Syndromes based on features Flashcards
1
Q
Holoprosencephaly, cleft palate
A
Trisomy 13 – Patau
2
Q
Tri 13 vs 18 – which has female bias?
A
Tri 18
4F:1M
3
Q
clenched hands at birth
A
Tri 18
4
Q
Rocker bottom feet
A
Tri 18 (1 in 5-8k)
5
Q
small for gestational age
A
Tri 18
6
Q
amenorrhea, short stature
A
Turner
7
Q
klinefelter, turner – recurrence risk?
A
Klinefelter – no evidence of increased risk
Turner – very low ;
8
Q
fibrosis of seminiferous tubules (infertility)
A
Klinefelter (almost universal symptom)
9
Q
what kind of cytogenetic change results in a dicentric chromosome?
A
90% of Robertsonian translocations are dicentric.
10
Q
Frequency of Robertsonian translocation?
A
1 in 1,000
11
Q
Frequency of Kleinfelter syndrome?
A
1 in 550
12
Q
Frequency of Turner?
A
1 in 1500-6000 (but 3% of conceptuses)
13
Q
Frequency of Robertsonian translocation (chr 13, 14, 15, 21, 22)
A
1 in 1,000
most commonly, 14/21 and 13/14
14
Q
Frequency of balanced translocation
A
1 in 500
15
Q
If one is a carrier for ___, a possibility is a child with UPD.
What are prenatal testing options for Uni Parental Disomy (UPD)?
A
Robertsonian translocation
NOT NIPT –> won’t tell you about UPD
UPD needs CVS/Amnio –> SNP CMA testing
16
Q
At which step in the cell cycle does the majority of non-disjuction occur? In which sex does the majority occur?
A
Meiosis I, maternal
UPD from trisomy rescue happens more often with 2 maternal chromosomes
17
Q
In non-disjunction,
If there is a trisomy rescue situation, uniparental disomy is more common from the ___’s chromosomes.
In contrast, in a monosomy situation, uniparental disomy is more common from the ___’s chromosomes.
A
Trisomy rescue –> UPD maternal
(UPD from trisomy rescue happens more often with 2 maternal chromosomes)
Monosomy duplication –> UPD paternal
…all because non-disjunction more commonly comes from mother’s side.
18
Q
UPD is often diagnosed following which clues?
A
- discrepancies between CVS and amnio
- confined placental mosaicism
- imprinting-related phenotype
- recessive disease in child when a parent is only a carrier
19
Q
Which chromosomes/conditions are associated with imprinting defects / imprinted genes expressed from which parent?
A
imprinted on __ results in ___
chr 15 - mat - Prader-Willi – [Prader needs Fader’s copy]
chr 15 - pat - Angelman – [man needs mam]
chr 7 - pat - Russel-Silver
chr 14 - pat - short/scoliosis/hypotonia/dev delay/prec puberty
chr 6 - mat - transient neonatal diabetes mellitus (also macroglossia)
chr 11 - mat - Beckwith-Wiedemann
chr 14 - mat - mental retardation, short-limb dwarfism
20
Q
growth retardation - except head, triangular facies, limb/face asymmetry
A
Russel-Silver
can be caused by upd(7)mat
21
Q
macroglossia, organomegaly, omphalocele, Wilm’s tumor
A
Beckwith-Wiedemann
22
Q
short stature, developmental delay, hyperextensible joints, , hypotonia, minor facial dysmorphism
A
upd(14)mat
23
Q
mental retardation, short-limb dwarfism with narrow thorax, scoliosis, low life expectancy due to due to respiratory issues
A
upd(14)pat –> more severe than upd(14)mat
24
Q
neonatal hypotonia and poor suck with failure to
thrive, developmental delay and/or mental retardation, childhood-onset
obesity, short stature, hypogonadism, and severe
behavior problems.
A
Prader-Willli
upd(15)mat (30%)
deletion at 15q12 (70%)
imprinting defect (2%)
25
severe mental retardation with absent speech, ataxic movements
and gait, increased tone after infancy, seizures, and a
happy disposition with paroxysmal laughter
Angelman -- paternally imprinted
deletion at 15q12 on mat chrom (70%)
UBE3A mutation (5%)
upd(15)pat (4%)
imprinting defect (3%)
unknown (12%)
26
chromosomes with proven imprinted genes
6, 7, 11, 14, 15
27
UPD testing guidelines
SUMMARY OF CLINICAL AND DIAGNOSTIC
CONSIDERATIONS
1. Chromosomes of known clinical relevance include 6, 7, 11,14, and 15.
2. UPD testing should be considered for
(a) patients presenting with prenatally detected mosaicism
or Robertsonian translocations for clinically relevant
chromosomes.
(b) patients presenting with features of disorders known to be associated with UPD.
3. Testing should be performed on DNA collected from the mother, father, and child/fetus using polymorphic markers.
4. Reporting of results includes at least two fully informative markers from each chromosome of int
28
Robertsonian translocation t(14;21)) - risk of Down syndrome birth based on if from mom and dad
female carrier - 10-15% (true for all acrocentrics paired w chr 21)
male - 3%
29
Cri-du-Chat
---> mechanism? traits?
5p deletion
```
General
Cry - Mewing Of A Kitten
Craniofacial Dysmorphism:
Microcephaly
Moonlike Face
Hypertelorism
Micrognathia
Rare 1 in 40 k
Larynx -->Laryngealmalasia, Laryngeal Stridor
Distinctive Cry
Intellectual Disability (severe, IQ
```
30
Wolf-Hirschhorn --> mechanism?
traits?
4p deletion
```
General
Severe growth retardation
Sever intellectual disability
Craniofacial Dysmorphism
Microcephaly
“Greek warrior helmet” ********
Genital abnormalities
```
Cardiac defects (~50%) *********
Defects in closure of scalp
Cleft lip and/or palate
Coloboma
Intellectual disability - Usually severe - IQ
31
Williams syndrome
- mechanism?
- features?
```
del(7)(q11.23q11.23)
Submicroscopic: requires FISH
Cardiac Defects
Cardiac defects in 75%
Supravalular aortic stenosis
Elastin gene deletions
Very outgoing, cute personality
Infantile hypercalcemia
Dysmorphic features
Elfin facies
```
32
Velocardiofacial VS DiGeorge
Velocardiofacial Syndrome
```
Dysmorphic features
Heart defect
Ventricular septal defect
Cleft palate
Velopharyngeal incompetence
Hypernasal speech
Learning Disabilities (99%)
```
DiGeorge Syndrome
```
Dysmorphic features
Heart defect -- Conotruncal
Thymus hypoplasia/aplasia
T-cell deficiency
Hypoparathyroidism
Hypocalcemia
Intellectual disability
--
```
33
22q deletion -- prevalence?
1 in 2,000 !!
del(22)(q11.21)
One of the most common deletions (~1/2000)
Can be inherited from a parent (~10% are inherited)
Most not visible by routine cytogenetics
Diagnosed by FISH
34
Miller-Dieker
- mechanism?
- traits?
17p microdeletion
Type I lissencephaly
Can have isolated lissencephaly
Dysmorphic facies
Dysmorphic facies and lissencephaly – Miller-Dieker syndrome
Visible deletions -- 50% of patients
FISH or molecular testing needed to detect all cases
35
Smith-Magenis
- mechanism?
- traits?
```
Dysmorphic facial features
Brachycephaly, flat mid-face, prognathism
Behavioral abnormalities
Self-destructive behavior
Seen in 75% of Smith-Magenis syndrome patients
Peripheral neuropathy
Sleep disorders
Intellectual disability
Deletion—17p11.2
```
36
Prader Willi
- mechanism?
- traits?
UPD15mat -- prader needs fader]
```
Moderate Intellectual disability
Neonatal hypotonia
Hypogenitalism
Hyperphagia – obesity
Short stature
Small hands and feet
Characteristic facies
```
37
Angelman
```
“Happy Puppet Syndrome”
Severe Intellectual disability
Seizures
Absent Speech
Paroxysms of laughter
Tongue protrusion
Stiff, ataxic gate
Characteristic facies
```
mostly mat deletion (60%), some UPD15, some UBE3A deletion (10%)
38
del 1p36 syndrome: accounts for what percent of idiopathic ID? prevalence?
