Summary Neurogene-cs
Class 1 – Introduc0on to Neurogene0cs
Neurological disorders are a major health problem
• What are neurological disorders and how many people are affected by them?
à Neurological disorders are diseases of the central and peripheral nervous system. In other
words, the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic
nervous system, neuromuscular junc?on, and muscles. These disorders include epilepsy,
Alzheimer disease and other demen?as, cerebrovascular diseases including stroke, migraine
and other headache disorders, mul?ple sclerosis, Parkinson’s disease, neuro-infec?ons, brain
tumors, trauma?c disorders of the nervous system due to head trauma, and neurological
disorders as a result of malnutri?on.
- neuro-infec?ons, trauma?c disorders of the nervous system due to head trauma, and
neurological disorders as a result of malnutri?on à these will not be covered in this
class
à Hundreds of millions of people worldwide are affected by neurological disorders. More than
6 million people die because of stroke each year, over 80% of these deaths take place in low-
and middle-income countries. More than 50 million people have epilepsy worldwide. It is
es?mated that there are globally 47.7 million people with demen?a with 7.7 million new cases
every year. Alzheimer’s disease is the most common cause of demen?a and may contribute to
60-70% of cases. The prevalence of migraine is more than 10% worldwide.
à In 2021, ~ 55 million people had demen?a. This number is expected to rise to 78 million in
2030 and 139 million in 2050
Classifica(on of Neurological disorders
• >200 neurological disorders have been described
• Many classifica?on systems exist e.g. based on clinical presenta?on, primary affected cell type
or brain region, temporal expression à some diseases are part of mul?ple categories!
• Not easy to think about a classifica?on system à different ways of classifica?on
• One par?cular classifica?on in these slides and we are going to follow this classifica?on (based
on the handbook of neurology)
Movement disorders Neurodevelopmental disorders
Demen?as Major adult psychiatric disorders
Diseases of white ma]er Neurocutaneous disorders
Neuromuscular disorders Cerebrovascular disorder
Paraxysmal disorders
Movement disorders
• Cerebellar ataxias, Parkinson disease (PD), Essen?al Tremor, Inherited dystonias, Hun?ngton’s
Disease (HD), Wilson Disease, Primary familial brain calcifica?ons
• The one we know best is Parkison disease
• Yellow = complete class about this diseases
• Cerebellum affected
- Too slow movement: hypokine?c disorders
- Too fast movement: hyperkine?c disorders
• Video: ataxia
- Group of neurological condi?ons that gradually destroys the cerebellum and affects your
ability to control movement and send signals throughout your nervous system
, - Less likely to have control over their legs and movement
- Different types
o Friedreich most common
o Over 200 types of ataxia have been discovered
- Each person is affected in their own way
- Children of the age of 2 can be diagnosed but also adults
- Some gene?c and other through circumstances
- Different symptoms
- No cures for ataxia à progressive condi?on
- Diagnose very difficult
Demen.as
• Alzheimer disease (AD), Frontotemporal demen?a (FTD), Demen?a with Lewy bodies (DLB),
prion disease
• Video: late-onset Alzheimer
- Moving video of an old lady which has late onset Alzheimer disease but her musical
memory stay preserved (Swan lake)
- Not every part of the brain is evenly affected
Disease of White Ma3er
• Dysmyelina?ng = primary abnormality of myelin forma?on
• Demyelina?ng = secondary destruc?on of normal myelin
• Adult-onset heritable white ma]er disorders
• Alexander disease, Pelizaeus Merzbacher disease, Mul?ple sclerosis (= demyelina?ng disease)
• Video: MS
- Very different for everyone
- She has spasmodic dysphonia
- Diagnosis takes a very long ?me
• Snow flake disease à every person has different symptoms, and that’s why it take a very long
?me to get diagnosed
Neuromuscular disorders
• Facioscapulohumeral muscular dystrophy (FSHD), Congenital myopathies, Spinal muscular
atrophy (SMA), Amyotrophic lateral sclerosis (ALS), Spinal and bulbar muscular atrophy
(SBMA), Hereditary spas?c paraplegia (HSP), Neuropathy, Duchenne muscular dystrophy
- ALS = affect the motor cells
• Large group of diseases that affect the motoneurons (upper and lower) also the neuromuscular
junc?on
• Some?mes it is difficult when you have a problem with the muscles if it is a primary defect of
the muscle or whether it is the spinal cord that is not giving the correct informa?on and that
the muscles are degenera?ng
• Video: amyotrophic lateral sclerosis
- Deadly or severe debilita?ng disease that affects the motoneurons
