears -monitor for signs of OSA/sleep apnea -hypothyroidism in 20-40%; hormone screen at 6 months, 12 months, then yearly -risk for atlanto-axial instability (controversial): sxs s new onset gait problems, bowel or bladder dysfunction, change in reflexes; no longer recommend Xrays but consider if contact sports or if symptomatic; if Xray concerning then do neck MRI -most with ID have mild to moderate ID; IQ in 50-70 or 35-50 range -expressive langauge more delayed than receptive -7% of DS have Autism -most common behavioral issues like ADHD ,conduct/ODD, aggressive behavior; higher rates of depression and anxiety -associated: stereotypies, bradykinesia, ataxia, seizures, early onset Alzheimers disease

Question 26

Klinefelter syndrome?

Answer 26

-47XXY -most common cause of primary hypogonadism (hyper-gonadotropic hypogonadiam, tx with androgen replacement) -small testes, sparse facial hair, gynecomastia -most are sterile ->50% with learning and developmental disabilities -difficulty with expressive langauge, auditory processing, social skills, low avg/avg IQ -increase risk of breast/mediastinal tumors

Question 27

Turner syndrome?

Answer 27

-1 in 2000 live birthss -caused by loss of part or all of an X chromosome (45X monosomy X account for 45%; 45X with mosaicism like X/46XX or 45X/47XXX accounts 50%) -clinical features: short stature, webbed neck, low hairline at back of neck, shield chest, cubitus valgus, Madelung deformity of forearm and wrist, "streak" ovaries (only a few follicals), primary hypogonadism, premature ovarian failure, congenital lymphedema of hands/feet -in adolescence: short stature, minimal or no breast development, no periods/primary amenorrhea -cardiac abnormalities 50%: bicuspid aortic valve, coarct of aorta -30-40% renal abnormalities (horseshoe kidney) -increase risk of autoimmune disorders like Hashimotor's thyroiditis, celiac disase, inflammatory bowel disease -most have normal IQ -more risk of nonverbal skill deficits, math problem skills, psychomotor deficits like clumsiness, problems with visual-spatial organization

Question 28

X-linked recessive: since males have only one X-chromosome, any male that inherits X-linked recessive disease allele will get dissease. Males get affected more than females. X-linked dominant: females affected more than males. One way to know if AD vs not XD is that affected father passes disease to son. This cannot happen in XD since males inherit X chromosome from moms.

Question 29

What is uniparental disomy (UPD)?

Answer 29

-both copies of a chromosome pair are from one parent (i.e. no copy is from the other parent) -can happen as random event during the formation of egg or sperm cels or may happen in early fetal development -most common disorder of UPD: Prader-Willi syndrome and Angelman syndrome ; due ot errors of imprinting on long arm of chromosome 15

Question 30

Fragile X Syndrome?

Answer 30

-cause by expansion of number of CGG repeats within FMR1 gene -expansion of CGG repeats ? 200 = hypermethylation of FMR1 --> impaired transcription and reduced production of FMRP which affects brain development -X-linked disorder -most common known genetic cause of inherited ID (2nd most common after Down syndrome) -most common single-gene cause of Autism -as repeat size increases, stability decreases leading to increases in number of repeats in the FMR1 region during gametogenesis

Question 31

CGG repeats ranges in Fragile X syndrome?

Answer 31

Normal: 5-44 CGG repeats Intermediate expansion: 45-54 CGG repeats Premutation: 55-200 CGG repeats Full mutation: >200 CGG repeats

Question 32

Fragile X physical features?

Answer 32

-prominent ears -long and narrow face -prominent jaw and forehead -macro-orchidism (usually after puberty) -hyperextensible joints -flat feet -strabismus Cognitive: DD, ID, LD common; most males have mild to moderate ID Behavioral :ASD, ADHD, anxiety common; ASD in 50-70%

Question 33

Fragile X in girls?

Answer 33

Full mutation: less affected due to X inactivation -normal intellect in 50%, borderline to mild ID -associated inattention/ADHD, shyness/ocia anxiety, 20% girls with ASD, 5% seizures Premutation: 55-200 CGG -get premature ovarian insufficiency -get fragile x associated tremor-ataxia syndrome (FXTAS) later in life -neurocognitive deficits

Question 34

Rett syndrome?

