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Study and Diagnosis of Disease > Lecture 15 - X-linked Disorders > Flashcards

Lecture 15 - X-linked Disorders Flashcards

1
Q

What is a pedigree

A

a pictorial representation of a family medical history to visualize whether a disease is tracking through a family and to identify inheritance patterns

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2
Q

What are requirements for a pedigree

A
  • All family members, including both maternal and
    paternal lineages
  • A minimum of three generations
  • Illnesses of each family member
  • Current age, age at diagnosis of an illness, and age at
    death
  • Miscarriages or stillbirths
  • Adoptions
  • Ethnicity
  • Birth defects
  • Neurodevelopmental disorders
  • Known genetic condition
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3
Q

What is a genotype

A

an individuals actual DNA sequence at a specific locus

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4
Q

What is a phenotype

A

observable ways in which that DNA sequence manifests in the individual

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5
Q

What is an allele

A

an alternate form of a gene

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6
Q

What is wild-type

A

an allele in its most common form in a population

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7
Q

What does variant mean

A

an allele that has a permanent alteration in its DNA sequence

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8
Q

What is homozygous

A

two identical alleles

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9
Q

What is heterozygous

A

two different alleles

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10
Q

What is hemizygous

A

a single allele in a male on their X-chromosome

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11
Q

What are indicators of an x-linked genetic disorder

A
  • Family history of multiple affected male family members in the maternal side
  • Family history of neonatal, infantile or childhood deaths in males in the
    maternal side
  • Family history of mildly affected females (e.g. sisters, mothers, maternal aunts
  • No known risk factors
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12
Q

What are characteristics of x-linked recessive inheritance

A
  • Phenotypic expression much higher in males
    than females
  • Heterozygous females usually do not have
    phenotypes, however
  • X-linked disorders inherited from fathers to all of their daughters
  • X-linked disorders never transmitted from father to their sons
  • Affected males within the same family always
    related through females
  • Significant proportion is due to new or de novo
    variants in a gene on the X-chromosome
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13
Q

What are characteristics of x-linked dominant inheritance

A
  • affected males have normal sons and effected daughters
  • male and female offspring of an affected females have 50% risk of having the genetic disease
  • more common phenotypic expression in females than males but females have milder phenotypic expression
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14
Q

What is X-inactive specific transcript

A
  • Non-coding untranslated RNA
  • Major effector of the X-inactivation process
  • Component of the X-chromosome
    inactivation centre located on the inactive X-chromosome
  • Causes chromatin condensation and
    inactivation, called Barr body
  • Epigenetics change, involving a change to
    gene but does not involve a base change
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15
Q

How can females ameliorate the effects of pathogenic variants

A

if they aren’t homozygous for the pathogenic variant, the X with the variant will always be silent as a protection mechanism

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16
Q

If a disorder has a lethal variant

A
  • most males die in utero
  • females or mosaic males survive
  • some x-linked diseases occur only in females or mosaic males
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17
Q

How to evaluate x chromosome inactivation

A

differential DNA methylation of x alleles, expressed polymorphisms, analysis of DNA replication timing

18
Q

What is the most accepted method of testing DNA methylation of X alleles

A

Human androgen receptor (HUMARA)

19
Q

How does HUMARA work

A
  • Methyl-CpG-sensitive restriction-endonuclease-based
    PCR assay
  • Targets the polymorphic short tandem repeat of the Xqlinked androgen receptor (AR) gene
  • Methylation status of the AR alleles on inactive X
    chromosome correlates with the whole X chromosome
    inactivation
  • Paternal X and maternal X have 50% probability of being
    methylated and inactivated
  • A 1:1 ratio for X chromosome inactivation is
    expected if a random event
  • Any deviations from this theoretical ratio skewed X
    inactivation
20
Q

What is methylation-specific PCR

A
  • Independent of the use of
    methylation-sensitive enzymes
  • Two-step approach:
  • PCR with primers specific for
    methylated versus
    unmethylated DNA
  • Chemical modification of DNA
    with sodium bisulfite
  • Sodium bisulfite
    treatment converts the
    methylation difference
    into a DNA sequence
    difference
  • Unmethylated
    cytosines are
    converted into uracil
21
Q

What is MECP2

A
  • located on Xq28
  • methyl-CpG binding protein 2
  • a chromatin associated protein
  • activates and represses transcription
  • highly expressed in human brain
22
Q

How does MECP2 present in symptomatic females

A

Progressive neurodevelopmental disorder
* Normal development first 6-18 months of life
* Developmental stagnation
* Rapid regression
* Repetitive, stereotypic hand movements replace
purposeful hand use
* Fits of screaming and inconsolable crying
* Autistic features
* Panic-like attacks
* Bruxism
* Episodic apnea and/or hyperpnea
* Gait ataxia and apraxia, tremors
* Seizures
* Acquired microcephaly

23
Q

How does MECP2 present in males

A
  • Severe neonatal-onset encephalopathy
  • Abnormal tone
  • Involuntary movements
  • Severe seizures
  • Breathing abnormalities
  • Death often occurs before age two years
24
Q

What is the diagnosis of MECP2

A
  • Sequencing and deletion/duplication
    analysis of MECP2
  • More than 99% are simplex cases
    (i.e., a single occurrence in a family)
25
Q

