Table of Contents
Key concepts class 1 – Introduction ............................................................................................... 4
1. Broad classification of neurological diseases (with example). .................................................... 4
2. How to identify a (neuro)genetic disorder? ................................................................................ 5
3. Understanding of inheritance patterns and knowledge on key factors influencing them. .............. 5
4. Concepts of gene identification: linkage versus genome-wide association studies. ..................... 6
5. Understanding of contribution of common and rare variants to neurological diseases. ................ 7
6. Overview of types of disease-causing genetic variation (coding and non-coding mutations). ....... 7
Terms .............................................................................................................................................. 8
Key concepts class 2 – Genetic mechanisms ................................................................................ 10
1. Characteristics of loss-of-function versus gain-of-function genetic mechanisms. ..................... 10
2. Presentation and disease mechanism associated with SMN. ................................................... 10
3. Presentation and disease mechanism associated with CADASIL.............................................. 11
4. Presentation and disease mechanism associated with Alexander disease. ............................... 12
5. Presentation and disease mechanism associated with FSHD. ................................................. 12
6. Key concepts on mosaic mutations in the brain with examples. ............................................... 13
7. Understand the consequence of timing of de novo mutation on mosaicism and disease
inheritance. ................................................................................................................................... 14
8. Ability to generate critical research questions to identify genetic disease mechanism of
neurological disease. ..................................................................................................................... 14
Terms ............................................................................................................................................ 15
Key concepts class 3 – Repeat expansion disorders ...................................................................... 16
1. Tandem repeats are awesome and challenging ....................................................................... 16
2. Disease mechanisms of a repeat expansion relative to the location in a gene............................ 17
3. Advantages and disadvantages of methods for investigation of tandem repeats. ....................... 17
4. The role of a founder e[ect for repeat expansions. ................................................................... 18
5. The role of motif interruptions for expansion and phenotype. ................................................... 18
6. Presentation and disease mechanism associated with Huntington Disease.............................. 19
7. Presentation and disease mechanisms associated with Fragile X Syndrome. ............................ 19
Terms ............................................................................................................................................ 20
Key concepts class 4 – Genetic disease modifiers ......................................................................... 21
1. Definition of genetic disease modifiers. .................................................................................. 21
2. Approaches to identify genetic disease modifiers and its pros and cons. .................................. 21
3. Key concepts on the disease mechanism in HD identified through genetic modifiers................. 22
4. Tools available in Drosophila to identify genetic modifiers. ....................................................... 22
5. Concept of collaborative cross and diversity outbred panel in mice. ......................................... 23
1
, 6. Types of genetic CRISPR/Cas9 screens in human cells. ........................................................... 23
Terms ............................................................................................................................................ 24
Key concepts class 5 – Therapeutic strategies ............................................................................... 25
1. Specific challenges to treating neurological diseases. ............................................................. 25
2. Broad approaches to treating genetic neurological diseases. ................................................... 25
3. Antisense oligonucleotides: what, how, where?....................................................................... 26
4. Gene-delivery by AAV: what, how, where? ............................................................................... 27
5. Phases of clinical trials and considerations in design for neurological diseases. ....................... 28
6. Should be able to explain and discuss available treatments for SMA. ....................................... 30
7. Should be able to design possible approaches to development of treatments for neurological
diseases, with ability to determine key information and experiments required in pre-clinical studies. . 31
Terms ............................................................................................................................................ 31
Key concepts class 6 – Frontotemporal Dementias........................................................................ 33
1. Understand relationship between clinical symptoms, neuropathology and diagnosis. ............... 33
2. Presentation and major genetic factors implicated in FTD. ....................................................... 33
