Syndromes based on features Flashcards
Holoprosencephaly, cleft palate
Trisomy 13 – Patau
Tri 13 vs 18 – which has female bias?
Tri 18
4F:1M
clenched hands at birth
Tri 18
Rocker bottom feet
Tri 18 (1 in 5-8k)
small for gestational age
Tri 18
amenorrhea, short stature
Turner
klinefelter, turner – recurrence risk?
Klinefelter – no evidence of increased risk
Turner – very low ;
fibrosis of seminiferous tubules (infertility)
Klinefelter (almost universal symptom)
what kind of cytogenetic change results in a dicentric chromosome?
90% of Robertsonian translocations are dicentric.
Frequency of Robertsonian translocation?
1 in 1,000
Frequency of Kleinfelter syndrome?
1 in 550
Frequency of Turner?
1 in 1500-6000 (but 3% of conceptuses)
Frequency of Robertsonian translocation (chr 13, 14, 15, 21, 22)
1 in 1,000
most commonly, 14/21 and 13/14
Frequency of balanced translocation
1 in 500
If one is a carrier for ___, a possibility is a child with UPD.
What are prenatal testing options for Uni Parental Disomy (UPD)?
Robertsonian translocation
NOT NIPT –> won’t tell you about UPD
UPD needs CVS/Amnio –> SNP CMA testing
At which step in the cell cycle does the majority of non-disjuction occur? In which sex does the majority occur?
Meiosis I, maternal
UPD from trisomy rescue happens more often with 2 maternal chromosomes
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.
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.
UPD is often diagnosed following which clues?
- discrepancies between CVS and amnio
- confined placental mosaicism
- imprinting-related phenotype
- recessive disease in child when a parent is only a carrier
Which chromosomes/conditions are associated with imprinting defects / imprinted genes expressed from which parent?
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
growth retardation - except head, triangular facies, limb/face asymmetry
Russel-Silver
can be caused by upd(7)mat
macroglossia, organomegaly, omphalocele, Wilm’s tumor
Beckwith-Wiedemann
short stature, developmental delay, hyperextensible joints, , hypotonia, minor facial dysmorphism
upd(14)mat
mental retardation, short-limb dwarfism with narrow thorax, scoliosis, low life expectancy due to due to respiratory issues
upd(14)pat –> more severe than upd(14)mat
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.
Prader-Willli
upd(15)mat (30%)
deletion at 15q12 (70%)
imprinting defect (2%)
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%)
chromosomes with proven imprinted genes
6, 7, 11, 14, 15
UPD testing guidelines
SUMMARY OF CLINICAL AND DIAGNOSTIC
CONSIDERATIONS
- Chromosomes of known clinical relevance include 6, 7, 11,14, and 15.
- 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. - Testing should be performed on DNA collected from the mother, father, and child/fetus using polymorphic markers.
- Reporting of results includes at least two fully informative markers from each chromosome of int
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%
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
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
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
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 --
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
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
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—17p11.2Prader Willi
- mechanism?
- traits?
UPD15mat – prader needs fader]
Moderate Intellectual disability Neonatal hypotonia Hypogenitalism Hyperphagia – obesity Short stature Small hands and feet Characteristic facies
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%)
del 1p36 syndrome: accounts for what percent of idiopathic ID? prevalence?
0.5-1.2% ;
1 in 5,000
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
McDermid- Phelan syndrome
microdel 22q13
Hypotonia Severe Language Delay Mild Facial Dysmorphism Intellectual disability Deletion of SHANK3
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:
- Multiple anomalies not specific to a well-delineated genetic syndrome
- Apparently non-syndromic DD/ID [developmental delay/intellectual disability]
- Autism spectrum disorders”
chance of finding CMA abnormality in population selected for
- pediatric
- ID/DD
17.4%
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
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
16p11.2
Microdeletions and microduplications
low copy repeats
Autism; minor facial anomalies; speech delay
parents may have no features
16p13.11
Microdeletions and microduplications
low copy repeats
Neuropsychiatric disorders; dysmorphic features; congenital heart defects
parents may have mild features
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
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)
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
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
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
if ultrasound abnormality, chance that CMA will yield DX that is NOT detectably by karyotyping?
6%
if AMA, chance that CMA will yield DX that is NOT detectably by karyotyping?
1.7%
When to use CMA in prenatal?
