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Diagnosis of Genetic Diseases > Lecture 14 > Flashcards

Lecture 14 Flashcards

1
Q

who do migraines mostly affect?

A

women

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2
Q

describe the overall occurrence of a migraine:

A

a transient attack

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3
Q

what are the 6 phases of a migraine?

A
  1. normal
  2. prodromes (symptoms that anticipate the attack)
  3. aura (phase beforehand)
  4. headache (acute phase - symptoms occur)
  5. resolution
  6. recovery
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4
Q

what is the migraine condition characterized by?

A

great variability, heterogeneity, and severity

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5
Q

who determines the classifications of migraines?

A

neurologists society

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6
Q

what are the two main classes of migraines?

A

migraine with aura and migraine without aura (and many subclasses as well)

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7
Q

what is the diagnosis of a migraine based off of?

A

the physicians assessment of the symptoms (there are NO clinical tests)

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8
Q

what do we have to do when we do not know the molecular basis for a disorder, but we want to?

A

we must start by looking at a similar cohort with a similar phenotype

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9
Q

do we know the genetic background of migraines?

A

no → we think there is a genetic predisposition

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10
Q

what are the two different cases of migraines to study?

A

the common migraine and the genetic / familial case

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11
Q

which form of a migraine is more difficult to study?

A

common - many patients and diverse set of symptoms

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12
Q

what is a familial hemiplegic migraine (FHM)?

A

a rare subtype of migraines with aura, and is characterized by an autosomal dominant linearism, often with an onset from childhood (~5yrs) until the age of 30

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13
Q

what is familial hemiplegic migraine characterized by?

A

different degrees of severity with heterogeneity in the frequency period and severity of migraine attacks - different clinical phenotypes in different members of the same family

in some cases these attacks are so severe that there is an alteration in the state of consciousness and can be associated with neurological disorders such as late onset cerebellar ataxia

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14
Q

where have loci been found to be associated with FHM?

A

chromosome 19

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15
Q

what did linkage analysis on chromosome 19 want to investigate?

A

sever traits of that chromosome and identified loci for both allele (for each affected and unaffected family member) to identify which loci on the chromosome was associated with the pathological phenotype

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16
Q

what did the linkage analysis discover?

A

that FHM is an autosomal dominant disorder characterized by variable onset and phenotype - possible to have two members with migraine and two with FHM

may also have late onset or the case of incomplete penetrance

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17
Q

although it is a rare disorder, where in the world are there a lot of cases of FHM?

A

Italy

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18
Q

what is the causative gene for FHM?

A

CACNA1A

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19
Q

what does CACNA1A code for?

A

neuronal calcium channels which play an important role in maintaining ion balance at the neuronal level

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20
Q

neuronal calcium channels of the gene CACNA1A are characterized by which subunits?

A

main subunit is ⍺ (⍺1 and ⍺2) but also β, 𝛾, δ

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21
Q

what is the neuronal calcium channel characterized by?

A

four different domains, each of which is composed of 6 different transmembrane domains

22
Q

what is the main mutation in FHM localized to?

A

the entire structure → we have missense or stop mutations that are localized on the entire protein

23
Q

what is the second most mutated gene in FHM?

A

ATP1A2

24
Q

what does ATP1A2 encode for?

A

sodium-potassium pump and is not located on chromosome 19, but on chromosome 1

25
Q

what is ATP1A2 composed of and how does the mutation affect this gene?

A

multimeric membrane protein composed of ⍺ and β subunits → protein that is expressed in the central nervous system and the main mutation is a missense mutation located on the entire protein

26
Q

name the third gene associated with FHM:

A

SCN1A located on chromosome 2

27
Q

what does SCN1A code for, and in what other disease is it found?

A

codes for the sodium channel expressed in the CNS - SCN5A is the causative gene in Brugada syndrome, and is the cardiac isoform of this gene

28
Q

name another mutation associated with FHM as well as epilepsy:

A

SAN1A - gene associated with epilepsy - implies an alteration in electrical activity

29
Q

what type of mutation do all of the genes associated with FHM have?

