An in-depth and complete summary of the course 'neurogenetics'. I got a 15 with this summary! The classes that are included are: introduction, genetic mechanisms, repeat expansion disorders, genetic disease modifiers, therapeutic strategies, prion disease, neurocutaneous disorders, epilepsy, fronto...
LESSON 1: INTRODUCTION
CLASSIFICATION OF NEUROLOGICAL DISORDERS
Many classification systems exist e.g. based on clinical presentation, primary affected cell type or brain region,
temporal expression → some diseases are part of multiple categories
- Epilepsy= chronic disease of the brain - Episodic ataxias
- Migraine - disorders of sleep and circadian rhythms
- Periodic paralysis
1
,NEURODEVELOPMENTAL DISORDERS
- Autism spectrum disorder - Cerebral palsy
- Tourette disorder and other tic disorders - Sex chromosome aneuploidies
- Fragile X syndrome and fragile X associated tremor ataxia syndrome
NEUROCUTANEOUS DISORDERS (PHAKOMATOSES)
- Neurofibromatosis type 1 (NF1) - Tuberous sclerosis complex (TSC)
- Von Hippel Lindau disease and Sturge Weber syndrome
CEREBROVASCULAR DISE ASES
Cerebral autosomal-dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL)
→ It effects the blood vessels in the brain (and the brain has a lot of blood vessels)
- Often multiple disease subtypes
- Multiple presentations of the disease even within a family
- Challenging to obtain diagnoses
- Progressive disease without a cure
- Patients are extremely motivated to participate in research
FACTORS SUGGESTING A NEUROGENETIC DISORDER
- A positive history of the same or a similar neurological disorder
o BUT ‘familial disorders are not always genetic and genetic disorders are not always familial
▪ Environmental factors
▪ Very common late-onset neurological conditions
▪ Sporadic cases
- A constellation of signs and symptoms suggesting a known genetic syndrome
- Subtle onset with chronic, progressive clinical course
- Consanguinity (= bloedverwantschap)
- Increased frequency in a specific ethnic groups
INHERITANCE PATTERNS IN NEUROLOGICAL DISORDERS
AUTOSOMAL DOMINANT
- Males and females are equally affected
- Every affected individual has at least one affected parent
- Affected individuals mating with unaffected individuals have
at least 50% chance of transmitting the trait to each child
- Two affected individuals may have unaffected children
- Phenotype generally appears in every generation
- Examples: Parkinson, Huntington, Alzheimer
2
,AUTOSOMAL RECESSIVE
- Males and females are equally affected
- Affected individual may have unaffected parents
- All children of two affected individuals are affected
- Phenotype may skip a generation
- Examples: Friedreich’s ataxia, Parkinson
X-LINKED DOMINANT
- Trait is never passed from father to son
- All daughters of an affected male and a normal female are affected
- All sons of an affected male and a normal female are normal
- Females are more likely to be affected than males
- Examples: Fragile X syndrome
X-LINKED RECESSIVE
- Trait is never passed from father to son.
- Males more likely to be affected than females.
- Trait or disease typically passed from an affected grandfather,
through carrier daughters, to half of his grandsons
- Examples: Duchenne muscular dystrophy
Y-LINKED INHERITANCE
- Male is affected and all his male children are affected
- No example in neurological disorders
MOST PATIENTS/FAMILIES AFFECTED DO NOT HAVE CLEAR INHERITANCE PATTERN
Even in families with monogenic disease, inheritance pattern may be unclear (so not in family but it is genetic):
- Incomplete family information
- Early death due to other causes in family members who transmitted the gene defect
- Non-paternity= the dad is not the real dad
- Broad spectrum in clinical presentations
- Reduced penetrance= some individuals who carry the disease gene may stay unaffected
IMPORTANT: often disease is not monogenic
- Complex genetic inheritance pattern
→ multiple genes and environment determine phenotype
- Even digenic (= two genes) inheritance will often look sporadic
3
, FROM MONOGENIC DISORDER TO COMPLEX DISEA SES
1. Monogenic (do these really exist?)
- One gene causes the disease
- Distinct phenotype
- Mendelian inheritance
2. Oligogenic → few genes with larger effect
- Variable phenotype (often)
- Multiple genes
3. Polygenic → lot of genes with smaller effect
- Complex traits
- Multifactorial: multiple genes + environment
- Extensive phenotypic heterogeneity (2 people with same genotype but different phenotype)
→ the more genes the more phenotypes possible
A single neurological disorder can present in all these ways!
IMPACT OF GENE DISCOVERY
- To provide definitive diagnosis
- Understanding biology of the disorder
- Provides potential biomarkers
- Therapeutic targets
- Genetic counseling
GENE IDENTIFICATION METHODS
CLASSICAL LINKAGE APPROACHES IN FAMILIES= LINKAGE ANALYSIS
- Based on the principal of genetic distance (centimorgans) and variant/haplotype sharing
- Screening the entire genome for shared regions between affected and unaffected family members
→ you screen with Short polymorphic repeat sequences (STR or microsatellites): 400-1000
- Mapping recombinations and generating minimal shared loci harboring likely disease gene/mutation
→ statistical probability= LOD score (>3 is prove of linkage)
- Extensive gene sequencing (coding exons only) in associated locus
→ for linkage analysis you need a big family, otherwise you can’t use it
GENETIC MARKERS FOR LINKAGE
- Repeat sequences (short tandem repeats) → 400-1000 STRs were normally used in a genome-wide
search for disease locus in family
- Micro-satellites: repeats of di- tri- or tetra nucleotides
- Mini-satellites: repeats of units of 5 bases or more
- Rarer than single nucleotide variants (SNPs)
- Multi-allelic genotypes (e.g. 5-12 repeats)
- Linkage analysis in families was very successful in neurodegenerative disease where large multi-
generational disease families were available
4
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller BMWJV. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $8.02. You're not tied to anything after your purchase.