- > = 1 major structural abnormality on u/s
[replaces karyotype!] - diagnostic procedure with structurally normal fetus (CVS, amnio) – can do CMA or Karyo
- NO AGE LIMIT – not just for 35+ women
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
advantage of SNP microarray over aCGH
- identity by descent (IBD)
- UPD
- contamination
- triploidy
bonus:
- complicated MCC delineation
- detection of complete mole
first cousins have +_____% risk of a kid with a congenital anomaly, relative to the general population
2-2.5% (due to recessive condition)
most common chromosome abnormalities at conception
Condition (% spontaneous abortion)
Total (94%)
- triploidy/tetraploidy (100%)–> thus importance of SNP CMA
- 45,X (99%)
- Tri16 (100%) –> most common trisomy in 1st trimester
- Tri18 (95%)
- Tri21 (78%)
- other Tri (99.5%)
- other sex chrom aneuploidy (21%) : XXY, XXX, XYY
- unbalanced rearrangements (85%)
- balanced rearrangements (16%)
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.
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
purpose of satellite in FISH
tracks centromeric regions for TOTAL chromosome count (generally)
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.
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.
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.
SNP array - what does log2 ratio tell you?
whether there is deletion/duplication in that area.
structural rearrangement breakpoints most often occur in these two places
- subtelomeric regions
- pericentromeric regions
i.e., near ends, or near center.
structural rearrangements: where most common? (“recurring”)
- 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.
- low-copy-number repeats –>reciprocal del/dup of regions between LCRs happens due to high homology of LCRs that “cross over”
- AT-rich palyndromes
- inversion polymorphisms
- non-homologous end joining (NHEJ)
- 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)
inverted Low-copy-number repeats (LCRs) on the same chromosome can lead to what genomic rearrangement for material between them?
inversion
inversion polymorphisms (submicroscopic) predispose to ___
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%)
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
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
etiologies of deletion in child can be caused by:
- gonadal mosaicism
- de novo
- parent may be balanced rearrangement carrier –> therefore need karyotype OR FISH
- parent may carry it/be mildly affected if small del
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)
in setting of DD/ID/autism spectrum:
what percent of time will traditional cytogenetics (karyotype) yield a diagnosis?
5-10%, closer to 5%
in setting of DD/ID/autism spectrum:
what percent of time will FISH yield a diagnosis?
0.5-7%
in setting of DD/ID/autism spectrum:
what percent of time will oligo(aCGH) /SNP CMA yield a diagnosis?
15-20%
Puerto Rican grandma with dementia
PSEN1 - presenilin1
autosomal dominant form of early-onset (
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.
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.
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)
Parkinson Disease - dominant gene?
LRK2 ~ reduced penetrance ~ 30-74%
- 5% of sporadic PD in USA
- 26% of familial PD in USA
15-20% of PD in Ashkenazi
30-40% of PD in North African
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
FrontoTemporal Dementia can mimic which disease?
Parkinsons (symptoms)
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
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%
c9orf72
expansion GGG - autosomal dominant
frontotemporal dementia and/or ALS w/w/o psychotic features
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)
Gowers sign is indicative of ___ muscle weakness
proximal muscle weakness
Duchenne carrier females - are they followed?
yes, must monitor cardiac health
Limb Girdle
strictly clinical dx - very unspecific
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
Limb Girdle (sarcoglycanopathies, types 2c -q) VS Duchenne – differences?
LG - recessive, not XL
LG - no cognitive impairment
which neuromuscular disorder comes with inability to release grip quickly?
Myotonic Dystrophy, type 1 ~ CPG expansion
“percussion myotonia” = grip symptom
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
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
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.
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
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
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
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
Congenital Muscular Dystrophy (Bethlem)
COL6A1/2/3 - less severe than Ullrich
keloid (big) scarring
nocturnal hypoventilation !!!
mostly autosomal dominant
no intellectual disability
DAG1 - molecular mechanism
aberrant alpha dystrtoglycan GLYCOSYLATION - muscular dystrophy spectrum of conditions WITH intellectual disability
Cobblestone Lissencephaly 1
Walker-Warburg (POMT1, etc)
presents with congenital:
- weakness, contractures
- seizures
- eye malformations
- death by age 3
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
Cobblestone lissencephaly 3
Muscle-Eye-Brain Disease (POMGnT1, etc)
- variable ID
- weakness, contractures, delayed milestones at 5 yo
- visual impairment (or just esotropia)
developmental delay + elevated CK –>
glycosylation disorders (muscular dystrophies with ID) -- muscle-eye-brain disease
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
FKRP gene
- muscular dystrophy gene
- broad phenotypic spectrum
- limb girdle muscular dystrophy (adult onset)
- walker-warburg (eye malform, death by 3)
weakness is face, shoulder, upper arms
Facio-Scapulo-Humeral muscular dystrophy
(autosomal dominant)
- elevated CK
- “dead gene come alive”
Facio-Scapulo-Humeral muscular dystrophy
–> mechanism of Type I?
