X-Linked Disorders Flashcards
1
Q
what does variant mean?
A
mutation in old terminology
allele that has a permanent alteration in its DNA sequence
2
Q
characteristics of an X-linked disorder
A
- multiple affected mal family members in maternal side
- family history of neonatal infantile or childhood deaths in males in the maternal side
- family history of mildly affected females (sisters, mothers, maternal aunts)
- no known risk factors
3
Q
x-linked recessive pattern
A
- phenotypic expression much higher in males than females
- heterozygous fmales usually no phenotypes; rare = depending on X-activation in tissues, females may have phenotypes
- daughtrs of afected father always have allele; but father never transmits to son
- affected males within same family always related through females
- significant proportion due to nw or de novo variants in a gene on the X chromosome
4
Q
x-linked dominant pattern
A
- affected males = normal sons and affected daughters
- male and female offspring of an affected female = 50% risk of having genetic disease
- more common phenotypic expression in females than males, but females have milder phenotypic expression of the genetic disease
5
Q
random x chromosome inactivation in females
A
- every tissue have 2 kinds of cells = either w maternal X active or with paternal X active
- less susceptible to pathogenic variants in genes on her active X chromosome
5
Q
x-chromosome inactivation
A
mammalian somatic cells can determine how many X-chr are present in order to transcriptionally silence all but one X chromosome
- compensates for dosage of X-linked genes in females vs males
- once established, mitotically tansmitted, ach cell contains both one active and on inactive chromosome in females
- both males and females hav one active X chromosome
- random X chromosome inactivation in females
6
Q
techniques to evaluate X chromosome inactivation
A
- differential DNA methylation of X alleles
- expressed polymorphisms
- analysis of DNA replication timing
7
Q
what is differential DNA methylation of X alleles?
A
- more widespread bc DNA more easily accessible and stable
- promoter regions of X-linked generally hypermethylated to maintain their inactive states
- HUMARA most accepted
>
8
Q
expressed polymorphisms
A
RNA-level polymorphisms of X-linked informative genes
9
Q
MECP2 gene
A
- located on Xq28
- methyl-CpG binding protein 2 gene
- binds methylated CpGs
- chromatin-associated protein
- can activate and repress transcription
- required for maturation of neurons
- highly expressed in human brain
10
Q
MECP2 disorders in females
A
- progressive neurodevelopmental disorder
- normal psychomotor in first 6-18mos of life
- developmental stagnation
- rapid regression in language and motor skills, followed by long-term stability
- epetitive, stereoptupic hand movements replace purposeful hand use
- fits of screaming and inconsolable crying
- autistic features
- panic-like attacks
- bruxism
- episodic apnea/hyperpnea
- gait ataxia and apraxia, tremors
- seizures
- acquired microcephaly
11
Q
MECP2 disorders in males
A
- more severe phenotypic neurdevelopmental features
- severe meonatal-onset encephalopathy
- abnormal tone
0 involuntary moements - severe seizures
0 breathing abnormalities
0 death occurs oftn before age 2
12
Q
DMD gene
A
- located on Xp21.2-p.21.1
- encodes dystrophin protein, a large muscle protein
- hemizygous or heterozygous pathogenic variants in DMD results in dystrophinopathies
13
Q
ABCD1 gene
A
- located on Xq28
- encodes ATp-binding cassette subfamily D member 1
> member of ABC protein transporter family - transporter of FAs into peroxisome
- failure to transport FAs = prevents beta-oxidation and allows continued elongation of fatty acids, resulting in accumulation of very long chain FAs
- result = lipids accumulate abnormally in all tissues but predominantly affect the nervous system, adrenal cortex, and Leydig cells of testes
- hemizygous or heterozygous pathogenic variants in ABCD1 results in X-linked adrenoleukodystrophy
14
Q
diagnosis of adrenoleukodystrophy
A
- suggestive clinical findings
- elevated very long chain fatty acids (VLCFA)
- brain MRI abnormal in boys with cerebral disease and often provides the first diagnostic lead
0 diagnosis of X-ALD usually established in female proband with detection of heterozygous ABCD1 pathogenic variant and elevated VLCFA
15
Q
F8 gene
A
- Xq28
- encodes coag factor VIII
> large plasma glycoprotein
> involved in the blood coagulation cascade as a cofactor for the factor Ixa-dependent activation factor X
> activated proteolytically by a variety of coagulation enzymes (thrombin)
> tightly associated in blood w vWF = protective carrier protein - hemizygous or heterozygous pathogenic variants in F8 = hem A
16
Q
FMR1 gene
A
- Xq27.3
- encodes fragile X messenger ribonucleoprotein 1
- selective RNA binding protein
- forms a messenger ribonucleoprotein complex that associates with polyribosomes, suggesting involved in translation
- plays central role in neuronal development and synaptic plasticity through:
> regulation of alternative mRNA splicing
> mRNA stability
> mRNA dendritic transport
> postsynaptic local protein synthesis of target mRNAs
17
Q
most common heritable form of intellectual disability
A
fragile X syndrome
> frequency 1 in 3000/4000 male births
18
Q
fragile X syndrome in males
A
- neurodevelopmental disorders
- cranofacial features = more obvious w age
- hypotonia
- gastroesophageal reflux
- strabismus
- seizures
- sleep disorders
- joint laxity
- Pes planus
- scoliosis
- recurrent otitis media
- mitral valve prolapse or aortic root dilatation
19
Q
pedigree is essential in genetic clinics for at least # generation
A
3
20
Q
essential first step in determining inheritance patterns
A
making a pedigree
21
Q
pictorial representation of a family medical history
A
pedigree
22
Q
an allele in its most common form ina population
A
wild type
23
Q
these individuals can ameliorate the effects of pathogenic variants
A
females
- not homozygous for pathogenic variant; x chr inactivation
24
some x-linked diseases occur only in females or mosaic males
incontinentia pigmenti
orofacial digital syndrome type 1
25
techniques to evaluate X chromosome inactivation
differential DNA methylation of X alleles
- more widespread; DNA more accessible and stable
- promoter regions of X-linked genes on inactivated X = hypermethylated = maintain inactive state
expressed polymorphisms
analysis of DNA replication timing
26
DNA methylation of X alleles
- HUMARA most accepted (human androgen receptor assay)
- methyl-CpG-sensitive resitriction-endonucleas-based PCR assay
- targets polymorphic short tandem repeat of X-linked androgen receptor (AR) gene
- methylation of AR alleles on inactive X chromosome = whole X chromosome inactivation
- patenral and maternal X = 50% pbty of being methylated and inactivated
27
T or F. For DNA methylation of X alleles, a 1:1 ratio for X chromosome inactivation is expected if a random event
T
any deviation from this theoretical ration = skewed X inactivation
28
methylation-speicific PCR
- independent of methylation-sensitive enzymes
- 2-step approach
29
Describe the 2-step approach of methylation-specific PCR
1. PCR w primers specific for methylated vs. unmethylated DNA
2. chemical modification of DNA with sodium bisulfite
- sod bisulf converts methylation difference into a DNA sequence difference; unmethylated cytosines are converted into uracil
30
expressed polymorphisms
RNA-level polymorphisms of X-linked informative genes
31
how are x-linked genetic diseases classified?