What is DMD

A
  • located on Xp21.22
  • encodes dystrophin protein (large muscle protein)
  • hemizygous or heterozygous pathogenic variants result in dystrophinopathies
26
Q

What is duchene muscular dystrophy

A
  • Delayed motor milestones including delays in
    walking independently and standing up from a
    supine position in early childhood
  • Waddling gait and difficulty climbing stairs,
    running, jumping, and standing up from a squatting
    position
  • Wheelchair dependent by age 12 years
  • Cardiomyopathy occurs in almost all individuals
    with DMD after age 18 years
  • Few survive beyond the third decade, with
    respiratory complications and progressive
    cardiomyopathy being common causes of death
27
Q

What is becker muscular dystrophy

A
  • later-onset skeletal muscle weakness
  • mild end includes men with onset symptoms after age 30
  • heart failure from dilated cardiomyopathy is a common cause of morbidity
  • mean age of death is in the mid-40s
28
Q

Females with DMD

A
  • sometimes females can have classic DMD
  • the prevalence of cardiomyopathy can vary from 3%-33%
  • no correleation of phenotype, age, CK level or muscle systems
29
Q

Phenotypes of females with DMD

A
  • Penetrance in heterozygous females
    varies, and may depend in part on
    patterns of X-chromosome
    inactivation (XCI)
  • Some studies have shown no clear
    correlation between the active-toinactive X-chromosome ratio
    observed in XCI studies in leukocytes
    and serum CK concentration, clinical
    signs, or the proportion of dystrophin-negative fibers observed
    on muscle biopsy
  • In another study of seven
    symptomatic heterozygous females,
    the XCI pattern was skewed toward
    non-random in the four with deletions or duplications but was
    random in the three with
    pathogenic nonsense variants
  • In another study more than 90% of heterozygous females with skewed XCI (defined as ≥75% of nuclei
    harboring the DMD pathogenic variant on the active X-chromosome)
  • Direct correlation with a skewed XCI
    pattern was also observed recently in
    cohorts of symptomatic and asymptomatic DMD/BMD carriers
30
Q

What is the ABCD1 gene

A

-located on Xq28
- encodes ATP-binding cassette subfamily D member 1
- results in X-linked adrenoleukodystrophy

31
Q

How does X-linked adrenoleukodystrophy present in males

A
  • Childhood cerebral form manifests most commonly between ages four and eight years.
  • Initially resembles attention-deficit disorder or hyperactivity
  • Progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial
    symptoms and often lead to total disability within six months to two years
  • Most individuals have impaired adrenocortical function
  • Adrenomyeloneuropathy (AMN): progressive stiffness and weakness of the legs, sphincter disturbances, sexual
    dysfunction, and often, impaired adrenocortical function in early adulthood, progressive over decades.
  • Primary adrenocortical insufficiency from 2 years of age
32
Q

How does X-linked adrenoleukodystrophy present in females

A
  • More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later
  • Adrenal function is usually normal
33
Q

How is X-linked adrenoleukodystrophy diagnosed

A
  • suggestive clinical findings
  • elevated very long chain fatty acids
  • MRI
34
Q

What is hemophilia A

A
  • located on Xq28
  • encodes coagulation factor VIII
35
Q

How does hemophilia A present in males

A
  • Prolonged bleeding after injuries, tooth extractions, or surgery
  • Delayed or recurrent bleeding prior to complete wound healing.
  • Severe hemophilia A: During the first two years of life
  • Spontaneous joint bleeds or deep-muscle hematomas
  • Prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth
    extractions
  • Moderate hemophilia A: Diagnosed before age five to six years
  • Prolonged or delayed bleeding after relatively minor trauma
  • Mild hemophilia A: Diagnosed later in life
  • Pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions
36
Q

How does hemophilia A present in females

A
  • Approximately 30%
    of heterozygous females have
    factor VIII clotting activity
    below 40% and are at risk for
    bleeding
  • After major trauma or
    invasive procedures,
    prolonged or excessive
    bleeding usually occurs
  • 25% of heterozygous females
    with normal factor VIII
    clotting activity report an
    increased bleeding tendency
37
Q

What is the FMR1 gene

A
  • located on Xq27.3
  • encodes fragile X messenger ribonucleoprotein 1
  • a selective RNA binding protien
  • plays a central role in neuronal development and synaptic plasticity
38
Q

What is fragile X syndrome

A
  • most common heritable form of intellectual disability
  • penetrance in females in the 50-60% range
  • a trinucleotide repeat disorder
39
Q

How does fragile X present in males

A
  • affected males may have characteristic craniofacial features
  • neurodevelopmental disorders
  • seizures
  • sleep disorders
  • scoliosis
  • mitral valve prolapse or aortic root dilation
40
Q

What is the SLC6A8 gene

A
  • located on Xq28
  • encodes solute carrier family 6 member 8
  • contains 13 exons, spans about 8.5kb of genomic dna
  • sodium-chloride-dependent transporter protein
41
Q

How to diagnose a creatine transporter deficiency

A
  • heterozygous novel missense variant
  • 50% of normal creatine uptake in fibroblasts
  • chromosome analysis
  • no skewed x-inactivation in peripheral blood

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