3. Explain (in broad terms) current knowledge on TMEM106B as disease modifier in FTLD ............. 34
4. Able to explain C9orf72-associated disease mechanisms. ...................................................... 34
Terms ............................................................................................................................................ 35
Key concepts class 7 – Neurocutaneous Disorders........................................................................ 36
1. Should be able to explain – in broad terms – the possible genetic mechanisms of neurocutaneous
disorders discussed in class. .......................................................................................................... 36
2. Describe the clinical presentation, genetic mechanisms and current treatment options for
patients with NF1 mutations. .......................................................................................................... 37
3. What is Legius syndrome and how does it relate to NF1? ......................................................... 39
Terms ............................................................................................................................................ 39
Key concepts class 8 – Parkinson Disease (AI) ............................................................................... 40
1. Explain the main clinical and pathological features of PD. ........................................................ 40
2. Contribution of environmental and genetic factors of the development of PD. ........................... 40
3. SNCA: discuss the mutational spectrum and implications for treatment strategies. .................. 41
4. LRRK2: discuss the mutational spectrum and implications for treatment strategies. ................. 41
5. Causal genes may also carry genetic risk or disease modifier variants. ..................................... 42
Key concepts class 9 – Prion Disease ............................................................................................ 43
1. Types of prion disease, general disease mechanism and disease presentation. ........................ 43
2. Broad knowledge on causal mutations and disease modifying variants in PRNP. ....................... 44
3. Overview of biomarkers currently used in prion disease with strengths and weaknesses. .......... 44
4. Possible therapeutic approaches for prion disease.................................................................. 45
5. Implications of prion-like properties for proteins involved in other neurodegenerative diseases. 45
Terms ............................................................................................................................................ 46
2
,Key concepts class 10 – Epilepsy .................................................................................................. 47
1. Describe the overall genetic architecture of the epilepsies using a Manolio plot. ....................... 47
2. Describe genetic and phenotypic spectrum associated with SCN1A mutations and their
functional impact. ......................................................................................................................... 48
3. How does loss of SCN1A function leads to epilepsy and cognitive problems? ........................... 49
4. Describe genetic and phenotypic spectrum of KCNQ2 related epilepsy and DEE. ..................... 50
5. What elements contribute to phenotypic heterogeneity of monogenic epilepsies? .................... 50
6. What avenues of precision medicine are considered for genetic epilepsies? ............................. 51
7. Discuss relevance of brain mosaicism in genetic epilepsies. .................................................... 52
Terms ............................................................................................................................................ 52
3
,Key concepts class 1 – Introduction
1. Broad classification of neurological diseases (with example).
Classifica(on of Neurological disorders
Movement Disorders
• Affect the cerebellum.
• You can have movement disorders that give you slowness of movement (hypokineCc) or too
much movement (hyperkineCc).
• Ex: Parkinson disease, HunCngton’s disease, cerebellar ataxias.
DemenCas
• Ex: Alzheimer disease (AD), Frontotemporal demenCa (FTD), Prion disease
Diseases of White MaPer
• DysmyelinaCng: primary abnormality of myelin formaCon.
• DemyelinaCng: secondary destrucCon of normal myelin.
• Ex: Alexander disease, mulCple sclerosis (=demyelinaCng)
Neuromuscular Disorders
• Affect the upper and lower motor neurons, also the neuromuscular juncCon and oTen results
in primary muscle diseases (= myopathies).
• Ex: Facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA),
amyotrophic lateral sclerosis (ALS).
Paroxysmal Disorders
• Disorders that occur unexpectedly in episodes.
• Ex: Epilepsy, migraine.
Neurodevelopmental Disorders
• Ex: Fragile X syndrome, auCsm spectrum disorders
Neurocutaneous Disorders
• These are basically tumours in the brain, but benign tumours that lead to things like epilepsy.
• Ex: Neurofibromatosis type 1 (NF1).
Cerebrovascular Diseases
• Blood vessels in the brain that cause neurological disorders
• Ex: cerebral autosomal dominant arteriopathie with subcorCcal infarcts and
leukoenceophalopathy (= CADASIL).
Major Adult Psychiatric Disorders
• Ex: AddicCon, obsessive compulsive disorder, bipolar disorder.
4
,2. How to identify a (neuro)genetic disorder?
Factors sugges(ng a neurogene(c disorder
• PosiCve family history of the same or similar neurological disorder
o Environmental factors;
o Common late-onset neurological condiCons;
o Sporadic cases.
• ConstellaCon of signs and symptoms suggesCng a known geneCc syndrome.
• Subtle onset with chronic, progressive clinical course.
• Consanguinity.
• Increased frequency in a specific ethnic group.
3. Understanding of inheritance patterns and knowledge on key
factors influencing them.