0.5-1.2% ;
1 in 5,000
39
del 1p36 syndrome
| - traits? -mechanism?
Variable breakpoints -- Different from many other contiguous gene syndromes
```
Maybe terminal or interstitial deletion
Maybe seen cytogenetically
Often missed with G-bands
Can be delineated by FISH
Telomeres studies
1p36.3 probe
Easily identified in array analysis
```
40
McDermid- Phelan syndrome
microdel 22q13
```
Hypotonia
Severe Language Delay
Mild Facial Dysmorphism
Intellectual disability
Deletion of SHANK3
```
41
ACMG recommends: “CMA [Cytogenetic microarray] testing for CNV [copy number variation] is recommended as a first-line test in the initial postnatal evaluation of individuals with the following:
1. Multiple anomalies not specific to a well-delineated genetic syndrome
2. Apparently non-syndromic DD/ID [developmental delay/intellectual disability]
3. Autism spectrum disorders”
42
chance of finding CMA abnormality in population selected for
1. pediatric
2. ID/DD
17.4%
43
1q21.1
1q21.1 aberrations:
- Microdeletions and microduplications
Facilitated by low copy repeats
Patients with 1q21.1 deletion show variable phenotype
- Mild-moderate ID; microcephaly; cataracts; neuropsychiatric disorders; cardiac anomalies;
Patients with 1q21.1 duplication show variable phenotype
- ID/ASD; neuropsychiatric disorders; macrocephaly; dysmorphic features
Parents with aberrations may be mildly affected
44
15q13.3
Mostly associated with ~ 1.5 Mb deletion
Variable phenotype –not well defined
Mild ID (~50%); neuropsychiatric disorders; behavior problems; seizures
Many deletion inherited
Facilitated by low copy repeats
Non-allelic homologous recombination (NAHR)
CHRNA7 involved; but if only CHRNA7 syndrome not well defined
45
16p11.2
Microdeletions and microduplications
low copy repeats
Autism; minor facial anomalies; speech delay
parents may have no features
46
16p13.11
Microdeletions and microduplications
low copy repeats
Neuropsychiatric disorders; dysmorphic features; congenital heart defects
parents may have mild features
47
17q12 microdel
Renal cystic dysplasia; renal hypoplasia; abnormal renal function; cryptorchidism; elevated hepatic enzymes; MODY5
Similar to MODY syndrome
Minimal deleted region ~ 1.5 Mb
De novo or inherited
Facilitated by low copy repeats (in most cases)
Non-allelic homologous recombination (NAHR)
TCF2 and LHX1 involved
48
17q12 microDUP
Cognitive impairment, behavior abnormalities, epilepsy, renal abnormalities
Minimal deleted region ~ 1.5 Mb
De novo or inherited
Often inherited from parents with no or minimal features
Facilitated by low copy repeats (in most cases)
Non-allelic homologous recombination (NAHR)
49
15q24 microdel
Hypospadius; cryptorchidism; joint laxity; bowel atresia; scoliosis; growth hormone deficiency
DELAYED BONE AGE; ELEVATED TRIGLYCERIDES
Minimal deleted region ~ 1.7 Mb
All reported thus far - de novo
Facilitated by low copy repeats
Non-allelic homologous recombination (NAHR)
P450sec involved
50
1q41-1q42 del
Cleft palate; talipes; diaphramagmatic hernia
ENLARGED VENTRICLES; GYRAL MALFORMATIONS; SMALL CEREBELLUM
Similar to Fryns syndrome
Minimal deleted region ~ 1.17 Mb
All de novo
Mechanism of formation - unknown
DISP1 involved
51
2p15-2p16.1 microdup
Optic nerve hypoplasia; renal abnormalities; spasticity of legs; high palate; calcaneovalgus
PACHYGYRIA; ENLARGED 4th VENTRICLE; HYPOPLASIA OF CEREBELLUM AND BRAINSTEM
Minimal deleted region ~ 200 kb
All de novo
Mechanism of formation - unknown
VRK2 involved
52
if ultrasound abnormality, chance that CMA will yield DX that is NOT detectably by karyotyping?
6%
53
if AMA, chance that CMA will yield DX that is NOT detectably by karyotyping?
1.7%
54
When to use CMA in prenatal?
1. >= 1 major structural abnormality on u/s
[replaces karyotype!]
2. diagnostic procedure with structurally normal fetus (CVS, amnio) -- can do CMA or Karyo
3. NO AGE LIMIT -- not just for 35+ women
55
what is a molar pregnancy? how common is it? which test is necessary to detect it?
molar pregnancy, a.k.a., gestational trophoblastic disease (GTD)
1 in 1,000
rapid growth of large and random collection of grape-like cell clusters.
genetic issue - mostly placenta - rarely fetus also
needs SNP microarray, not just aCGH
56
advantage of SNP microarray over aCGH
1. identity by descent (IBD)
2. UPD
3. contamination
4. triploidy
bonus:
5. complicated MCC delineation
6. detection of complete mole
57
first cousins have +_____% risk of a kid with a congenital anomaly, relative to the general population
2-2.5% (due to recessive condition)
58
most common chromosome abnormalities at conception
Condition (% spontaneous abortion)
Total (94%)
1. triploidy/tetraploidy (100%)--> thus importance of SNP CMA
2. 45,X (99%)
3. Tri16 (100%) --> most common trisomy in 1st trimester
4. Tri18 (95%)
5. Tri21 (78%)
6. other Tri (99.5%)
7. other sex chrom aneuploidy (21%) : XXY, XXX, XYY
8. unbalanced rearrangements (85%)
9. balanced rearrangements (16%)
59
Product of Conception --> why MCC studies done?
MCC = maternal cell studies
Cytogenetic studies on female POC can give false negative if contaminated with maternal cells. Need to also rule out complete moles.
60
Resolution of molecular methods
Metaphase banding
High-resolution banding
FISH
CMA
multicolor FISH
Metaphase banding / 5-10 Mb
High-resolution banding / 3-5 Mb
FISH / 35 Kb [1kb in research]
CMA / 200-500 Kb [1kb in theory]
multicolor FISH / 5-10 Mb
61
purpose of satellite in FISH
tracks centromeric regions for TOTAL chromosome count (generally)
62
what is a marker chromosome?
A marker chromosome (mar) is
a structurally abnormal chromosome in which no part can be identified.
The significance of a marker is very variable as it depends on what material is contained within the marker.
It is essentially a partial trisomy.
63
role of Y chromosome in Turner syndrome
Turner syndrome (TS) is one of the most common types of aneuploidy among humans, and is present in 1:2000 newborns with female phenotype. Cytogenetically, the syndrome is characterized by sex chromosome monosomy (45,X), which is present in 50-60% of the cases. The other cases present mosaicism, with a 45,X cell line accompanied by one or more other cell lines with a complete or structurally abnormal X or Y chromosome. The presence of Y-chromosome material in patients with dysgenetic gonads increases the risk of gonadal tumors, especially gonadoblastoma [ benign, but can turn into other malignant tumors]. The greatest concern is the high risk of developing gonadoblastoma or other tumors and virilization during puberty if chromosome Y-specific sequences are present.
64
significance of subtelomeric FISH
subtelomeric portions have higher rates of recombination, and are gene-rich -- imbalances/rearrangements/tiny deletions are more likely to cause phenotype in these regions.
5% of unexplained MR caused by this.
Although CMA used, FISH still useful to find BALANCED rearrangements.
65
SNP array - what does log2 ratio tell you?
whether there is deletion/duplication in that area.
66
structural rearrangement breakpoints most often occur in these two places
1. subtelomeric regions
2. pericentromeric regions
i.e., near ends, or near center.
67
structural rearrangements: where most common? ("recurring")
0. Non-allelic homologous recombination (NAHR)--> most common. This means recombination between genes/repeats that are duplications of one another, at other cytogenetic locations - potentially on another chromosome.
