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
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,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
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,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
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, 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
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