- Gradually loss of different func?ons à people become more dependent
Paroxysmal disorders
• disorders that occur unexpectedly in episodes
• Epilepsy, Migraine, Periodic paralysis, Episodic ataxias, Disorders of sleep and circadian
rhythms
,Neurodevelopmental Disorders
• Au?sm spectrum disorder, Cerebral palsy, Toure]e disorder and other ?c 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
• (usually benign) tumors in the brain
• Video: Tuberous sclerosis complex
- Usually these tumors are benign, but they are in the brain causing epilepsy
- They don’t really kill the children but they have other effects
- Missing gene that prevents tumors from growing
- Tumor in brain, in kidneys and in eyes
Cerebrovascular diseases
• Cerebral autosomal-dominant arteriopathy with subcor?cal infarcts and leukoencephalopathy
(CADASIL)
• 650 k blood vessels in one brain
Major Adult Psychiatric Disorders
• Addic?on, Obsessive compulsive disorder, bipolar disorder
Unifying themes in Neurological disorders
• Omen mul?ple disease subtypes
• Mul?ple presenta?ons of the disease even within a family
• Challenging to obtain diagnoses (can take a long ?me)
• Progressive disease without a cure
• Pa?ents are extremely mo?vated to par?cipate in research
Factors sugges(ng a neurogene(c disorder
how do we recognize whether gene?cs take a roll in these diseases? à e.g. when more people in 1
family have the same symptoms / same disorders
• A posi?ve family history of the same or a similar neurological disorder but… “Familial disorders
are not always gene?c and gene?c disorders are not always familial”
- Environmental factors
- Common late-onset neurological condi?ons
o because the disease is so common, you can see it mul?ple ?mes within one family
(but there is not 1 gene involved)
- Sporadic cases
o reduced penetrance à not everyone with the muta?on will get the disease
o a parent can die young (but he carries the disease) à the son gets the disease, but
they think it skipped a genera?on (they didn’t know the dad was also a carrier
because he died before the symptoms occurred)
o the dad is not the dad
o de novo muta?on
• A constella?on of signs and symptoms sugges?ng a known gene?c 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 cri?cal!
, • Subtle onset with chronic, progressive clinical course
• Consanguinity à when family members get a child together
• Increased frequency in a specific ethnic group
- Gene?c composi?on of the genome is different between different groups
+ slides 20 – 26
Most pa.ents/families affected by neurological disorders do not have clear inheritance
pa3ern!
Summary why it looks like a disease may not be happening in every genera?on of a family
à Even in families with monogenic disease, inheritance pa]ern may be unclear:
• Incomplete family informa?on
• Early death due to other causes in family members who transmi]ed the gene defect
• Non-paternity
• Broad spectrum in clinical presenta?ons
• Reduced penetrance: some individuals who carry the disease gene may stay unaffected
- Not everyone that have the muta?on will get the symptoms
• Importantly, omen disease is not monogenic!
- Complex gene?c inheritance pa]ern
è Mul?ple genes and environment determine phenotype
- Even digenic (=two genes) inheritance will omen look sporadic
o (it is not always monogenic (not always 1 gene is involved)
à There is no disease where everyone have the exact same phenotype !!
• Monogenic (do these really exist?)
- Dis?nct phenotype
- Mendelian inheritance
• Oligogenic = a few genes are involved
- Variable phenotype (omen)
- Mul?ple genes
• Polygenic = many genes are involved
- Complex traits: mul?ple genes plays a role
- Mul?factorial: mul?ple genes and the environment
- Extensive phenotypic heterogeneity
A single neurological disorder can present in all these ways!
• A single disease can present in different ways
- Caused by one gene, other forms caused by different genes…
• The more genes involved, the more difficult/complex the phenotype of the pa?ents become
Impact of gene discovery
• To provide defini?ve diagnosis
• Understanding biology of the disorder
• Provides poten?al biomarkers
- Diseases that look quite similar, have overlapping symptoms, and by learning about the
gene?cs and which proteins are involved, you can develop tools to measure those in
people à hopefully this will lead to be]er diagnosis + telling the next genera?on if they
have a higher risk for the disease
• Therapeu?c targets
• Gene?c counseling
• !! all these diseases don’t have a cure at the moment à we know certain genes and
mechanisms that are involved = the basis for developing therapies
Class 1 – Introduc0on to Neurogene0cs
Neurological disorders are a major health problem
• What are neurological disorders and how many people are affected by them?