1. low-copy-number repeats -->reciprocal del/dup of regions between LCRs happens due to high homology of LCRs that "cross over"
2. AT-rich palyndromes
3. inversion polymorphisms
4. non-homologous end joining (NHEJ)
5. FoSTeS/MMBIR [e.g. X22q del/dup aka Pelizaeus-Merzbacher, MECP2dup, 17p13.3 del/dup]
FoSTeS: Fork stalling and template switching
MMBIR: microhomology-mediated break induced replication (MMBIR)
68
inverted Low-copy-number repeats (LCRs) on the same chromosome can lead to what genomic rearrangement for material between them?
inversion
69
inversion polymorphisms (submicroscopic) predispose to ___
how did these inversion polymorphisms arise?
----
which condition is classic example of inversion in parent predisposing to structural issue in child?
rearrangements
inversion polymorphisms arose through NAHR mediated by LCRs
```
Williams syndrome (28% of parents have inversion!)
Sotos (100%)
```
70
non-homologous end-joining (NHEJ) is due to ____
conditions linked to NHEJ
```
LONG tandem repeats
Alu repeats (short interspersed element - SINE)
TTTAAA sequence --> curves DNA --> more prone to breaks
```
Duchenne
1p36
71
SAS - segmental aneusomy syndrome?
contiguous gene syndrome?
recurring SASs detectable by ____ technology
loss of gene or several genes resulting in a segment of aneusomy
several genes lost --> contigyous gene syndrome, e.g., 22q
1 gene --> e.g., Angelman
recurring SAS detectable by FISH
72
etiologies of deletion in child can be caused by:
1. gonadal mosaicism
2. de novo
3. parent may be balanced rearrangement carrier --> therefore need karyotype OR FISH
4. parent may carry it/be mildly affected if small del
73
asymmetric crying facies --> prompt you to look for issues with what organ system?
heart.
part of spectrum of 22q11.2 (formerly Cayler - asymmetric crying facies and heart stuff)
74
in setting of DD/ID/autism spectrum:
what percent of time will traditional cytogenetics (karyotype) yield a diagnosis?
5-10%, closer to 5%
75
in setting of DD/ID/autism spectrum:
what percent of time will FISH yield a diagnosis?
0.5-7%
76
in setting of DD/ID/autism spectrum:
what percent of time will oligo(aCGH) /SNP CMA yield a diagnosis?
15-20%
77
Puerto Rican grandma with dementia
PSEN1 - presenilin1
autosomal dominant form of early-onset (
78
Which ApoE allele is the risk allele for late-onset Alzheimers?
Which is the protective?
ApoE4 = risk (neither necessary, nor sufficient, though)
-- 1 copy 3-5x risk
-- 2 copies 10-15x risk
2/3 of AD patients have at least 1 copy
potential mechanism: decreasing age-at-onset
ApoE2 = protective, but associated with increased risk of apolipoproteinemia type 3
complex: ApoE2 is risk for macular degeneration, ApoE4 is protective.
79
ApoE - which pathway?
is testing it recommended (as of 2016)? In what cases?
ApoE in cholesterol pathway, risk factor for
Testing is NOT recommended due to limited cliinical utility and poor predictive value, even if a person is affected.
direct-to-consumer testing is not advised.
80
Parkinson Disease - recessive gene?
PARK2 - recessive - most inherited PD is caused by this.
the younger the age-at-onset, the more likely mutation in this gene (e.g., especially 20s)
Parkinson's displays many inheritance patterns (AD, AR, XL)
81
Parkinson Disease - dominant gene?
LRK2 ~ reduced penetrance ~ 30-74%
0. 5% of sporadic PD in USA
0. 26% of familial PD in USA
15-20% of PD in Ashkenazi
30-40% of PD in North African
82
Parkinson Disease - can be symptom of which disease? Due to which gene?
Gaucher
GBA carrier status (glucocerebrosydase) ~
earlier onset
increased rate of dementia
~ 5x increased risk
83
FrontoTemporal Dementia can mimic which disease?
Parkinsons (symptoms)
84
Frontotemporal Dementia (FTD) - most common gene?
c9orf72 ~ autosomal dominant ~ GGG repeats
>30 repeats = "affected" , but typically see >1,000
found in sporadic FTD5%
found in familial 25%
Most common cause of sporadic ALS 5-10%
up to 50% of familial ALS is caused by ALS
onset 50s-60s
presentation: FTD and/or ALS +/- psychotic features
85
ALS -gene? (amyotrophic lateral sclerosis)
c9orf72 (expansions - most commonly)
SOD1 (20%)
TARDDP -- makes tdp protein (1-4%)
c9orf72, SOD, TARDDP, etc can be also found in sporadic cases.
X-linked types, recessive (juvenile), dominant
PANEL APPROACH
familial 5%
86
c9orf72
expansion GGG - autosomal dominant
frontotemporal dementia and/or ALS w/w/o psychotic features
87
neuro genetic pedigree: things to focus on
age-at-onset
first symptoms
unaffected people -- truly unaffected, or died young?
ancestry (Puerto Rican, Ashkenazi, N African)
diagnosis -- never assume it is correct unless autopsy
(can see tau/beta - AD or lewey bodies - PD)
88
Gowers sign is indicative of ___ muscle weakness
proximal muscle weakness
89
Duchenne carrier females - are they followed?
yes, must monitor cardiac health
90
Limb Girdle
strictly clinical dx - very unspecific
91
Limb Girdle Muscular Dystrophy - why important to know subtype?
Because some subtypes have cardiac involvement - need to know for screening regimen.
Also because nocturnal hypoventilation possible in some types.
Type 1 A-H -- dominant
Type 2A-Q -- recessive
92
Limb Girdle (sarcoglycanopathies, types 2c -q) VS Duchenne -- differences?
LG - recessive, not XL
| LG - no cognitive impairment
93
which neuromuscular disorder comes with inability to release grip quickly?
Myotonic Dystrophy, type 1 ~ CPG expansion
| "percussion myotonia" = grip symptom
94
mild myotonic dystrophy, type 1 can have which extra-muscular features, typically?
triplet repeat size correlates w severity of disease
cardiaca arrhythmias
cataracts
diabetes
hypothyroidism
95
myotonic distrophy -- CPG repeat cutoffs
expands through which parent?
normal 5-37
premutation 38-49
mild 50-150 (20-70yo onset) -- usually extramusuclar
classic 100-1,000 (10-30 yo onset) -- muscle involvement
expands through mom (case reports of dad exist)
500+ cognitive impairment -- disability
1,000-2,000: congenital presentation
96
myotonic dystrophy type 1:
if mom has >100 CPG repeats, what is chance that child will have congenital presentation of myotonic dystrophy?
1/2 * 60% = 30%
1 in 2 chance that she passes it on, and 60% that it will expand to 1,000.
97
main difference between DM1 and DM2
DM1 - distal muscles affected ; all types of onset ; CPG repeat ; repeat size correlates with severity
DM2 - proximal ; typically adult onset/no congenital ; CCTG repeat in CNBP gene ; 75-11k repeats/no correlation with severity - no anticipation - usually contraction across generations
98
Myotonic dystrophy features (muscular and extramuscular)
myotonia, slowly progressing weakness
cataracts
endocrine issues (diabetes, hypothyroid, male fertility)
heart (arrhythmias, AV conduction block, ...)
