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MLSCI 480 > X-Linked Disorders > Flashcards

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

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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
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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
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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
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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
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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

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6
Q

techniques to evaluate X chromosome inactivation

A
  • differential DNA methylation of X alleles
  • expressed polymorphisms
  • analysis of DNA replication timing
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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
    >
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8
Q

expressed polymorphisms

A

RNA-level polymorphisms of X-linked informative genes

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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
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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
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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
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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
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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
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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
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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
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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
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17
Q

most common heritable form of intellectual disability

A

fragile X syndrome
> frequency 1 in 3000/4000 male births

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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
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19
Q

pedigree is essential in genetic clinics for at least # generation

A

3

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20
Q

essential first step in determining inheritance patterns

A

making a pedigree

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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
Q

some x-linked diseases occur only in females or mosaic males

A

incontinentia pigmenti
orofacial digital syndrome type 1

25
Q

techniques to evaluate X chromosome inactivation

A

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
Q

DNA methylation of X alleles

A
  • 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
Q

T or F. For DNA methylation of X alleles, a 1:1 ratio for X chromosome inactivation is expected if a random event

A

T
any deviation from this theoretical ration = skewed X inactivation

28
Q

methylation-speicific PCR

A
  • independent of methylation-sensitive enzymes
  • 2-step approach
29
Q

Describe the 2-step approach of methylation-specific PCR

A
  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
Q

expressed polymorphisms

A

RNA-level polymorphisms of X-linked informative genes

31
Q

how are x-linked genetic diseases classified?

A

phenotypes in M vs F
X-inactivation status
location on X chr
affected organ

32
Q

MECP2 gene

A
  • 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
Q

MECP2 disorders in females

A

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
Q

MECP2 in males

A

severe neonatal onset encephalopathy
- abnormal tone
- inv movements
- severe seizures
- breathing abnormalities
- death before age 2

35
Q

how to diagnose MECP2 disorder

A

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
Q

DMD gene

A

Xp21.2-p.21.1
dystrophin protein = large muscle protein

37
Q

how do dystrophinopathies arise?

A

hemizygous or heterozygous pathogenic variants in DMD -> dystrophinopathies

38
Q

Duchene muscular dystrophy

A
  • 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
Q

Becker muscular dystrp[hy

A

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
Q

most common cause of death of Becker muscular dystrophy (BMD)

A

heart failure from dilated cardiomyopathy

41
Q

females with DMD

A

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
Q

diagnosis of DMD/BMD

A

charactristic clinical findings = progressive muscle deficiency, early onset, delayed muscle development

elevated CK concentration

identification of a hemizygous pathogenic variant in DMD

43
Q

male X-linked adrenoleukodystrophy

A
  • 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
Q

X-linked adrenoleukodystrophy in females

A

more than 20% of carriers develop mild-to-moderate spastic paraparesis in middle age or later
adrenal function normal usually

mistaken for MS

45
Q

T or F. affected males transmit the ABCD1 pathogenic variant to all of their duaghters and none of their sons

A

T!

46
Q

ABCD1 inheritance

A

M with pathogenic variant = affected
F with variant = carriers and usually not seriously affected
carrier females = 50% chance of transmitting

47
Q

The phenotypic expression and prognosis of an affected male in this disorder is unpredictably variable

A

adrenoleukodystrophy

48
Q

males FVIII def

A
  • prolonged bleeding
  • delayed or recurrent bleeding prior to complete wound healing
  • severe hem A, moderate hem A and mild hem A
49
Q

severe hemophilia A

A

first two years of life; spontaneous joint bleeds, deep-muscle hematomas, prolonged bleeding or excessive pain + swelling from minor injuries

50
Q

moderate hemophilia A

A

diagnosed before age 5-6 years
prolonged or delayed bleeding after relatively minor trauma

51
Q

mild hemophilia A

A

diagnosed later in life
pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions

52
Q

hemophilia A in females

A
  • ~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

MLSCI 480 (16 decks)

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