NEUROGENETICS
LES 1: INTRODUCTION
WHAT ARE NEUROLOGICAL DISORDERS
Diseases of the central and peripheral nervous system (the brain, spinal cord, cranial na peripheral
nerves, nerve roots, autonomic system, neuromuscular junction and muscles.
Examples: epilepsy and dementia are the most common.
It affects a 100 millions of people worldwide.
Neurological disorders can be caused by: neuroinfections, traumatic disorders, result of malnutrition,
neurogenetics.
CLASSIFICATION OF NEUROLOGICAL DISORDERS
Classification is done based on:
Clinical presentation
Primary affected cell type
Affected brain region
Temporal expression
Some disease can belong to different categories
MOVEMENT DISORDERS
Cerebellum coordinates movements. In this type of disorders the cerebellum is affected.
Hypokinetic disorder = slower movements
Hyperkinetic disorders = uncontrolled, excessive movements
Example: ataxia → destroys the cerebellum
Most important one is Parkinson disease (PD).
DEMENTIA
Can occur in a lot of different ways. Resulting in memory problems and behavioral problems.
Frontotemporal dementia is the most important one. It is a prion disease
DISEASE OF THE WHITE MATTER
Dysmyelinating = primary abnormality of myelin formation. Already present at birth.
Demyelinating = secondary destruction of normal myelin. Typical example is MS
In this type of diseases, the brain cells attack the myelin.
Multiplesclerosis (MS): it is a snowflake disease, this mean the symptoms are different for everyone.
Symptoms of MS: loss of balance, voice, vision, muscle control,…
1
,NEUROMUSCULAR DISORDERS
These affect the upper and lower motorneuron, neuromuscular junctions and result in muscle disease.
ALS = amyotrophic lateral sclerosis: most patients die 3 years after the diagnosis. Goes together with
respiratory failure. No cure or treatment.
Facioscapulohumeral luscular dystrophy 5FSHD) and duchenne muscular dystrophy are primary
muscular disorders. It can also be a result of a problem in the muscles, so not always a neurological
disorder.
PAROXYSMAL DISORDERS
Disorders that occur unexpectedly in episodes. It comes and go. Some of these diseases can also fit
in the other categories.
Example: epilepsy, migraine
NEURODEVELOPMENTAL DISORDERS
Fragile X syndrome, autism spectrum
MAJOR ADULT PSYCHIATRIC DISORDERS
Addiction, obsessive compulsive disorder, bipolar disorder
Braincells are not dying. The functioning of the brain is affected.
NEUROCUTANEOUS DISORDERS
Tumor in the brain, mostly benign and they lead to epilepsy.
Example: neurofibromatosis type 1 (NF1) → mostly affects children
CEREBROVASCULAR DISEASES
CADASIL = cerebral autosomal-dominant arteriopathy with subcortical infarcts and
leukoencephalopathy.
IMPORTANT CHARACTERISTICS OF NEUROLOGICAL DISEASES
A positive family history of the same or a similar neurological disorder, familial disorders are not
always genetic and genetic disorders are not always familial.
A disease that is not genetic, but runs in a family can be the result of:
Environmental factors (everyone in the family exposed to the same thing)
Common late-onset neurological conditions (Alzheimer)
Sporadic cases
It can be genetic, but doesn’t look like it is genetic because only one person in the family has it. This
can be due to:
Reduced penetrance: they are carrier but don’t develop the symptoms
De novo: one parent has it, but it doesn’t occur, because the parent passed away at a young
age or if you don’t know who the biological parents are,…
2
,A constellation of signs and symptoms suggesting a known genetic syndrome
Facial acne and seizures can suggest tuberous sclerosis
Muscle weakness associated with muscle cramps.
Cataracts suggests myotonic dystrophy
It is important to have a broad knowledge of possible syndromes (helps with the diagnosis)
Other characteristics:
Subtle onset with chronic, progressive clinical course
Consanguinity: related to the family
Increased frequency in a specific ethnic group
Multiple disease subtypes
Different presentations of one disease in different people
Multiple presentations of the disease even within a family
Challenging to obtain diagnoses
Progressive disease without a cure
Patients are extremely motivate to participate in research
INHERITANCE PATTERNS IN NEUROLOGICAL DISORDERS
AUTOSOMAL DOMINANT
Characteristics
Males and females are 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, huntington’s disease, Alzheimer disease, ALS, frontotemporal
dementia,…
AUTOSOMAL RECESSIVE
Characteristics
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
Example: friedreich’s ataxia, parkinson’s disease, ALS,…
3
, X-LINKED DOMINANT
Characteristics
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
Example: Fragile X Based on the pedigree, sex-linked inheritance is never confirmed only
suggested
X-LINKED RECESSIVE
Characteristics
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, X-linked
adrenoleukodystrophy
Y-LINKED INHERITANCE
Male is affected and all his male children are affected, no examples in neurological disorders
MOST PATIENTS DO NOT HAVE A CLEAR INHERITANCE PATTERN
Even families with monogenic disease, inheritance pattern may be unclear, due to:
Incomplete family information
Early death to other causes in family members who transmitted the gene defect
Non-paternity: the dad isn’t the father of the child
Broad spectrum in clinical presentations
Reduced penetrance: some individuals who carry the disease gene may stay unaffected
Often, the disease is not monogenic: it has a complex genetic inheritance pattern. This means multiple
genes and environment determine the phenotype. If the disease is digenic, inheritance can also look
sporadic.
FROM MONOGENIC DISORDERS TO COMPLEX DISEASES
MONOGENIC (DO THESE REALLY EXIST?)
On genes, no environmental factors are involved. Not sure of diseases like this exist.