CNS - learning disabilities to severe ID
99
LAMA2
```
autosomal recessive
Merosin Deficient CMD
contractures
non ambulation in later childhood
non-specific white matter changes - leukoencephalopathy - non-progressive
can be mild-severe spectrum
```
100
Congenital Muscular Dystrophy (Ullrich) - is most characterized by which feature?
proximal contractures, distal hyperlaxity
skin findings due to COL6A1/2/3 (recessive or dominant) - scarring, soft skin, keratosis pilaris
early nocturnal hypoventilation !!! needs sleep study
no intellectual disability
101
Congenital Muscular Dystrophy (Bethlem)
COL6A1/2/3 - less severe than Ullrich
keloid (big) scarring
nocturnal hypoventilation !!!
mostly autosomal dominant
no intellectual disability
102
DAG1 - molecular mechanism
aberrant alpha dystrtoglycan GLYCOSYLATION - muscular dystrophy spectrum of conditions WITH intellectual disability
103
Cobblestone Lissencephaly 1
Walker-Warburg (POMT1, etc)
presents with congenital:
- weakness, contractures
- seizures
- eye malformations
- death by age 3
104
Cobblestone Lissencephaly 2
Fukuyama Congenital Muscular Dystrophy (fukutin, etc)
Congenital:
- weakness, contractures, high CK
- polymicrogeria/abnormal white matter (+lissencephaly)
- severe ID
- seizures
- cardiomyopathy
- death by 10 yo
105
Cobblestone lissencephaly 3
Muscle-Eye-Brain Disease (POMGnT1, etc)
- variable ID
- weakness, contractures, delayed milestones at 5 yo
- visual impairment (or just esotropia)
106
developmental delay + elevated CK -->
```
glycosylation disorders (muscular dystrophies with ID)
-- muscle-eye-brain disease
```
107
Limb-Girdle muscular weakness:
proximal or distal?
arm vs leg?
face?
PROXIMAL more than distal
ARM more than leg
FACIAL weakness
- teen or adult onset
- CARDIOMYOPATHY
- high CK
FKRP gene - broad phenotypic spectrum, also includes Walker-Warburg
108
FKRP gene
- muscular dystrophy gene
- broad phenotypic spectrum
- limb girdle muscular dystrophy (adult onset)
- walker-warburg (eye malform, death by 3)
109
weakness is face, shoulder, upper arms
Facio-Scapulo-Humeral muscular dystrophy
(autosomal dominant)
- elevated CK
- "dead gene come alive"
110
Facio-Scapulo-Humeral muscular dystrophy
| --> mechanism of Type I?
"dead gene come alive"
D4Z4 repeats 11+ is normal
111
Facio-Scapulo-Humeral muscular dystrophy
| --> mechanism of Type II?
```
normal # of D4Z4 repeats
abnormal methylation (loss) --> DUX4 expression (dominant negative)
```
112
LGMD -- mostly which inheritance pattern?
90% recessive, 10% dominant
113
muscular dystrophy vs myopathy?
muscular dystrophy = defect of muscle membrane
myopathy = structural abnormalities of muscle cell
in myopathies, CK levels are NORMAL because there is no myonecrosis
114
Congenital myopathy
e.g., nemaline
- many inheritance patterns (AR, AD, XL)
- many, many genes
115
Slender body habitus and some facial features - associated with which muscle condition?
```
Nemaline Myopathy
(mostly AD)
- arm weakness
-long face, face/neck weakness
-diaphragmatic involvement
-abn muscle biopsy
```
116
congenital hip dislocation, spinal deformities, pectus, arched feet, delayed motor milestones
Central core disease (a congenital myopathy - RYR1)
| - also positive Gowers, Trendelnburg gait
117
arthrogryposis
congenital contracture
118
Central core disease - presentation, associated condition
either milder (Gowers, Trendelenburg), hip dislocation, delayed motor, pectus, spinal dformities (dominant, RYR1)
or
congenital - severe hypotonia, weakness, contracture, respiratory issues, (recessive, RYR1)
RYR1 gene mutations also cause Malignant Hyperthermia (pharmacogenetic reaction to anaesthetic/succinylcholine, Rx: dentrolene, reaction involves hyperthermia, rhabdomyolisis, muscl rigid) -- RYR1 is on ACMG incidental findings gene list!
119
RYR1
RYR1 gene mutations also cause Malignant Hyperthermia (pharmacogenetic reaction to anaesthetic/succinylcholine, Rx: dentrolene, reaction involves hyperthermia, rhabdomyolisis, muscl rigid) -- RYR1 is on ACMG incidental findings gene list! - DOMINANT inheritance, always [can have normal muscle histology]
can come with or without:
Central Core Disease - a congenital myopathy, more mild version
120
Pompe disease
lysosomal glycogen storage disease (GSDII)- RECESSIVE
(store glycogen other places, in part - muscle)
carriers unaffected;
if enzyme activity is below 30% = clinical symptoms
can present as myopathy, e.g., distal weakness, fatigue, muscle cramps, heart/liver sometimes affected, aneurism, noctural hypoventilation --
mortality due to respiratory issues usually
Rx: MYOZYME, LUMIZYME; on newborn screen
congenital severe form also exists (most present w HCM)
121
hypotonia, enlarged tongue and liver, hearing loss, HYPERTROPHIC CARDIOMYOPATHY, high CK
Pompe disease - congenital metabolic myopathy. Death by 9 months.
122
severe symmetric hypotonia, contractures, weakness; CK normal on day 7;
EMG: absence of motor and sensory reflexes
SMA - recessive
progressive degeneration and loss of the ANTERIOR HORN CELLS in the spinal cord and brain stem nuclei (which leads to loss of MOTOR NEURONS)
4 subtypes, varies by age-at-onset/whether sitting/walking achieved and when; mostly onset at 1 yo or below
123
tongue fasciculations (twitching)
associated with motor neuron involvement (SMA or ALS)
124
SMA - carrier rate, prevalence
1 in 10k
1:40 - 1:47 -- very common recessive condition
AJ 1:60
Asian, Hispanic, AA -- more rare
panethnic - 1:54
125
SMA - molecular mechanism?
homozygous deletion of exon 7 in SMN1 (95%)
point mutation in SMN1 (5%)
severity attentuated by copy # of SMN2
(most causes truncated/degraded protein, 10% produces functional ~SMN1-like protein)
126
SMA - testing
SMN1/SMN2 - copy number testing
| previously, PCR w/restriction enzyme that cuts SMN2, but not SMN1
127
SMA - recurrence risk - what testing to be done?
Haplotype analysis in parents
SMN1 can be 2:0 or 1:1 in parental allele (eg, 2 copies on 1 allele, 0 copies on second.)
2: 0 -- 25% recurrence
1: 1 --
128
congenital myasthenic syndromes
has treatment! AChe inhibitors or Potassium channel blockers
onset - infancy/ childhood, typically
CK normal/mild elevation
no heart of cognitive issues
129
Primary hereditary MOTOR and SENSORY NEUROPATHIES
test?
Charcot-Marie-Tooth disease
```
1 in 2,500
genetically heterogeneous
DISTAL atrophy
feet > hands, dop-foot gait, high arches
thinning below knees
paraesthesias, loss of perception
slowly progressive
```
NERVE CONDUCTION TEST
130
CMT subtypes, inheritance patterns, and nerve conduction velocities
CMT1 - demyelinating - reduced conduction velocity AD
CMT2 - reduced amplitude ("axonal") - AD
CMT4 - axonal or demyelinating - AR
CMTX - axonal or demyelinating - XL
131
most common CMT - mechanism?
CMT1A - AD/demyelinating
-- duplication of PMP22
(deletion causes HNPP - hereditary __, pressure palsies)
132
Neuromuscular disease work-up:
1. localize muscle symptom (neuro eval)
| 2. CK level if weakness (normal
133
Whole Exome Sequencing does NOT detect which muscular conditions (5 !!)
1. dystrophinopathies (del/dup - 60% DMD, 90% Becker)
2. CMT1A (duplication at 17p12 PMP22 gene, or del causing HNPP
3. Myotonic Dystrophy (CTG or CCTG repeats)
4. Facio-Scapulo-Humeral Dystrophy (contraction of D4Z4 repeat)
5. SMA - Spinal Muscular Atrophy (homozygous del SMN1)
134
CMT1A, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy, OR SMA (Spinal Muscular Atrophy)
EACH has a prevalence of ~
1 in 10,000
135
Tetralogy of Fallot
- associations?