A

gain of function of the protein → generates an increased release of glutamate in the synaptic terminal, resulting in a synaptic increase of the glutamate neurotransmitter and to an increase excitability o the neuron

30
Q

when testing a patient for FHM, what else can finding the causative gene tell us?

A

identification of the mutation but also be useful for the classification of the form of FHM

31
Q

what do the majority of the cases result in when there is only a single nucleotide variation?

A

a nonsense or missense mutation

32
Q

what is another important approach that was exploited to identify the genetic basis of the common form of migraines?

A

genome wise association study (GWAS)

33
Q

what are the major issues of GWAS?

A

necessary to have a huge number of patients and a lot of controls and is near impossible to validate in most cases

34
Q

what is the GWAS study of migraines find?

A

one statistically significant SNP associated with the susceptibility to the common form of migraine → it is not possible to consider that polymorphism in the diagnostic workflow because there is no additional information and the quality of the data on which this polymorphism is based is quite poor

35
Q

to sum it up, what is a migraine?

A

a heterogenous disorder with a genetic predisposition

36
Q

what occurs during a seizure in epilepsy?

A

there is a sudden alteration of the electrical conduction and activity of the brain, which can lead to sensory, moron, cognitive, or also psychic functional modification

37
Q

what is the diagnosis of epilepsy based on?

A

the clinical evaluation → there are no laboratory tests

38
Q

what are the three forms of onset in epilepsy?

A
  1. focal onset
  2. generalized onset
  3. unknown onset
39
Q

what is the focal onset form of epilepsy?

A

there is aware or impaired awareness and a motor or non-motor phenotype

40
Q

describe the generalized form of epilepsy:

A

there is an impaired awareness with motor or non-motor phenotype, also characterized by different tonic-clonic crisis or by the absence (loss of consciousness)

41
Q

describe the other forms of epilepsy:

A

clinical characterization is very difficult, and cannot be categorized in either of the other two groups

42
Q

what are the three ways the epilepsy can be caused?

A

genetic form, inherited, or because of a traumatic brain injury

43
Q

what is the genetic form of epilepsy caused by?

A

incomplete penetrance and by the presence of phenocopies: this results in a genetic heterogeneity → different genes are associated to the different forms, and in a variability in the inheritance of the genetic cause makes it difficult to have a clear clinical diagnosis

44
Q

what did an evaluation of twins discover about the weight of genetic and environmental factors on epilepsy?

A

high concordance among homozygotic twins was reported indicating a strong genetic predisposition

45
Q

when a genetic study is performed, what determines a successful result?

A

the identification of known genes to a known phenotype or if we identify a new mutation associated to a specific gene

46
Q

what is a candidate gene?

A

a gene that probably is the causative gene for a phenotype, but in order to define a causative gene it is necessary to demonstrate that this gene has a pathological effect and a pathological involvement in eh phenotype → if it is not possible to demonstrate this relationship, it is defined as a candidate gene

47
Q

why is it impossible to quantify the success rate when we consider the genetic characterization of different forms of epilepsy?

A

in the case of a negative result, nothing is reported

48
Q

so far, what percentage of autosomal dominant and autosomal recessive forms of epilepsy are we able to characterize ?

A
  • 25% of autosomal dominant
  • 40% of autosomal recessive
49
Q

why is it easier to characterize autosomal recessive forms of epilepsy?

A

it is easier to identify segregation when there is recessive inheritance

50
Q

when genetic research was performed on epilepsy, what occurred if there was the identification of a variant in a known gene or gene of good candidacy?

A

it was possible to proceed considering the segregation of those variants in other family members

51
Q

if a positive segregation was found, what was the next step in the genetic analysis of the family?

A

it was possible to perform the molecular diagnosis for that family

Diagnosis of Genetic Diseases (18 decks)

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