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Summary - Neurogenetics (2078FBDBMW)

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Neurogenetics (2078FBDBMW)

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Universiteit Antwerpen (UA)

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...

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Type Samenvatting

neurogenetics
genetic
disorders
prion
epilepsy
parkinson
frontotemporal
dementia
expansion
therapeutic
disease
modifier

Instelling
Universiteit Antwerpen (UA)
Studie
Biomedische Wetenschappen
Vak
Neurogenetics (2078FBDBMW)

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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

→ you need to know examples of each category

MOVEMENT DISORDERS

- Cerebellar ataxias - Huntington’s disease (HD)
- Parkinson disease (PD) - Wilson disease
- Essential tremor - Primary familial brain calcifications
- Inherited dystonias

Coordinate movements:
1. Hypokinetic disorders → Slowness of movement
2. Hyperkinetic disorders → Excessive involuntary movement= too fast

DEMENTIAS

- Alzheimer disease (AD) - Dementia with Lewy bodies (DLB)
- Frontotemporal dementia (FTD) - Prion disease= young form of dementia

DISEASES OF WHITE MATTER

- Adult onset heritable white matter disorders - Pelizaeus Merzbacher disease
- Alexander disease - Multiple sclerosis (= demyelinating disease)

Two forms:
1. Dysmyelinating= primary abnormality of myelin formation
2. Demyelinating= secondary destruction of normal myelin

NEUROMUSCULAR DISORDERS (EFFECTS THE MOTOR NEURONS)

- Facioscapulohumeral muscular dystrophy (FSHD) - Spinal and bulbar muscular atrophy (SBMA)
- Congenital myopathies - Hereditary spastic paraplegia (HSP)
- Spinal muscular atrophy (SMA) - Neuropathy
- Amyotrophic lateral sclerosis (ALS) - Duchenne muscular dystrophy

PAROXYSMAL DISORDERS

- 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)

MAJOR ADULT PSYCHIATRIC DISORDERS

- Addiction - Bipolar disorder
- Obsessive compulsive disorder

UNIFYING THEMES IN NEUROLOGICAL DISORDERS

- 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

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