- what are the four features?
etiology mostly unknown
15% due to 22q
some due to maternal diabetes
Features:
1. Pulmonary Valve Stenosis [a type of Right Ventricle Outflow Tract Obstruction. There can be other reasons for this obstruction in ToF]
2. VSD
3. Overriding aorta [aorta shifted right toward VSD]
3. Right ventricular hypertrophy
de-ox blood has trouble getting from right heart to lungs due to pulmonary valve stenosis, so it's shunted across the VSD to left ventricle -- this is inefficient for blood oxygenation. This blood can also be shunted directly to the overriding aorta (main artery leaving the heart, which should have oxygenated blood, but in this case, has mixed.). Right ventrivular hypertrophy develops because the heart has to work harder to overcome the stenosis. This develops after bith.
136
```
neonatal hypoparathyroidism (parathyroid hypoplasia -->hypocalcemia)
immunodeficiency (thymus hypoplasia) &/or autoimmunity!
congenital heart disease (conotruncal)
```
etiologies?
DiGeorge (WIDER etiology than only 22q)
maternal diabetes
maternal alcohol
retinoic acid exposure
22q del
4q del
10p del
137
low neonatal calcium
DiGeorge - due to hypoparathyroidism
138
DiGeorge can be seen on karyotype __% of the time
25% of DiGeorge is BIG deletions, visible on karyotype
75% are microdeletions = 22q11.2
139
22q11.2 - de novo rate?
90%
140
conditions with high de novo rate
Cornelia de Lange - almost 100% de novo
McCune Albright - 100%
22q11.2 - 90%
Rett - 95% (inconsolable crying, mostly females, autism, hand-wringing)
141
22q prevalence
1 in 1,000 to 1 in 2,000 -- most common microdeletion syndrome
142
Tetralogy of Fallot is more common in __ than in Down Syndrome
22q11.2
143
prenatal polyhydramnios
22q + velopharyngeal dysfunction
basically, one of a FEW prenatal indication of 22q except for congenital heart disease.
Also:
hydronephrosis, renal agenesis, duplicated collecting system
144
prenatal absent thymus
indication for 22q testing
145
newborn screen - severe combined immunodeficiency
associated with 22q - need to order microarray or MLPA
146
baby: nasal regurgitation and GERD -- condition?
22q ; nasal regurgitation is never normal
147
Heart defects in 22q (76%)
```
Tetralogy of Fallot (20%)
VSD (17%) ---> most common prenatal CHD in all population
Interrupted Aortic Arch type B (13%)
Aortic arch anomalies
ASD/VSD
ASD
Other
```
NOT ALL are identifiable on fetal echo, or prenatally, without barium swallow. may come to medical attention following stroke!
148
physical manifestations of endocrine abnormalities in 22q
prenatal IUGR
short stature
hypo/hyper-thyroidism
growth hormone deficiency
149
These cancers in a child prompt suspicion of which condition:
Hepatoblastoma, Wilms tumor, renal cell carcinoma, thyroid carcinoma, leukemia, melanoma, neuroblastoma
22q11.2
likely immune-mediated
150
RARE 22q prenatal findings:
Diaphragmatic hernia
Polyhydramnios
Polydactyly !!
-- Pre and postaxial
Club Foot
Radial ray defects
craniosynostosis
hemifacial microsomia
151
22q ear findings
```
Microtia/Anotia
Preauricular tags
Preauricular pits
Helical differences
Protuberant ears
```
152
22q can unmask recessive disorders:
Bernard-Souilier syndrome (GP1BB mutation)
- - Thrombocytopenia
- - Increased megakaryocytes
CEDNIK syndrome (SNAP29 mutation)
- - Cerebral dysgenesis (polymicrogyria)
- - Neuropathy
- - Ichthyosis
- - Keratoderma
153
proper testing for 22q
MLPA or microarray
FISH can miss "nested deletions" -- associations with heard disease, schizophrenia, ENT issues, Immune issues, GI, CNS, eye, orthopaedic, delay -- all can be missed
These nested deletions are OFTEN familial (64%)
154
22q - if negative, can consider:
```
if FISH testing done, MLPA or microarray
TBX1 mutation (is within 22q region)
```
155
differential diagnoses of 22q
```
CHARGE
Kabuki
Smith-Lemli-Opitz (elevated msAFP)
Goldenhar (butterfy vertebrae)
Alagille (butterfly vertebrae)
Jacobsen (11qter del)
```
156
prenatal 22q signs
Congenital heart disease
Overt cleft palate/cleft lip/Pierre Robin
```
Renal anomalies
Congenital diaphragmatic hernia
T-E fistula
IUGR
Polydactyly
Club foot
Craniosynostosis
Micrognathia
Neural tube defects
Polyhydramnios
```
157
most nuclear-encoded mitochondrial disorders are __ inheritance
autosomal recessive
but AD, XL, and trinucleotide repeats also (Friedrich Ataxia)
158
Mito disorders -- which molecular processes?
pyruvate ----(PDHC)---> acetate --> Krebb Cycle --> Complex i, Complex II --> Electron Transport chain
159
mito disorder - PDHC - Pyruvate Dehydrogenase Complex Deficiency -- E1 alpha-- inheritance?
XL-recessive in males with point mutation
XL-dominant in females (lethal in males)
"overwhelming lactic acidosis" (pyruvate funneled to lactate because can't go on to acetate)
congenital abnormalities
or neurocog disease
carb-induced ataxia
other subunits of SDCD can be AUTOSOMAL RECESSIVE
160
mitochondrial complexes
- - nuclear or mitochondrial?
- - functions?
Complex 1 - mito/nuc - proton pump across inner mb
Complex 3 "
Complex 4 "
COMPLEX 2 = NUCLEAR ONLY
Complex 5 - mito/nuc - uses proton gradient to make ATP
161
mitochondria - ribosome / tRNA ?
mito genome encodes own ribosome 16S/12S
mito genome encodes tRNA, rRNA (because mito genetic code is slightly different) !!!
162
mito disease: tissues with high energy demands
```
Nerves/CNS
Muscle
Endocrine
Renal Tubule / Liver
Growth
```
severe: will get CNS involvement
mild: will get maybe endocrine, except in times of extreme stress, then get neurological.
163
Common Mito clinical manifestations
migraine
depression
bowel disease
commonly present with eye disease first, since eye muscles move around a lot, e.g., Kearns-Sayre syndrome (hetero)
KSS - caused by del/dup/mutations. Dups have higher recurrence risk than dels. This pheno can have mutations can be AD/AR. This del can also cause Pearsons (exocrine pancreatitis, and bone marrow failure/low blood count)
164
most common MELAS mutation **** important!
most common MELAS pheno?
3243A>G in tRNA-leuUUR. [HETROplasmic mutation; not seen in homoplasmic, because that would be lethal.]
(stroke-like episodes = aka "malignant migraine")
MELAS can also be nuclear, mutations in other genes, dels
most common pheno of this mutation is Diabetes with, or without deafness. [ super common in Finnish ] deafness in middle age, diabetes is late-onset.
also common: stroke, migraines
165
LHON (Lebers Hereditary Optic Neuropathy)
- - hetero or homo?
- - which complex?
- - prevalence?
LHON (Lebers Hereditary Optic Neuropathy)
--most common mt disorder (1 in 45,000)
-- rapid vision loss in 20s-30s
-- HOMO - LHON is HOMO
--3 mtDNA mutations in
complex 1 genes:
11778G>A (most common), 3460G>A and
14484T>C (associated with visual recovery).
-- low penetrance; 4:1 M:F - male sex bias
LHON - male - homo - complex 1
LHON and complex 1 rhyme.
166
mito-caused hearing loss
- - how common among hearing loss?
- - syndromic, or not?
- - common mtDNA mutation that causes hearing loss in multifactorial manner
--5% among kids with post-lingual hearing los
--can be syndromic, or not.
--The homoplasmic 1555A>G mutation in the 12S-rRNA gene often
causes hearing loss in a multifactorial manner with other genetic
(tRNA processing genes and the mtDNA haplogroup) and
environmental (aminoglycosides) factors.
167
multifactorial hearing loss due to mitochondrial disorder: mutation. homo or hetero?
1555A>G in 12S-rRNA (mito)
HOMO
+ genetic factors (tRNA processing, etc)
+ environmental (aminoglycosides = antibiotic/ China)
168
lactic acidosis can be sign of
mitochondrial disease (pyruvate goes to lactate, instead of to acetate, and Krebb cycle.)