Inheritance pa8erns in neurological disorders
Autosomal dominant
• Males and females are equally affected.
• Every affected individual has at least one affected parent.
• Affected individuals maCng with unaffected individuals have at least a
50% chance of transmibng the trait to each child.
• Two affected individuals may have unaffected children.
• Phenotype generally appears in every generaCon.
• E.g.: Parkinson’s disease, frontotemporal demenCa
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 generaCon.
• E.g.: Parkinson’s disease, Friedreich’s ataxia
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.
• E.g.: Fragile X
5
, 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.
Key factors influencing the inheritance pa8erns
• Incomplete family informaCon.
• Early death due to other causes in family members who transmiPed the gene defect.
• Non-paternity.
• Broad spectrum in clinical presentaCons.
• Reduced penetrance = some individuals who carry the disease gene may be unaffected
• OTen disease is not monogenic:
o Complex geneCc inheritance paPern;
o MulCple genes and environment determine phenotype;
o Even digenic inheritance will oTen look sporadic.
4. Concepts of gene identification: linkage versus genome-wide
association studies.
Linkage analysis
• Classical linkage approaches in families.
• Based on the principal of geneCc distance and variant/haplotype sharing.
• Screening the enCre genome for shared regions between affected and unaffected family
members.
• Short polymorphic repeat sequences (STR or microsatellites) are used.
• Mapping recombinaCons and generaCng minimal shared loci harboring likely disease
gene/mutaCon.
• StaCsCcal probability = LOD score (LOD > 3 is usually considered sufficient).
• Extensive gene sequencing (coding exons only) in associated locus.
Caveats to familial linkage:
• Large mulC-incident mulC-generaConal families with clear Mendelian inheritance paPerns of
disease are rare.
• In many individuals, the disease appears sporadic, or inheritance paPern is unclear.
• Phenocopies and (age-related) reduced penetrance will bias linkage analysis.
o Phenocopy is an individual with the same clinical phenotype as the rest of the family but
this individual does not carry the disease gene present in the other affected individuals
• Reliant on excellent clinical evaluaCons.
• Time-consuming and relaCvely costly at the Cme.
6
Key concepts class 1 – Introduction ............................................................................................... 4
1. Broad classification of neurological diseases (with example). .................................................... 4
2. How to identify a (neuro)genetic disorder? ................................................................................ 5
3. Understanding of inheritance patterns and knowledge on key factors influencing them. .............. 5
4. Concepts of gene identification: linkage versus genome-wide association studies. ..................... 6
5. Understanding of contribution of common and rare variants to neurological diseases. ................ 7
6. Overview of types of disease-causing genetic variation (coding and non-coding mutations). ....... 7
Terms .............................................................................................................................................. 8
Key concepts class 2 – Genetic mechanisms ................................................................................ 10
1. Characteristics of loss-of-function versus gain-of-function genetic mechanisms. ..................... 10
2. Presentation and disease mechanism associated with SMN. ................................................... 10
3. Presentation and disease mechanism associated with CADASIL.............................................. 11
4. Presentation and disease mechanism associated with Alexander disease. ............................... 12
5. Presentation and disease mechanism associated with FSHD. ................................................. 12
6. Key concepts on mosaic mutations in the brain with examples. ............................................... 13
7. Understand the consequence of timing of de novo mutation on mosaicism and disease
inheritance. ................................................................................................................................... 14
8. Ability to generate critical research questions to identify genetic disease mechanism of
neurological disease. ..................................................................................................................... 14
Terms ............................................................................................................................................ 15
Key concepts class 3 – Repeat expansion disorders ...................................................................... 16
1. Tandem repeats are awesome and challenging ....................................................................... 16
2. Disease mechanisms of a repeat expansion relative to the location in a gene............................ 17
3. Advantages and disadvantages of methods for investigation of tandem repeats. ....................... 17
4. The role of a founder e[ect for repeat expansions. ................................................................... 18
5. The role of motif interruptions for expansion and phenotype. ................................................... 18
6. Presentation and disease mechanism associated with Huntington Disease.............................. 19
7. Presentation and disease mechanisms associated with Fragile X Syndrome. ............................ 19
Terms ............................................................................................................................................ 20
Key concepts class 4 – Genetic disease modifiers ......................................................................... 21
1. Definition of genetic disease modifiers. .................................................................................. 21
2. Approaches to identify genetic disease modifiers and its pros and cons. .................................. 21