phenotypes in M vs F
X-inactivation status
location on X chr
affected organ
32
MECP2 gene
- Xq28
- methyl-CpG binding protein 2 gene
- binds methylated CpGs
- chromatin-associated protein
- can activate and repress transcription
- required for maturation of neurons
- highly expressed in human **brain**
33
MECP2 disorders in females
progressive neurodevelopmental disorder
- normal psychomotor (6-18 mos)
- rapid regression in language, motor skills then long-term stability
- repetitive hand movement to replace purposeful hand use
- screaming and crying fits
- autistic features
- panic-like attacks
- bruxism
- episodic apnea/ hyperpnea
- acquired microcephaly, seizures, etc.
34
MECP2 in males
severe neonatal onset encephalopathy
- abnormal tone
- inv movements
- severe seizures
- breathing abnormalities
- death before age 2
35
how to diagnose MECP2 disorder
sequencing and deletion/dup analysis of MECP2 gene
more than 99% = simplex = single occurrence in family
- de novo pathogenic variant
- small possibility of inheritance of pathogenic variant from a parent who has germline mosaicism
36
DMD gene
Xp21.2-p.21.1
dystrophin protein = large muscle protein
37
how do dystrophinopathies arise?
hemizygous or heterozygous pathogenic variants in DMD -> dystrophinopathies
38
Duchene muscular dystrophy
- delayed motor milestones; delays in walking independently, standing up from a supine position in early childhood
- waddling gait and difficulty climbing stairs, running, jumping, etc.
- wheelchair dependent by ag 12
- few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death
39
Becker muscular dystrp[hy
milder than DMD
- later onset skeletal muscle weakness
- men onset of symptoms after 30 y/o; remain ambulatory till 60
- heart failure from dilated cardiomyopathy is a common cause of morbidity
- mean age of death = mid-40s
40
most common cause of death of Becker muscular dystrophy (BMD)
heart failure from dilated cardiomyopathy
41
females with DMD
can have classic DMD
prevalence of cardiomyopathy can vary from 3 to 33%
no correlation of phenotype (DMD vs BMD), age, CK level, or muscle symptoms was noted
42
diagnosis of DMD/BMD
charactristic clinical findings = progressive muscle deficiency, early onset, delayed muscle development
elevated CK concentration
identification of a hemizygous pathogenic variant in DMD
43
male X-linked adrenoleukodystrophy
- childhood cerebral form = 4 to 8 y/o
> ADHD? hyperactivity?
> progressive impairment of cognition, behaviour, motor function follow initial symptoms
> most have impaired adrenocortical function
- adrenomyeloneuropathy (AMN) manifests in an individual in his twenties to mid-age = progressive stiffness and leg weakness, sphincter disturbances, sexual dysfunction, etc.
- "Addison disease only" = primary adrenocortical insufficiency btween 2y/o and adulthood; most common by age 7.5; no evidence of neurologic abnormality BUT AMN usually develops by mid age
44
X-linked adrenoleukodystrophy in females
more than 20% of carriers develop mild-to-moderate spastic paraparesis in middle age or later
adrenal function normal usually
mistaken for MS
45
T or F. affected males transmit the ABCD1 pathogenic variant to all of their duaghters and none of their sons
T!
46
ABCD1 inheritance
M with pathogenic variant = affected
F with variant = carriers and usually not seriously affected
carrier females = 50% chance of transmitting
47
The phenotypic expression and prognosis of an affected male in this disorder is unpredictably variable
adrenoleukodystrophy
48
males FVIII def
- prolonged bleeding
- delayed or recurrent bleeding prior to complete wound healing
- severe hem A, moderate hem A and mild hem A
49
severe hemophilia A
first two years of life; spontaneous joint bleeds, deep-muscle hematomas, prolonged bleeding or excessive pain + swelling from minor injuries
50
moderate hemophilia A
diagnosed before age 5-6 years
prolonged or delayed bleeding after relatively minor trauma
51
mild hemophilia A
diagnosed later in life
pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions
52
hemophilia A in females
- ~30% of heterozyghous females have FVIII clotting activity below 40%; at risk for bleeding
- major trauma/invasive procedures = prolonged or excessive bleeding
- 25% heterozygous females with nomal FVIII clotting activity report increased bleeding tendency