169
Friedrich Ataxia - mechanism?
GAA trinucleotide repeat expansion (recessive)
insufficient frataxin = mitochondrial iron chaperone
--> mitochondrial dysfunction / mito phenotype
170
Leigh syndrome
- maternal complex 4, 5,
- AR, XL, complex 2
progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within a couple of years, usually due to respiratory failure.
171
Progressive External Ophthalmoplegia (PEO)
-- Ocular myopathy without systemic disease is termed PEO. In some cases, systemic disease develops later (Kearns- Sayre). Adult-onset.
- AD mutation causes multiple mtDNA deletions in muscle.
172
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
--autosomal recessive mutation in thymidine
phosphorylase, LEADS TO mitochondrial deletions because too much thymidine
-ECGF1, ANT1, andPOLG are associated with multiple mtDNA deletions.
Inheritance is autosomal recessive or dominant.
-can do prenatal testing for MNGIE! and POLG!
173
early-onset liver disease
mitochondrial DNA depletion
| - can be caused by nuclear DNA mutations
174
POLG - pol gamma polymerase
-- is prenatal testing available?
mito disease gene.
replicates and proofreads mtDNA (exonuclease)
-AD, AR mutations ; thus can do prenatal testing.
Phenotypes associated with POLG mutations:
- --AD PEO w or w/o parkinsonism (w or w/o other features)
- --AR PEO w or w/o parkinsonism (w or w/o other features)
Alpers syndrome (psychomotor regression with hepatic cirrhosis,usually with infantile onset) LIVER DISEASE
SANDO (Sensory Ataxia, Neuropathy, Dysarthria,
Ophthalmoplegia)
Male subfertility (more or less than the usual 10 repeats in a trinucleotide repeat)
Premature menopause
Cataracts
175
common mito mutations
MELAS 3243A>G
MERRF (Myoclonic Epilepsy, Ragged-Red
Fibers) 8344A>G
NARP (Neuropathy, Ataxia, Retinitis
Pigmentosa) and Maternally Inherited Leigh
Syndrome) 8993G>T or G>C
Maternally inherited deafness 1555A>G
176
suspicion for mitochondrial disease:
Multiple symptoms
e.g., 2 or + neuromuscular, endocrine, renal
Functional (bowel, psychiatric, "nebulous", autism)
Transient or intermittent
- - Cluster into “episodes”
- - Present during viral illnesses or fasting
Ask about problems often excluded from pedigrees:
migraine, dysautonomia, SIDS, learning disabilities,
psychiatric disease.
177
Testing for mito disease
- lactate (low sensitivity/specificity)
- urine organic acids (non-specific; includes shock);
Elevated Krebs cycle intermediates, dicarboxylic
acids, lactate, ketones and specific markers (3-
methylglutaconate, etc.) Metabolic acidosis during infections.
-muscle bx, enzyme testing. Muscle bx - ragged red fibers = "mito protein synth deficiency" - but, rare in kids.
GENETIC:
(1) standard mito testing (common pt mutations, large rearr. LOW sensitivity - 6%)
(2) NextGen - to find heteroplasmy. Otherwise, if suspect homoplasmy, then plain sequencing ok.
178
Mito disease mimics
-fatty acid oxidation with plasma acylcarnitines
- peroxismal disorders with very long chain fatty acids
- CNV abnormalities if MR, dysmorphic, birth defect
- methylation Angelman/Prader-Willi --> have a lot of mt dysfunction on muscle biopsy!
-
179
mito disease - inheritance?
- -> infantile, severe
- -> later-onset, less severe
- -> infantile, severe -- AUTOSOMAL RECESSIVE
| - -> later-onset, less severe --- MATERNAL MT
180
mito treatment
- avoid stress, high energy demand (e.g., fasting, steroids, fever, illness)
- cofactors to increase energy(Co-Q, L-carnitine, creatine, riboflavin, etc.)
- exercise to increase energy
- antioxidants (to protect mito from ROS)
181
mito prevalence
1.6 in 10,000 - Finland
1.2 in 10,000 - N England
0.5 in 10,000 - Australia
....but this is underestimate
MOST common metabolic disorder seen in peds clinic.
182
Kearns Sayre - inheritance?
MOST of the time, sporadic
but since it's due to mutation/del in mtDNA, it has mitochondrial inheritance.
183
steatosis (fat deposition) of
liver
heart
muscle
which conditions?
fatty acid oxidation disorders (especially the long chain, and very long chain)
MCAD only has heart steatosis. SCAD has heart steatosis, but no fibrosis or abnl mitochondria.
can't convert fat to energy, so fat gets deposited in these organs.
184
blue sclerae
osteogenesis imperfecta
COL1A1, COL1A2 genes --
mostly autosomal dominant
if severe type 2 form in infant, then likely de novo
CRTAP, P3H1 genes --
mostly recessive, but very rare.
most OI is still AD inheritance.
Types 1-8,
1 is most mild (common),
2 is most severe
```
bone fractures from minor trauma
hearing loss in adulthood
+/- short stature
+/- dentinogenesis imperfecta
+/- respiratory difficulties
```
Type 2 - underdeveloped ribcage/lungs, die shortly after birth
0.6 in 10,000
185
Galactosemia
inability to use galactose (esp in lactose/breastmilk)
1 in 30,000-100,000, depending on type
Mutations in GALT, GALK1, and GALE
usually almost no enzyme activity.
RECESSIVE
Duarte variant: mutation in GALT - mild disease
```
life-threatening complications appear within a few days after birth.
feeding difficulties
lack of energy (lethargy)
failure to gain weight and grow as expected (failure to thrive),
jaundice
liver damage
abnormal bleeding.
bacterial infections
shock
```
RISK of: delayed development, clouding of the lens of the eye (cataract), speech difficulties, and intellectual disability
186
Smith-Lemli-Opitz
7-dehydrocholesterol reductase.
1 in 20-60k ; DHCR7 gene ; RECESSIVE
AUTISM / ID or learning/behavior problems - spectrum.
MALFORM: heart, lungs, kidneys, gastrointestinal tract, and genitalia
HYPOTONIA
feeding difficulties
2-3 TOE SYNDACTYLY (kind of how the three last names of the disease name are fused together)
POLYDACTYLY (poly # of last names)
prenatal: very low uE3
187
broad thumbs, toes
Rubinstein-Taybi
CREBBP; dominant ; 1 in 100k
Rubinstein-Taybi syndrome is a condition characterized by short stature, moderate to severe INTELLECTUAL DISABILIITY, distinctive FACIAL features, and broad thumbs and first toes. Additional features of the disorder can include EYE abnormalities, HEART and KIDNEY defects, DENTAL problems, and OBESITY. These signs and symptoms vary among affected individuals. People with this condition have an increased risk of developing noncancerous and cancerous tumors, including certain kinds of brain tumors. Cancer of blood-forming tissue (leukemia) also occurs more frequently in people with Rubinstein-Taybi syndrome.
188
cat eye syndrome
region of the long arm of chromosome 22 (i.e., 22pter-22q11) are present three or four times (trisomy or tetrasomy) rather than twice
mild growth delays before birth; mild mental deficiency; and malformations of the skull and facial (craniofacial) region, the heart, the kidneys, and/or the anal region.
CAT EYE:
frequently have coloboma(s),
downslanting palpebral fissures
hypertelorism
189
Pallister-Killian
MOSAIC SYNDROME
extra 12: isochromosome 12p or i(12p).
usually severe
(but potentially mild cases are underascertained)
```
hypotonia
coarse facies
intellectual disability
+/- clefts
+/- sparse hair
+/- hearing loss, vision impairment, seizures, extra nipples, genital abnormalities, and heart defects
congenital diaphragmatic hernia (40%) !!!
big large toe
polydactyly
skin pigmentation stuff
```
190
Loeys-Dietz
dominant
```
aortic dilation/aneurism
bifid uvula/cleft
arterial tortuosity
hypertelorism
craniosynostosis
```
HIGH RATE of pregnancy-related complications
191
Ornithine transcarbamylase deficiency
ammonia accumulates in the blood = urea cycle disorder
1 in 80k ; X-linked
boys affected (Severe neonatal is rare in females)
boys and girls can be mildly affected, or late-onset
still dangerous if late-onset
```
baby: lethargy, poor body temp regulation
seizures
coma
liver damage
INTELLECTUAL DISABILITY
skin lesions
```
Typical: neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention deficit hyperactivity disorder (ADHD), and executive function deficits.