3. Key concepts on the disease mechanism in HD identified through genetic modifiers................. 22
4. Tools available in Drosophila to identify genetic modifiers. ....................................................... 22
5. Concept of collaborative cross and diversity outbred panel in mice. ......................................... 23
1
, 6. Types of genetic CRISPR/Cas9 screens in human cells. ........................................................... 23
Terms ............................................................................................................................................ 24
Key concepts class 5 – Therapeutic strategies ............................................................................... 25
1. Specific challenges to treating neurological diseases. ............................................................. 25
2. Broad approaches to treating genetic neurological diseases. ................................................... 25
3. Antisense oligonucleotides: what, how, where?....................................................................... 26
4. Gene-delivery by AAV: what, how, where? ............................................................................... 27
5. Phases of clinical trials and considerations in design for neurological diseases. ....................... 28
6. Should be able to explain and discuss available treatments for SMA. ....................................... 30
7. Should be able to design possible approaches to development of treatments for neurological
diseases, with ability to determine key information and experiments required in pre-clinical studies. . 31
Terms ............................................................................................................................................ 31
Key concepts class 6 – Frontotemporal Dementias........................................................................ 33
1. Understand relationship between clinical symptoms, neuropathology and diagnosis. ............... 33
2. Presentation and major genetic factors implicated in FTD. ....................................................... 33
3. Explain (in broad terms) current knowledge on TMEM106B as disease modifier in FTLD ............. 34
4. Able to explain C9orf72-associated disease mechanisms. ...................................................... 34
Terms ............................................................................................................................................ 35
Key concepts class 7 – Neurocutaneous Disorders........................................................................ 36
1. Should be able to explain – in broad terms – the possible genetic mechanisms of neurocutaneous
disorders discussed in class. .......................................................................................................... 36
2. Describe the clinical presentation, genetic mechanisms and current treatment options for
patients with NF1 mutations. .......................................................................................................... 37
3. What is Legius syndrome and how does it relate to NF1? ......................................................... 39
Terms ............................................................................................................................................ 39
Key concepts class 8 – Parkinson Disease (AI) ............................................................................... 40
1. Explain the main clinical and pathological features of PD. ........................................................ 40
2. Contribution of environmental and genetic factors of the development of PD. ........................... 40
3. SNCA: discuss the mutational spectrum and implications for treatment strategies. .................. 41
4. LRRK2: discuss the mutational spectrum and implications for treatment strategies. ................. 41
5. Causal genes may also carry genetic risk or disease modifier variants. ..................................... 42
Key concepts class 9 – Prion Disease ............................................................................................ 43
1. Types of prion disease, general disease mechanism and disease presentation. ........................ 43
2. Broad knowledge on causal mutations and disease modifying variants in PRNP. ....................... 44
3. Overview of biomarkers currently used in prion disease with strengths and weaknesses. .......... 44
4. Possible therapeutic approaches for prion disease.................................................................. 45
5. Implications of prion-like properties for proteins involved in other neurodegenerative diseases. 45
Terms ............................................................................................................................................ 46
2
,Key concepts class 10 – Epilepsy .................................................................................................. 47
1. Describe the overall genetic architecture of the epilepsies using a Manolio plot. ....................... 47
2. Describe genetic and phenotypic spectrum associated with SCN1A mutations and their
functional impact. ......................................................................................................................... 48
3. How does loss of SCN1A function leads to epilepsy and cognitive problems? ........................... 49
4. Describe genetic and phenotypic spectrum of KCNQ2 related epilepsy and DEE. ..................... 50
5. What elements contribute to phenotypic heterogeneity of monogenic epilepsies? .................... 50
6. What avenues of precision medicine are considered for genetic epilepsies? ............................. 51
7. Discuss relevance of brain mosaicism in genetic epilepsies. .................................................... 52
Terms ............................................................................................................................................ 52
3
,Key concepts class 1 – Introduction
1. Broad classification of neurological diseases (with example).
Classifica(on of Neurological disorders
Movement Disorders
• Affect the cerebellum.
