Summary
Summary Neurogenetics - - Class 1 to 9 (all)
- Course
- Institution
Summary of Neurogenetics course in Master Biomedical Sciences at UAntwerp. Complete description of slides including notes made during classes.
[Show more]
Seller
Follow
e18
Content preview
1. Introduction to NeurogeneticsClassification of Neurological disorders
What are neurological disorders?
• Neuroinfections
Focus on neurogenetic
• Traumatic disorders
disorders
• Neurological disorders as a result of malnutrition
Classification
>200 neurological disorders have been described
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!
❖ Movement Disorders ❖ Neurodevelopmental Disorders
❖ Dementias ❖ Major Adult Psychiatric Disorders
❖ Diseases of White Matter ❖ Neurocutaneous Disorders
❖ Neuromuscular Disorders ❖ Cerebrovascular Diseases
❖ Paroxysmal Disorders
Movement Disorders:
• Cerebellar ataxias • Inherited dystonias • Wilson Disease
• Parkinson disease (PD) • Huntington’s Disease • Primary familial brain
• Essential Tremor (HD) calcifications
Dementias:
• Alzheimer’s disease (AD) • Dementia with Lewy bodies (DLB)
• Frontotemporal dementia (FTD) • Prion disease
Diseases of White matter:
➔ Dysmyelinating = primary abnormalilty of • Multiple sclerosis
myelin formation • Adult onset heritable white matter
➔ Demyelinating = secondary destruction of disorders
normal myelin • Alexander disease
• Pelizaeus Merzbacher disease
1
,Neuromuscular disorders:
• Facioscapulohumeral muscular dystrophy • Spinal and bulbar muscular atrophy
(FSHD) (SBMA)
• Congenital myopathies • Hereditary spastic paraplegia (HSP)
• Spinal muscular atrophy (SMA) • Neuropathy
• Amyotrophic lateral sclerosis (ALS) • Duchenne muscular dystrophy
Paroxysmal disorders:
➔ Disorders that occur • Epilepsy • Episodic ataxias
unexpectedly in • Migraine • Disorders of sleep and
episodes • Periodic paralysis circadian rhythms
Neurodevelopmental disorders:
• Autism spectrum disorder • Sex chromosome aneuploidies
• Cerbral palsy • Fragile X syndrome & Fragile X associated
• Tourette disorder & other tic disorders tremor ataxia syndrome
Neurocutaneous disorders (phakomatoses):
➔ Basically tumors in the brain • Von Hippel Lindau disease & Sturge Weber
• Neurofibromatosis type 1 (NF1) syndrome
• Tuberous sclerosis complex (TSC)
Cerebrovascular diseases:
• Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL)
Major Adult Psychiatric disorders:
• Addiction
• Obsessive compulsive disorder (OCD)
• Bipolar disorder
Unifying themes in Neurological disorders
➢ Often multiple disease subtypes
➢ Multiple presentations of the disease even within a family
➢ Challenging to obtain diagnosis
➢ Progressive disease without a cure
➢ Patients are extremely motivated to participate in research
Factors suggesting a neurogenetic disorder
• A positive family history of the same or a similar neurological disorder but…
“Familial disorders are not always genetic and genetic disorders are not always familial”
• Environmental factors
• Common late-onset neurological conditions
• Sporadic cases
• A constellation of signs and symptoms suggesting a known genetic syndrome
• E.g atypical facial “acne” and a seizure disorder suggest tuberous sclerosis or muscle weakness
associated with muscle cramps and cataracts suggests myotonic dystrophy
• Broad knowledge of the various possible syndromes is critical!
• Subtle onset with chronic, progressive clinical course
• Consanguinity: related parents (incest)
• Increased frequency in a specific ethnic group
2
,Inheritance patterns
I. Autosomal dominant
➢ Males and females equally affected
➢ Every affected individual has at least one affected parent
➢ Affected individuals mating with unaffected individuals
have at least a 50% chance of transmitting the trait to
each child
➢ Two affected individuals may have unaffected children
➢ Phenotype generally appears in every generation
Examples:
• Parkinson’s disease
• Charcot-Marie-Tooth disease
• Huntington’s disease
• Frontotemporal dementia
• Amyotrophic lateral sclerosis
• Alzheimer’s disease
II. 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’s disease
• Charcot-Marie-Tooth disease
• Amyotrophic lateral sclerosis
III. 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
➔ Based on pedigree, sex-linked inheritance is never confirmed only suggested
IV. 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 affected grandfather,
through carrier daughters, to half of his grandsons
Examples:
• Duchenne muscular dystrophy
• X-linked adrenoleukodystrophy
V. Y-linked inheritance
➢ Male is affected and all his male children are too
No examples in neurological disorders.
➔ See example exercises in PPT
3
, Mostly inheritance pattern is not clear, can be due to
• Incomplete family info
• Early death to other causes in family members who transmitted the gene defect
• Non-paternity
• Broad spectrum in clinical presentation
• Reduced penetrance: some individuals who carry disease gene may stay unaffected
Often diseases are not monogenic: complex inheritance pattern (multiple genes and environment
determine phenotype), or even digenic inheritance than will look sporadic.
Reasons diseases may not look genetic:
• Multifactorial diseases
• Reduced penetrants
• De novo mutations
• Different affected regions in individuals with same default
Types of diseases
I. Monogenic II. Oligogenic III. Polygenic
➢ Distinct phenotype ➢ Variable phenotype ➢ Complex traits
➢ Mendelian inheritance ➢ Multiple genes ➢ Multifactorial
➢ Extensive phenotypic
heterogeneity
➔ A single neurological disorders 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
• Short polymorphic repeat sequences (STR or microsatellites) are used
• Mapping recombinations and generating minimal shared loci harboring likely disease
gene/mutation
➔ Statistical probability = LOD score
• Extensive gene sequencing (coding exons only) in associated locus
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) Examples:
- PD: LRRK2, VPS35 & SNCA mutations
Linkage analysis in families was very successful in - FTD: MAPT & PGRN mutations
neurodegenerative disease where large multi- generational - Perry Syndrome: DCTN1 mutation
disease families were available. - ALS/FTD: C9orf72 mutation
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 e18. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $16.62. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
56326 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now