Pregnancy management: Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period. Although protein restriction is the mainstay of therapy, when protein intake is too low, catabolism can cause chronic hyperammonemia just as high protein intake does.
192
Pendred syndrome
congenital or childhood-onset hearing loss
thyroid enlargement (GOITER)
..a PEND-ant goes around your neck, but it'd be hard to put it on if you had GOITER. Also, Pendred sounds like Mildred, an old deaf lady.
accounts for 10% of hereditary hearing loss (!!)
SLC26A4; RECESSIVE
in asians, southeast asians, 5.5% are carriers.
193
connexin 26
Connexin 26 mutations are responsible for at least
20% of all genetic hearing loss and
10% of all childhood hearing loss.
Deafness occurs in 1:1000 neonates1 and the cause is hereditary in about half.
194
Krabbe disease
leukodystrophy
myelin issues due to shortage of galactosylceramidase.
recessive
vision loss
seizures
onset
195
cysteinuria
Cystinuria is a rare condition in which stones made from an amino acid called cystine form in the kidney, ureter, and bladder. (due to buildup of cystine)
SLC3A1 or SLC7A9 ; recessive
1 in 10,000
196
x-linked adrenoleukodystrophy
weakness in legs (paraparesis)+ abnormalities in urinary/genitals develop in children or adults
mental changes/adhd/behavior issues - MRI is always abnormal
dementia eventually
progressive impairment of vision, hearing, motor, leading to total disability/death
adrenal issues
mechanism: buildup of VLCFA -- toxicity
tx: bone marrow transplant.
ABCD1 gene
20% female carriers affected ; 1 in 20,000 males affected
males + females = 1 in 16k
Addison disease = mild form; only adrenocortical issues, and maybe neurologic disability later
197
urea cycle defect: what happens to blood pH?
metabolic/respiratory?
alkalosis/acidosis?
primary respiratory alkalosis
-- response to high ammonia.
198
Maple Syrup Urine disease
poor feeding, vomiting, lack of energy (lethargy), and developmental delay.
untreated, can lead to seizures, coma, and death.
Old Mennonite: 1 in 380
Other: 1 in 185,000
can't break down: leucine, isoleucine, and valine,
---> sweet-smelling urine
recessive; BCKDHA, BCKDHB, and DBT genes.
199
NTBC
pesticide
miracle drug for Tyrosinemia
blocks upstream of homogentisate so that several reactions downstream, toxic succinylacetone isn't made.
200
Tyrosinemias
in phenylalanine--> tyrosine --> xyz pathway
Type 1 (hepatorenal) is most severe - most downstream
- NTBC helps
- succinylacetone isn't produced (toxic)
- liver/kindey damage/failure
Type 2 (between tyrosine and 4-OH phenylpyruvate)
- corneal ulcers
- hyperkeratosis
Type 3 (between 4-OH phenylpyruvate and homogentisate)
- intellectual disability
- NTBC works to block this reaction
201
cram.com biochemical genetics flashcards
http://www.cram.com/flashcards/biochemical-genetics-iemcancer-genetics-i-ii-2934076
202
Familial hypercholesterolemia
Defects in LDL receptor mechanism, so LDL cannot enter cell --> cholesterol production in overdrive
Symptoms include high plasma cholesterol
300-500 mg/dl for heterozygotes,
600-900 mg/dl for homozygotes
premature heart disease, xanthomas, atheromas, and cholesterol deposits around cornea (arcus corneae).
Homozygotes usually die around 30 years old.
Heterozygote incidence is about 1 in 500, homozygote about 1 in 1,000,000.
203
Alkaptonuria
Example of too much substrate interfering with normal cellular processes
Deficiency is in homogentistic acid oxidase which converts homogentistic acid (a metabolite of tyrosine) to maleylacetoacetic acid. Homogentistic acid accumulates and is deposite in connective tissue, interfering with collagen formation.
Symptoms are pigment deposition in collective tissue (ochronosis), turning sclera and ear cartilage dark, dark urine, degenerative joint disease.
tx: vitamin C ; pain tx
204
Ochronosis
The deposition of pigment in connective tissue observed in alkaptonuria.
205
Hemochromatosis: definition and how it's treated
too much iron. Phlebotomy to take out iron.
Actually a fairly common disorder but has low penetrance.
206
Tay-Sachs
TSD is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When Hexosaminidase A is no longer functioning properly, the lipids (gangliosides) accumulate in the brain and interfere with normal biological processes.
Causes a relentless deterioration of mental and physical abilities that commences around six months of age and usually results in death by the age of four.
More common in Ashkenazi Jewis, French Canadians, Cajuns, Amish where carrier frequency is 1/30. Carrier frequency is 1/300 in other populations.
207
Shpritzen-Goldberg vs Loeys-Dietz/Marfan
hypotonia
intellectual disability
radiographic findings
all present in S-G, but not the other two
most SG is de-novo or due to Germline Mosaicism
SK1
208
Ehlers-Danlos
all AD
Type 1/2 - skin stretchy/atrophic scars, hypermobility -- 50% genetic detection - COL5A1/2 - classic - 1 in 20,000
Type 3 - hypermobility type - aortic root dilation -(11-30%) 1 in 5-20,000 - TNX-B (skin smooth or normal, NO fragility or atrophic scars). -- genetic testing UNAVAILABLE in USA.
Type IV - vascular - rupture of arteries/intestines/uterus, bruising, thin skin, acrogeria (prominent eyes, thing face/nose, less ubcutaneous fat_ 1 in 100,000 -- 100% genetic detection
[confused often with Loeys-Dietz: multiple arterial aneurisms and tortuosity, bifid uvula, hypertelorism; TGFBR1/2]
Type 6 - kyphoscoliotic - at birth, sclera fragility, marfanoid, atrophic scars, club foot. LH1
Arthrochalasis (Type 7A/B) - severe joint hypermobility, atrophic, COL1A1/2
vs Williams: joint laxity, facies, cardio issues, connective tissue issues, ID, endocrine issues, elastin arteriopathy (ELN)
209
Stickler
sensorineural hearing loss
cleft palate
COL2/9/11
vs Williams: joint laxity, facies, cardio issues, connective tissue issues, ID, endocrine issues, elastin arteriopathy (ELN)
210
elevated msAFP
could be:
Smith-Lemli-Opitz, esp if breech, or low uE3
gastroschesis (median 9 MoMs)
211
gastroschisis
multifactorial
younger, white mother bias
2.4% recurrence risk
elevated msAFP
1-5 in 10,000
10% associated w major unrelated defect
2% syndromic
1% chromosomal abnormalities, esp w other struct abn
25% other GI symptoms, e.g., malrotation, atresia, stenosis = complex (vs simple)
can present w oligohydramnios, or polyhydramnios
40% develop IUGR
4% intrauterine fetal demise
30% premature
212
Prenatal:
| reliable, isolated markers?
echogenic bowel 6.1xrisk
shortened humerus (arm) 7.5x risk
[both humerus and femur are NOT considered markers for fetal aneuploidy]
thickened nuchal fold >=6mm -- 17xrisk
2 markers = 6.2x risk
congenital anomaly = 22x risk
213
Prenatal:
| isolated, unreliable
shortened femur
echogenic intracardiac focus
pyelectasis (>= 4mm)
two-vessel umbilical cord
--> doesn't significantly change risk for DS in low-risk, or high-risk patients, if isolated
214
ONTD risk in kid if:
1 parent or 1 child w ONTD
2 children
sibling
sibling's child / aunt/uncle
1 parent or 1 child w ONTD -- 3%
2 children --10%
sibling - 1/200 or 0.5%
sibling's child / aunt or uncle -1/300
215
risk aneuploidy at age 40
~1/40
actually, 1/41, at mid-pregnancy
DS is about 1/2 as common
216
risk aneuplodiy at 35
~1/135
actually, 1/130, at mid-pregnancy
DS is about 1/2 as common
217
CVS mosaicism
-- what percent of CVS?