Answer 34

-mutations in MECP2 on X chromosome -1 in 10,000 live birth -X-linked dominant pattern (more girls) -acquired microcephaly -get developmental regression 6-18 months of normal development before developing severe impairments in communication, cognitive, fine motor skills, coordination -stereotypic hand movements: affects girls lose purposeful use of hands and begin making repeated hand writing, washing, or clapping motions -autistic-like behaviors and hyperventilation episodes -ataxia -seizures -autonomic nervous system dysfunction -sleep disturbances

Question 35

Lesch-Nyhan syndrome?

Answer 35

-caused by mutations in HPRT1 gene that results in deficiency or complete absence of enzyme hypoxanthine phosphoribosyltransferase 1 X-linked recessive inheritance pattern (more males than females) -due to enzyme deficiency purines are broken down but not recycled; gets abnormally high level of uric acid, low levels of dopamine resulting in movement problems -associated movement disorders including dystonia, chorea -**self-injury (biting, head banging)

Question 36

Neurofibromatosis (NF1)?

Answer 36

-autosomal dominant -due to pathogenic variants in NF1 gene located on chromosome 17q11.2 resulting in loss of reduced function of protein, neurofibronin -50% caused by spontaneous mutation

Question 37

Diagnostic criteria for NF-1

Answer 37

need 2 or more 1. >6 or more cafe au lai macules (>5 mm before puberty, >15 mm in after puberty individuals) 2. 2 or more neurofibromas of any type or one plexiform neurofibroma 3. freckling in axilla and inguinal regions 4. optic glioma 5. 2 or more Lisch nodules (iris hamartomas) 6. distinctive bony lesion such as sphenoid dysplasia or thickening of long bone cortex with or without pseudoarthrosis 7. first degree relative (parent, sibling, or offspring) with NF1 based on above criteria -can get renal artery stenosis which can cause Hypertension -50 % with learning disability

Question 38

Tuberous sclerosis?

Answer 38

-autosomal dominant -caused by mutation in TSC1 gene or TSC2 gene -get benign tumors in multiple organs including brain, heart, kidney, skin, eyes, lung, and liver -diagnosis based on genetic testing and/or clinical findings

Question 39

Diagnostic criteria for Tuberous sclerosis?

Answer 39

need 2 major features or one major + 2 or more minor features Major Features: 1. hypomelanotic macules (3 or more, at least 5 mm diameter); Ash leaf spots 2. Angiofibromas (3 or more) or fibrous cephalic plaque 3. Ungual fibromas (2 or more) 4. Shagreen patch (cobblestone/orange peel appearing skin) 5. multiple retinal hamartomas 6. cortical dysplasia (includes tubers); may present as seizures 7. Subependymal nodules 8. Subependymal giant cell astrocytoma 9. cardiac rhabdomyoma 10. lymphangioleiomyomatosis (LAM) 11. Angiomyolipomas (2 or more) Minor Features: 1. "confetti" skin lesions (1 to 2mm hypomelanotic macules) 2. dental enamel pits (3 or more) 3. intraoral fibromas (2 or more) 4. retinal achromic patch 5. multiple renal cysts 6. non-renal hamartomas Developmental and behavioral manifestations: ID/LD in 50% of patients; Autism and AUtism-like behaviors, hyperactivity, inattention, SIB common Associated conditions: seizures (80-90%), incrased risk neuroendocrine tumors

Question 40

Smith-Lemli-Opitz Syndrome?

Answer 40

-caused by mutations in DHCR7 gene on chromosome 11 -leads to deficiency of C7 reductase (necessary for cholesterol production), decrease in cholesterol levels and accumulation of its precursors -autosomal recessive

Question 41

Clinical Features of Smith-Lemli-Opitz syndome?

Answer 41

1. microcephaly 2. facial features: short upturned nose, high arched palate, low set ears, micrognathia 3. growth impairment 4. moderate to severe ID 5. multiple major and minor malformations like cleft palate, heart defects, underdeveloped external genitalia in males, postaxial polydactylyl, and 2-3 syndactylyl of the toes

Question 42

Phenylketonuria (PKU)

Answer 42

-autosomal recessive -deficiency of phenylalanine hydroxylase (PAH) which leads to elevated blood and urine concentrations of phenylalanine and its metabolites -on chromosome 12q24.1 -diagnosed on newborn screen

Question 43

What happens if PKU is untreated?

Answer 43

-progressive ID -behavior problems (irritability, hyperactivity), microcephaly, seizures, white matter brain changes, spasticitiy, hypertonia, movement disorders -pale complexion/skin -"mousy" odor (due to increased amount of phenylacetic acid)

Question 44

What is epigenetics?

Answer 44

chemical alterations to DNA nucleotides or proteins that control gene expression but do not alter the DNA sequence