Distinct phenotype
Mendelian inheritance
4
LES 1: INTRODUCTION
WHAT ARE NEUROLOGICAL DISORDERS
Diseases of the central and peripheral nervous system (the brain, spinal cord, cranial na peripheral
nerves, nerve roots, autonomic system, neuromuscular junction and muscles.
Examples: epilepsy and dementia are the most common.
It affects a 100 millions of people worldwide.
Neurological disorders can be caused by: neuroinfections, traumatic disorders, result of malnutrition,
neurogenetics.
CLASSIFICATION OF NEUROLOGICAL DISORDERS
Classification is done based on:
Clinical presentation
Primary affected cell type
Affected brain region
Temporal expression
Some disease can belong to different categories
MOVEMENT DISORDERS
Cerebellum coordinates movements. In this type of disorders the cerebellum is affected.
Hypokinetic disorder = slower movements
Hyperkinetic disorders = uncontrolled, excessive movements
Example: ataxia → destroys the cerebellum
Most important one is Parkinson disease (PD).
DEMENTIA
Can occur in a lot of different ways. Resulting in memory problems and behavioral problems.
Frontotemporal dementia is the most important one. It is a prion disease
DISEASE OF THE WHITE MATTER
Dysmyelinating = primary abnormality of myelin formation. Already present at birth.
Demyelinating = secondary destruction of normal myelin. Typical example is MS
In this type of diseases, the brain cells attack the myelin.
Multiplesclerosis (MS): it is a snowflake disease, this mean the symptoms are different for everyone.
Symptoms of MS: loss of balance, voice, vision, muscle control,…
1
,NEUROMUSCULAR DISORDERS
These affect the upper and lower motorneuron, neuromuscular junctions and result in muscle disease.
ALS = amyotrophic lateral sclerosis: most patients die 3 years after the diagnosis. Goes together with
respiratory failure. No cure or treatment.
Facioscapulohumeral luscular dystrophy 5FSHD) and duchenne muscular dystrophy are primary
muscular disorders. It can also be a result of a problem in the muscles, so not always a neurological
disorder.
PAROXYSMAL DISORDERS
Disorders that occur unexpectedly in episodes. It comes and go. Some of these diseases can also fit
in the other categories.
Example: epilepsy, migraine
NEURODEVELOPMENTAL DISORDERS
Fragile X syndrome, autism spectrum
MAJOR ADULT PSYCHIATRIC DISORDERS
Addiction, obsessive compulsive disorder, bipolar disorder
Braincells are not dying. The functioning of the brain is affected.
NEUROCUTANEOUS DISORDERS
Tumor in the brain, mostly benign and they lead to epilepsy.
Example: neurofibromatosis type 1 (NF1) → mostly affects children
CEREBROVASCULAR DISEASES
CADASIL = cerebral autosomal-dominant arteriopathy with subcortical infarcts and
leukoencephalopathy.
IMPORTANT CHARACTERISTICS OF NEUROLOGICAL DISEASES
A positive family history of the same or a similar neurological disorder, familial disorders are not
always genetic and genetic disorders are not always familial.
A disease that is not genetic, but runs in a family can be the result of:
Environmental factors (everyone in the family exposed to the same thing)
Common late-onset neurological conditions (Alzheimer)
Sporadic cases
It can be genetic, but doesn’t look like it is genetic because only one person in the family has it. This
can be due to:
Reduced penetrance: they are carrier but don’t develop the symptoms
De novo: one parent has it, but it doesn’t occur, because the parent passed away at a young
age or if you don’t know who the biological parents are,…
2
,A constellation of signs and symptoms suggesting a known genetic syndrome
Facial acne and seizures can suggest tuberous sclerosis
Muscle weakness associated with muscle cramps.
Cataracts suggests myotonic dystrophy
It is important to have a broad knowledge of possible syndromes (helps with the diagnosis)
Other characteristics:
Subtle onset with chronic, progressive clinical course
Consanguinity: related to the family
Increased frequency in a specific ethnic group
Multiple disease subtypes
Different presentations of one disease in different people
Multiple presentations of the disease even within a family
Challenging to obtain diagnoses
Progressive disease without a cure
Patients are extremely motivate to participate in research
INHERITANCE PATTERNS IN NEUROLOGICAL DISORDERS
AUTOSOMAL DOMINANT
Characteristics
Males and females are 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, huntington’s disease, Alzheimer disease, ALS, frontotemporal
dementia,…
AUTOSOMAL RECESSIVE
Characteristics
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
Example: friedreich’s ataxia, parkinson’s disease, ALS,…
3
, X-LINKED DOMINANT
Characteristics
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
Example: Fragile X Based on the pedigree, sex-linked inheritance is never confirmed only
suggested
X-LINKED RECESSIVE
Characteristics
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, X-linked
adrenoleukodystrophy
Y-LINKED INHERITANCE
Male is affected and all his male children are affected, no examples in neurological disorders
MOST PATIENTS DO NOT HAVE A CLEAR INHERITANCE PATTERN
Even families with monogenic disease, inheritance pattern may be unclear, due to:
Incomplete family information
Early death to other causes in family members who transmitted the gene defect
Non-paternity: the dad isn’t the father of the child
Broad spectrum in clinical presentations
Reduced penetrance: some individuals who carry the disease gene may stay unaffected
Often, the disease is not monogenic: it has a complex genetic inheritance pattern. This means multiple
genes and environment determine the phenotype. If the disease is digenic, inheritance can also look
sporadic.
FROM MONOGENIC DISORDERS TO COMPLEX DISEASES
MONOGENIC (DO THESE REALLY EXIST?)
On genes, no environmental factors are involved. Not sure of diseases like this exist.
Distinct phenotype
Mendelian inheritance
4