à Neurological disorders are diseases of the central and peripheral nervous system. In other
words, the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic
nervous system, neuromuscular junc?on, and muscles. These disorders include epilepsy,
Alzheimer disease and other demen?as, cerebrovascular diseases including stroke, migraine
and other headache disorders, mul?ple sclerosis, Parkinson’s disease, neuro-infec?ons, brain
tumors, trauma?c disorders of the nervous system due to head trauma, and neurological
disorders as a result of malnutri?on.
- neuro-infec?ons, trauma?c disorders of the nervous system due to head trauma, and
neurological disorders as a result of malnutri?on à these will not be covered in this
class
à Hundreds of millions of people worldwide are affected by neurological disorders. More than
6 million people die because of stroke each year, over 80% of these deaths take place in low-
and middle-income countries. More than 50 million people have epilepsy worldwide. It is
es?mated that there are globally 47.7 million people with demen?a with 7.7 million new cases
every year. Alzheimer’s disease is the most common cause of demen?a and may contribute to
60-70% of cases. The prevalence of migraine is more than 10% worldwide.
à In 2021, ~ 55 million people had demen?a. This number is expected to rise to 78 million in
2030 and 139 million in 2050
Classifica(on of Neurological disorders
• >200 neurological disorders have been described
• Many classifica?on systems exist e.g. based on clinical presenta?on, primary affected cell type
or brain region, temporal expression à some diseases are part of mul?ple categories!
• Not easy to think about a classifica?on system à different ways of classifica?on
• One par?cular classifica?on in these slides and we are going to follow this classifica?on (based
on the handbook of neurology)
Movement disorders Neurodevelopmental disorders
Demen?as Major adult psychiatric disorders
Diseases of white ma]er Neurocutaneous disorders
Neuromuscular disorders Cerebrovascular disorder
Paraxysmal disorders
Movement disorders
• Cerebellar ataxias, Parkinson disease (PD), Essen?al Tremor, Inherited dystonias, Hun?ngton’s
Disease (HD), Wilson Disease, Primary familial brain calcifica?ons
• The one we know best is Parkison disease
• Yellow = complete class about this diseases
• Cerebellum affected
- Too slow movement: hypokine?c disorders
- Too fast movement: hyperkine?c disorders
• Video: ataxia
- Group of neurological condi?ons that gradually destroys the cerebellum and affects your
ability to control movement and send signals throughout your nervous system
, - Less likely to have control over their legs and movement
- Different types
o Friedreich most common
o Over 200 types of ataxia have been discovered
- Each person is affected in their own way
- Children of the age of 2 can be diagnosed but also adults
- Some gene?c and other through circumstances
- Different symptoms
- No cures for ataxia à progressive condi?on
- Diagnose very difficult
Demen.as
• Alzheimer disease (AD), Frontotemporal demen?a (FTD), Demen?a with Lewy bodies (DLB),
prion disease
• Video: late-onset Alzheimer
- Moving video of an old lady which has late onset Alzheimer disease but her musical
memory stay preserved (Swan lake)
- Not every part of the brain is evenly affected
Disease of White Ma3er
• Dysmyelina?ng = primary abnormality of myelin forma?on
• Demyelina?ng = secondary destruc?on of normal myelin
• Adult-onset heritable white ma]er disorders
• Alexander disease, Pelizaeus Merzbacher disease, Mul?ple sclerosis (= demyelina?ng disease)
• Video: MS
- Very different for everyone
- She has spasmodic dysphonia
- Diagnosis takes a very long ?me
• Snow flake disease à every person has different symptoms, and that’s why it take a very long
?me to get diagnosed
Neuromuscular disorders
• Facioscapulohumeral muscular dystrophy (FSHD), Congenital myopathies, Spinal muscular
atrophy (SMA), Amyotrophic lateral sclerosis (ALS), Spinal and bulbar muscular atrophy
(SBMA), Hereditary spas?c paraplegia (HSP), Neuropathy, Duchenne muscular dystrophy
- ALS = affect the motor cells
• Large group of diseases that affect the motoneurons (upper and lower) also the neuromuscular
junc?on
• Some?mes it is difficult when you have a problem with the muscles if it is a primary defect of
the muscle or whether it is the spinal cord that is not giving the correct informa?on and that
the muscles are degenera?ng
• Video: amyotrophic lateral sclerosis
- Deadly or severe debilita?ng disease that affects the motoneurons