-- of those with mosaic findings, what % are
true mosaics?
confined placental mosaics?
-- if mosaic on CVS, which test to order?
CVS mosaicism
-- what percent of CVS? 1-2%
-- of those with mosaic findings, what % are
true mosaics? 20%
confined placental mosaics? 80%
-- if mosaic on CVS, which test to order?
UPD testing
218
lemon sign and or banana sign
neural tube defect
219
duodenal atresia - risk for DS?
30%
220
omphalocele
- -% associated abn?
- - which ones?
```
omphalocele
--% associated abn?
60%
-- which ones?
Trisomies (20%)
cardiac (30%)
Beckwith-Wiedemann (4%)
Intestinal abn (11%)
```
vs gastroschisis
- associated abn 14%
- intestinal abn 14%
- cardiac 5%
221
choroid plexus cyst
1% of 2nd tri ultrasouds
doesn't matter, 1 or many
assoc w Edwards (Tri 18)
222
congenital diaphragramtic hernia
- prevalence?
- genetic syndromes?
1 in 2,000
```
Pallister-Killian (i12p mosaic)
Cornelia de Lange
CHARGE
Beckwith-Wiedemann
Goldenhaar
Fryns
```
223
Marfan
upper/lower segment ratio =2
family history
FBN1 mutation
systemic features
alternatively, MASS = myopia, MVP, borderline aortic root dilation, striae, skeletal findings
224
prenatal:
| extremely low levels of unconjucated estriol uE3 (
majority: intrauterine fetal demise
minority: X-linked ichthiosis, aka steroid sulfatase deficiency - 1 in 1,300
minority: Smith-Lemli-Opitz
225
risk cut-off to screen positive on
FTS
second tri screen
FTS: 1 / 230
2nd: 1/270
226
gestational diabetes - risk of malf?
cardiac : 1%
anencephaly/NT defects 0.3-0.5%
spina bifida 0.2%
caudal regression 0.07%
risk scales with HbA1c
>9.4 = 6% (vs 3% background)
>14.5 = 42%
227
Hemoglobin A2 elevation over 3.5%
if 4-6% = confirms beta thal trait dx
if MCV low, and A2 low, consider alpha thal.
a-/-- = Hemoglobin H = splenomegaly, bone changes, anemia
228
alpha thal
a-/--
--/--
a-/-- = Hemoglobin H = splenomegaly, bone changes, anemia = Hb beta 4
--/-- = Hydrops fetalis. preeclampsia, hemorrhage in mom.
= Hb Bart = Hb gamma4 .. mostly SE asians
229
CBC - is it useful for sickle cell?
no. unless person has alpha thal trait.
230
HbA2
```
two alpha globin chains, and two gamma globins
normal to have 2-3%
rest, 97%, HbA = two alpha, two beta
should have
0 HbS
0 HbC
```
231
Holoprosencephaly
```
Tri 18
Tri 13
Meckel-Gruber (cystic kidneys, poly dact, agenesis of cc/encephalocele, CL/P)
18p-
Aicardii
(isolated)
maternal diabetes
Fryns syndrome [also can give congenital diaph. hern]
Goldenhaar
CHARGE
```
232
cauliflower sign
gastroschisis
233
cystic kidneys
Tri 13
Meckel Gruber
adult PKD
234
Sickle cell disease features
mutations
stroke/silent stroke (10/25%)
painful crises (hypoxia acidosis, dehydration, cold/swim)
anemia
infections (penicillin) - functional asplenia
hand/foot syndrome (swelling/edema)
other: priapism (painful erection), cardiomegaly, skin ulcers, delayed puberty, retinopathy, chronic kidney failure, avascular necrosis (bone death), sleep apnea, pulmonary hypertension
usually point mutations in Beta globin genes --> cause polymerization under hypoxic conditions
235
sickle cell dz
carrier rate
prevalence
8% in AA
1 in 375 = HbSS
1 in 835 = HbSC
1 in 1667 = sickle beta-thal
6% carry hemoglobin disorder worldwide
236
sickle cell treatments
tx:
hydroxyurea (switches to HbF = fetal = alpha2gamma2)
-prevents polymerization of SS - dilutes with F
transfusions
prophylactic penicillin within 2 weeks of birth
bone marrow transplant
237
G6PD mechanism
G6PD can't recycle glutathione
glutathione = antioxidant
without glutathione, Hb oxidizes, and RBC membranes become more rigid
leading to hemolysis
associated w
kernicterus
238
How to differentiate between VHL1 and VHL2? geno-pheno?
VHL
Type 1 = no pheo
Type 2 = yes pheo
yes geno-pheno. 100% mutations picked up in VHL gene.
239
factor V Leiden -
prevalence?
mechanism?
clotting predisposition due to excess of factor V.
6% (more than 1 in 20)
mechanism: Protein C can't hook up to factor V to inhibit it, so factor V is overproduced.
btw: 85% of CVD has to do with clotting.
240
Von Willebrand
prevalence?
bleeding
prevalence 1-2% ; autosomal dominant
microvasc. bleeding: bruising, vaginal, dental. equivalent of taking Aspirin.
most caused by deficiency in VW (which is a carrier molecule for factor 8 [mutated 8=hemophelia].) without VW, factor 8 gets metabolized faster.
if homozygous deletion (rare) then =~hemophelia severity.
241
Beckwith-Wiedemann
imprinted on maternal
(needs fader like the other "overgrowth" syndrome, Prader-Willi)
but: mechanism of action is
1. Loss of maternal methylation --> both maternal AND paternal chromosomes express these growth-related genes (50% of cases)
2. inheritance of TWO copies of father's ACTIVE genes (UPDpat11) -- unlike Prader-Willi, where disease results from UPDmat15. (20% of cases)
3. . also can be caused by deletions
4. translocations
5. maternal GAIN of methylation
85% de novo
15% autosomal dominant
(of dominant, 40% are del/dup)
242
Usher syndrome
retinitis pigmentosa
progressive hearing loss, esp high tone
balance issues
responsible for 50% of deaf-blindness
recessive ; many genes
Usher (the singer) is ALWAYS wearing sunglasses
--> retinitis pigmentosa
Also, if he had hearing loss, he'd be a worse singer.
243
Alport syndrome
kidney disease [hematuria, almost universal + proteinuria]
--> ESRD (end stage renal dz)
hearing loss
eye abnormalities
1 in 50,000
M>F
COL4A3, COL4A4, and COL4A5
X-linked (80%) --females can be affected, esp w hematur.
recessive (15%)
dominant (5%)
244
elevated msAFP - another cause of it
IUGR
can be detected around 23 weeks, need 3 weeks between measurements to assess growth retardation
245
isovaleric acidemia
sweaty feet smell during illness
246
hemochromatosis
lower penetrance
1 in 10 euro is carrier; incidence is 1 in 1,000
recessive
should consider testing people who have severe and continuing fatigue, unexplained cirrhosis, joint pain or arthritis, heart problems, erectile dysfunction, or diabetes because these health issues may result from hemochromatosis.
247
Wilson Disease
copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances,
Kayser-Fleischer rings in cornea
recessive
248
Tuberous sclerosis complex
tsc1, tsc2
tumor suppressor
dominant
2/3 de novo
SEGAs
dev. delay
renal angiomyolipomas
ashfield spots
249
incontinentia pigmenti
```
rash in infancy
missing/late teeth
brown/light whorl pattern on skin
alopecia
hearing/vision issues
seizures
delayed motor skills
learning disabilities
```
X-linked DOMINANT
--> male embryonic lethal --> miscarriages
250
mt depletion syndrome
autosomal recessive
encephalopathy
liver failure
251
Kearns-Sayre syndrome
ocular myopathy
ataxia
heart conduction defect
increased CSF protein
onset