“dead gene come alive”
D4Z4 repeats 11+ is normal
Facio-Scapulo-Humeral muscular dystrophy
–> mechanism of Type II?
normal # of D4Z4 repeats abnormal methylation (loss) --> DUX4 expression (dominant negative)
LGMD – mostly which inheritance pattern?
90% recessive, 10% dominant
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
Congenital myopathy
e.g., nemaline
- many inheritance patterns (AR, AD, XL)
- many, many genes
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
congenital hip dislocation, spinal deformities, pectus, arched feet, delayed motor milestones
Central core disease (a congenital myopathy - RYR1)
- also positive Gowers, Trendelnburg gait
arthrogryposis
congenital contracture
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!
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
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)
hypotonia, enlarged tongue and liver, hearing loss, HYPERTROPHIC CARDIOMYOPATHY, high CK
Pompe disease - congenital metabolic myopathy. Death by 9 months.
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
tongue fasciculations (twitching)
associated with motor neuron involvement (SMA or ALS)
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
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)
SMA - testing
SMN1/SMN2 - copy number testing
previously, PCR w/restriction enzyme that cuts SMN2, but not SMN1
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 –
congenital myasthenic syndromes
has treatment! AChe inhibitors or Potassium channel blockers
onset - infancy/ childhood, typically
CK normal/mild elevation
no heart of cognitive issues
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
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
most common CMT - mechanism?
CMT1A - AD/demyelinating
– duplication of PMP22
(deletion causes HNPP - hereditary __, pressure palsies)
Neuromuscular disease work-up:
- localize muscle symptom (neuro eval)
2. CK level if weakness (normal
Whole Exome Sequencing does NOT detect which muscular conditions (5 !!)
- dystrophinopathies (del/dup - 60% DMD, 90% Becker)
- CMT1A (duplication at 17p12 PMP22 gene, or del causing HNPP
- Myotonic Dystrophy (CTG or CCTG repeats)
- Facio-Scapulo-Humeral Dystrophy (contraction of D4Z4 repeat)
- SMA - Spinal Muscular Atrophy (homozygous del SMN1)
CMT1A, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy, OR SMA (Spinal Muscular Atrophy)
EACH has a prevalence of ~
1 in 10,000
Tetralogy of Fallot
- associations?
- what are the four features?
etiology mostly unknown
15% due to 22q
some due to maternal diabetes
Features:
- Pulmonary Valve Stenosis [a type of Right Ventricle Outflow Tract Obstruction. There can be other reasons for this obstruction in ToF]
- VSD
- Overriding aorta [aorta shifted right toward VSD]
- 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.
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
low neonatal calcium
DiGeorge - due to hypoparathyroidism
DiGeorge can be seen on karyotype __% of the time
25% of DiGeorge is BIG deletions, visible on karyotype
75% are microdeletions = 22q11.2
22q11.2 - de novo rate?
90%
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)
22q prevalence
1 in 1,000 to 1 in 2,000 – most common microdeletion syndrome
Tetralogy of Fallot is more common in __ than in Down Syndrome
22q11.2
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
prenatal absent thymus
indication for 22q testing
newborn screen - severe combined immunodeficiency
associated with 22q - need to order microarray or MLPA
baby: nasal regurgitation and GERD – condition?
22q ; nasal regurgitation is never normal
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!
physical manifestations of endocrine abnormalities in 22q
prenatal IUGR
short stature
hypo/hyper-thyroidism
growth hormone deficiency
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
RARE 22q prenatal findings:
Diaphragmatic hernia
Polyhydramnios
Polydactyly !!
– Pre and postaxial
Club Foot
Radial ray defects
craniosynostosis
hemifacial microsomia
22q ear findings
Microtia/Anotia Preauricular tags Preauricular pits Helical differences Protuberant ears
22q can unmask recessive disorders:
Bernard-Souilier syndrome (GP1BB mutation)
- Thrombocytopenia
- Increased megakaryocytes
CEDNIK syndrome (SNAP29 mutation)
- Cerebral dysgenesis (polymicrogyria)
- Neuropathy
- Ichthyosis
- Keratoderma
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%)
22q - if negative, can consider:
if FISH testing done, MLPA or microarray TBX1 mutation (is within 22q region)
differential diagnoses of 22q
CHARGE Kabuki Smith-Lemli-Opitz (elevated msAFP) Goldenhar (butterfy vertebrae) Alagille (butterfly vertebrae) Jacobsen (11qter del)
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
most nuclear-encoded mitochondrial disorders are __ inheritance
autosomal recessive
but AD, XL, and trinucleotide repeats also (Friedrich Ataxia)
Mito disorders – which molecular processes?
pyruvate —-(PDHC)—> acetate –> Krebb Cycle –> Complex i, Complex II –> Electron Transport chain
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
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
mitochondria - ribosome / tRNA ?
mito genome encodes own ribosome 16S/12S
mito genome encodes tRNA, rRNA (because mito genetic code is slightly different) !!!