- Gradually loss of different func?ons à people become more dependent
Paroxysmal disorders
• disorders that occur unexpectedly in episodes
• Epilepsy, Migraine, Periodic paralysis, Episodic ataxias, Disorders of sleep and circadian
rhythms
,Neurodevelopmental Disorders
• Au?sm spectrum disorder, Cerebral palsy, Toure]e disorder and other ?c 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
• (usually benign) tumors in the brain
• Video: Tuberous sclerosis complex
- Usually these tumors are benign, but they are in the brain causing epilepsy
- They don’t really kill the children but they have other effects
- Missing gene that prevents tumors from growing
- Tumor in brain, in kidneys and in eyes
Cerebrovascular diseases
• Cerebral autosomal-dominant arteriopathy with subcor?cal infarcts and leukoencephalopathy
(CADASIL)
• 650 k blood vessels in one brain
Major Adult Psychiatric Disorders
• Addic?on, Obsessive compulsive disorder, bipolar disorder
Unifying themes in Neurological disorders
• Omen mul?ple disease subtypes
• Mul?ple presenta?ons of the disease even within a family
• Challenging to obtain diagnoses (can take a long ?me)
• Progressive disease without a cure
• Pa?ents are extremely mo?vated to par?cipate in research
Factors sugges(ng a neurogene(c disorder
how do we recognize whether gene?cs take a roll in these diseases? à e.g. when more people in 1
family have the same symptoms / same disorders
• A posi?ve family history of the same or a similar neurological disorder but… “Familial disorders
are not always gene?c and gene?c disorders are not always familial”
- Environmental factors
- Common late-onset neurological condi?ons
o because the disease is so common, you can see it mul?ple ?mes within one family
(but there is not 1 gene involved)
- Sporadic cases
o reduced penetrance à not everyone with the muta?on will get the disease
o a parent can die young (but he carries the disease) à the son gets the disease, but
they think it skipped a genera?on (they didn’t know the dad was also a carrier
because he died before the symptoms occurred)
o the dad is not the dad
o de novo muta?on
• A constella?on of signs and symptoms sugges?ng a known gene?c 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 cri?cal!
, • Subtle onset with chronic, progressive clinical course
• Consanguinity à when family members get a child together
• Increased frequency in a specific ethnic group
- Gene?c composi?on of the genome is different between different groups
+ slides 20 – 26
Most pa.ents/families affected by neurological disorders do not have clear inheritance
pa3ern!
Summary why it looks like a disease may not be happening in every genera?on of a family
à Even in families with monogenic disease, inheritance pa]ern may be unclear:
• Incomplete family informa?on
• Early death due to other causes in family members who transmi]ed the gene defect
• Non-paternity
• Broad spectrum in clinical presenta?ons
• Reduced penetrance: some individuals who carry the disease gene may stay unaffected
- Not everyone that have the muta?on will get the symptoms
• Importantly, omen disease is not monogenic!
- Complex gene?c inheritance pa]ern
è Mul?ple genes and environment determine phenotype
- Even digenic (=two genes) inheritance will omen look sporadic
o (it is not always monogenic (not always 1 gene is involved)
à There is no disease where everyone have the exact same phenotype !!
• Monogenic (do these really exist?)
- Dis?nct phenotype
- Mendelian inheritance
• Oligogenic = a few genes are involved
- Variable phenotype (omen)
- Mul?ple genes
• Polygenic = many genes are involved
- Complex traits: mul?ple genes plays a role
- Mul?factorial: mul?ple genes and the environment
- Extensive phenotypic heterogeneity
A single neurological disorder can present in all these ways!
• A single disease can present in different ways
- Caused by one gene, other forms caused by different genes…
• The more genes involved, the more difficult/complex the phenotype of the pa?ents become
Impact of gene discovery
• To provide defini?ve diagnosis
• Understanding biology of the disorder
• Provides poten?al biomarkers
- Diseases that look quite similar, have overlapping symptoms, and by learning about the
gene?cs and which proteins are involved, you can develop tools to measure those in
people à hopefully this will lead to be]er diagnosis + telling the next genera?on if they
have a higher risk for the disease
• Therapeu?c targets
• Gene?c counseling
• !! all these diseases don’t have a cure at the moment à we know certain genes and
mechanisms that are involved = the basis for developing therapies