• You can have movement disorders that give you slowness of movement (hypokineCc) or too
much movement (hyperkineCc).
• Ex: Parkinson disease, HunCngton’s disease, cerebellar ataxias.
DemenCas
• Ex: Alzheimer disease (AD), Frontotemporal demenCa (FTD), Prion disease
Diseases of White MaPer
• DysmyelinaCng: primary abnormality of myelin formaCon.
• DemyelinaCng: secondary destrucCon of normal myelin.
• Ex: Alexander disease, mulCple sclerosis (=demyelinaCng)
Neuromuscular Disorders
• Affect the upper and lower motor neurons, also the neuromuscular juncCon and oTen results
in primary muscle diseases (= myopathies).
• Ex: Facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA),
amyotrophic lateral sclerosis (ALS).
Paroxysmal Disorders
• Disorders that occur unexpectedly in episodes.
• Ex: Epilepsy, migraine.
Neurodevelopmental Disorders
• Ex: Fragile X syndrome, auCsm spectrum disorders
Neurocutaneous Disorders
• These are basically tumours in the brain, but benign tumours that lead to things like epilepsy.
• Ex: Neurofibromatosis type 1 (NF1).
Cerebrovascular Diseases
• Blood vessels in the brain that cause neurological disorders
• Ex: cerebral autosomal dominant arteriopathie with subcorCcal infarcts and
leukoenceophalopathy (= CADASIL).
Major Adult Psychiatric Disorders
• Ex: AddicCon, obsessive compulsive disorder, bipolar disorder.
4
,2. How to identify a (neuro)genetic disorder?
Factors sugges(ng a neurogene(c disorder
• PosiCve family history of the same or similar neurological disorder
o Environmental factors;
o Common late-onset neurological condiCons;
o Sporadic cases.
• ConstellaCon of signs and symptoms suggesCng a known geneCc syndrome.
• Subtle onset with chronic, progressive clinical course.
• Consanguinity.
• Increased frequency in a specific ethnic group.
3. Understanding of inheritance patterns and knowledge on key
factors influencing them.
Inheritance pa8erns in neurological disorders
Autosomal dominant
• Males and females are equally affected.
• Every affected individual has at least one affected parent.
• Affected individuals maCng with unaffected individuals have at least a
50% chance of transmibng the trait to each child.
• Two affected individuals may have unaffected children.
• Phenotype generally appears in every generaCon.
• E.g.: Parkinson’s disease, frontotemporal demenCa
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 generaCon.
• E.g.: Parkinson’s disease, Friedreich’s ataxia
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.
• E.g.: Fragile X
5
, 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.
Key factors influencing the inheritance pa8erns
• Incomplete family informaCon.
• Early death due to other causes in family members who transmiPed the gene defect.
• Non-paternity.
• Broad spectrum in clinical presentaCons.
• Reduced penetrance = some individuals who carry the disease gene may be unaffected
• OTen disease is not monogenic:
o Complex geneCc inheritance paPern;
o MulCple genes and environment determine phenotype;
o Even digenic inheritance will oTen look sporadic.
4. Concepts of gene identification: linkage versus genome-wide
association studies.
Linkage analysis
• Classical linkage approaches in families.
• Based on the principal of geneCc distance and variant/haplotype sharing.
• Screening the enCre genome for shared regions between affected and unaffected family
members.
• Short polymorphic repeat sequences (STR or microsatellites) are used.
• Mapping recombinaCons and generaCng minimal shared loci harboring likely disease
gene/mutaCon.
• StaCsCcal probability = LOD score (LOD > 3 is usually considered sufficient).
• Extensive gene sequencing (coding exons only) in associated locus.
Caveats to familial linkage:
• Large mulC-incident mulC-generaConal families with clear Mendelian inheritance paPerns of
disease are rare.
• In many individuals, the disease appears sporadic, or inheritance paPern is unclear.
• Phenocopies and (age-related) reduced penetrance will bias linkage analysis.
o Phenocopy is an individual with the same clinical phenotype as the rest of the family but
this individual does not carry the disease gene present in the other affected individuals
• Reliant on excellent clinical evaluaCons.
• Time-consuming and relaCvely costly at the Cme.
6
