1. Introduction to Neurogenetics
Classification 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
Classification 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
