Tara Newcomb, MS, LCGC University of Utah June 29, 2012
Genetics of AHC
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Objectives Overview of DNA, genes and chromosomes Inheritance
implications to AHC Genetic testing
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DNA DNA is a code that acts as the instruction manual for our
body. Code 4 letters: A, T, G, C
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DNA DNA is organized into units called genes. Different genes
are expressed in different parts of the body and have different
jobs.
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DNA In order for all of our DNA to fit into each cell in our
body, it is compressed and wrapped around proteins. The end result
are structures called chromosomes. Chromosomes help to organize our
DNA and are key in how our DNA is passed on from one generation to
the next.
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Chromosomes Typically we each have 46 chromosomes in each cell.
The chromosomes come in 23 pairs. We get 1 set of 23 from our
father and 1 set of 23 from our mother
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Changes in DNA Changes in DNA are called mutations Everyone has
mutations in his or her DNA Some mutations have no visible effects
Some mutations cause disease
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Changes in DNA Deletion/Duplication extra or missing DNA
Deletion come in different sizes Different sizes: Whole chromosome
Entire gene Part of a gene A few base pairs Missing DNA if the
information is not there the body cannot read it to make a protein
Disrupt the pattern used to make the protein More is not always
better Extra DNA and extra protein can also cause problems
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Changes in DNA Change to the DNA sequence Spelling error in the
DNA sequence Causes the wrong piece to be added to the protein the
protein cant function Our body recognizes the error and breaks down
the protein
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Inheritance Inheritance patterns are how we describe how
genetic information is passed from one generation to the next. In
general The egg or sperm from each parent has one of each of the
pairs of chromosomes There is a 50% chance to pass on either
chromosome in the pair When the egg and sperm join together to form
the embryo the embryo has a full set of 46 chromosomes 23 from each
parent.
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Inheritance Autosomal Dominant Autosomal Recessive X-linked
Dominant X-linked Recessive Mitochondrial De Novo Mutations (No
Family History)
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Autosomal Recessive Mutations needed in both copies of the same
gene to express disease. A mutation in only 1 copy of the gene does
not cause disease = carrier 25% chance for 2 parents who are
carriers to have an affected child
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Autosomal Dominant A mutation is needed in only 1 copy of the
gene to cause disease The copy with the mutation dominates over the
normal copy. An individual with an AD disease has a 50% chance to
pass the disease on to each child
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De Novo Mutation In many genetic diseases, the mutation in the
gene is not inherited from a parent, but is a new mutation in a
child. Mutations can occur in the creation of the egg or sperm or
when the embryo is created. Changes the recurrence risk
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De Novo Mutation If a mutation is identified in a child and
neither parent has the mutation, the chance of the parents having
another child with the disease is very low. If the affected child
goes on to have children of their own, the chance of them passing
on the mutation is still 50%.
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Penetrance Penetrance refers to whether or not all individuals
with a mutation in a specific gene show symptoms of the disease
related to that gene. 100% Penetrance = everyone with a mutation
shows symptoms of disease 50% penetrance = half of all indivuals
with a muation show symptoms of disease
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Incomplete Penetrance In some diseases, 2 people can have the
same mutation 1 person will have the disease, the other person will
not have the disease. We do not always understand what causes one
person to show symptoms of disease over another.
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Variable Expressivity Children with the same disease have
different symptoms of the disease. Even 2 people with the same
change in their DNA can have different symptoms.
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Genetics of AHC Up to this point: No single genetic cause has
been identified for AHC. Diagnosis of exclusion No way for
physicians to confirm a child has AHC via a specific single
test.
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Genetics of AHC Familial Hemiplegic Migraines Some patients
with AHC-like symptoms have had mutations identified in the
following genes:CACNA1A, ATP1A2, SCN1A Associated with FHM, family
history of migraines is usually present Mutations in these genes
account for a very small number of individuals diagnosed with
AHC.
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Genetics of AHC Majority of cases are sporadic No other family
members with AHC Few familial cases Multiple siblings with AHC
Multiple generations with AHC Different inheritance = Different
genes?
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How do we find a genetic cause for AHC? Then: Family Studies
Difficult with few families with more than 1 individual with AHC.
Usually need several generations to find an answer Needle in a
haystack
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How do we find a genetic cause for AHC? Now: Whole Genome and
Whole Exome Sequencing New technology to look at all of the genes
in a persons cells at once. Information overload?
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WGS Advantages Provides all of the data from a persons DNA at
once. Good tool for identifying a genetic cause when there is not a
good single gene candidate
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WGS Disadvantages/Hurdles We are all different 100s of changes
per individual compared to reference sequence. Interpretation Which
one is the causative mutation ? More specific studies usually need
to be done.
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Genetic Counseling Important to help interpret ANY genetic
testing results. Helps to put information into perspective for each
family. Taking the time needed with each family.
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Acknowledgements Our many physician collaborators and
colleagues especially: Kenneth Silver Frederic and Eva Andermann
Alexis Arzimanoglou Mohamad Mikati David Goldstein Erin Heinzen
Joanna Jen Alternating Hemiplegia of Childhood Foundation
Especially: Sharon Ciccodicola, Lynn Egan, Vicky Platt, Jeff
Wuchich Association Franaise de l'Hmiplgie Alternante: Dominique
Poncelin Associazione Italiana per la Sindrome di Emiplegia
Alternante: Rosaria Vavasorri AHC Families and Children