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.
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)
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
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.
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.
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)
lactic acidosis can be sign of
mitochondrial disease (pyruvate goes to lactate, instead of to acetate, and Krebb cycle.)
Friedrich Ataxia - mechanism?
GAA trinucleotide repeat expansion (recessive)
insufficient frataxin = mitochondrial iron chaperone
–> mitochondrial dysfunction / mito phenotype
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.
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.
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!
early-onset liver disease
mitochondrial DNA depletion
- can be caused by nuclear DNA mutations
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
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
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.
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.
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!
-
mito disease - inheritance?
- -> infantile, severe
- -> later-onset, less severe
- -> infantile, severe – AUTOSOMAL RECESSIVE
- -> later-onset, less severe — MATERNAL MT
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)
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.
Kearns Sayre - inheritance?
MOST of the time, sporadic
but since it’s due to mutation/del in mtDNA, it has mitochondrial inheritance.
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.
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
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
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
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.
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
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
Loeys-Dietz
dominant
aortic dilation/aneurism bifid uvula/cleft arterial tortuosity hypertelorism craniosynostosis
HIGH RATE of pregnancy-related complications
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.
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.
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.
Krabbe disease
leukodystrophy
myelin issues due to shortage of galactosylceramidase.
recessive
vision loss
seizures
onset
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
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
urea cycle defect: what happens to blood pH?
metabolic/respiratory?
alkalosis/acidosis?
primary respiratory alkalosis
– response to high ammonia.
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.
NTBC
pesticide
miracle drug for Tyrosinemia
blocks upstream of homogentisate so that several reactions downstream, toxic succinylacetone isn’t made.
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
cram.com biochemical genetics flashcards
http://www.cram.com/flashcards/biochemical-genetics-iemcancer-genetics-i-ii-2934076
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.
Alkaptonuria
Example of <b> too much substrate interfering with normal cellular processes </b>
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
Ochronosis
The deposition of pigment in connective tissue observed in alkaptonuria.
Hemochromatosis: definition and how it’s treated
too much iron. Phlebotomy to take out iron.
Actually a fairly common disorder but has low penetrance.
Tay-Sachs
TSD is caused by insufficient activity of an enzyme called <b>hexosaminidase A</b> 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,<b> the lipids (gangliosides) accumulate in the brain and interfere with normal biological processes. </b>
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.
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
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)
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)
elevated msAFP
could be:
Smith-Lemli-Opitz, esp if breech, or low uE3
gastroschesis (median 9 MoMs)
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
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
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
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
risk aneuploidy at age 40
~1/40
actually, 1/41, at mid-pregnancy
DS is about 1/2 as common
risk aneuplodiy at 35
~1/135
actually, 1/130, at mid-pregnancy
DS is about 1/2 as common
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
lemon sign and or banana sign
neural tube defect
duodenal atresia - risk for DS?
30%
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%
choroid plexus cyst
1% of 2nd tri ultrasouds
doesn’t matter, 1 or many
assoc w Edwards (Tri 18)
congenital diaphragramtic hernia
- prevalence?
- genetic syndromes?
1 in 2,000
Pallister-Killian (i12p mosaic) Cornelia de Lange CHARGE Beckwith-Wiedemann Goldenhaar Fryns
Marfan
upper/lower segment ratio =2
family history
FBN1 mutation
systemic features
alternatively, MASS = myopia, MVP, borderline aortic root dilation, striae, skeletal findings
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
risk cut-off to screen positive on
FTS
second tri screen
FTS: 1 / 230
2nd: 1/270
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%
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
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
CBC - is it useful for sickle cell?
no. unless person has alpha thal trait.
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
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
cauliflower sign
gastroschisis
cystic kidneys
Tri 13
Meckel Gruber
adult PKD
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
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
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
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
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.
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.
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.
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)
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.
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%)
elevated msAFP - another cause of it
IUGR
can be detected around 23 weeks, need 3 weeks between measurements to assess growth retardation
isovaleric acidemia
sweaty feet smell during illness
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.
Wilson Disease
copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances,
Kayser-Fleischer rings in cornea
recessive
Tuberous sclerosis complex
tsc1, tsc2
tumor suppressor
dominant
2/3 de novo
SEGAs
dev. delay
renal angiomyolipomas
ashfield spots
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
mt depletion syndrome
autosomal recessive
encephalopathy
liver failure
Kearns-Sayre syndrome
ocular myopathy
ataxia
heart conduction defect
increased CSF protein
onset
