Transcript Neurogenetics for Pediatrician

Pediatric Neurogenetics
Zheng (Jane) Fan, MD
Medical Genetics Fellow
UNC-CH
04/2006
What is Neurogenetics?
• Neurogenetics: the study of genetic factors
that contribute to development of
neurological disorders
• One third of known single gene defect cause
diseases that affect the nervous system
• Not to intent to cover everything
• A field with rapid progress
Outlines
• Basics of human genetics
• Pediatric Neurogenetics
– Classification
– Common disorders
Human Genetics
• Human Genome Project finished in
2003 (13 years effort)
– Identified approximately 20,000-25,000
genes
• International HapMap Project (phase
I) finished in the end of 2005
– HapMap: Haplotype map
– Haplotype: A set of closely linked genes
that tends to be inherited together as a
unit (block of genes)
Human Genetics (continued)
• Human genome size: 2.85 Gb
• Protein coding genes only consist of 1.5%
of genome
• The vast majority of the rest genome:
repeats {transposon-derived repeats,
pseudogenes, SSR (micro- and
minisatellites), segmental duplication,
blocks of tandem repeats} and non-coding
genes (introns). Little is known about these
regions.
Types of genetics conditions
and commonly used studies
• Chromosomal aberrations: aneuploidy, deletion
and duplication/multiplications.
– Karyotype, subtelomere study (study of the ends of the
chromosomes), FISH (florescent in situ hybridization),
CGH (comparative genomic hybridization, signature
chip is one of them)
• Mutations
– Mutation scanning for common mutations, sequencing
(commonly the coding region = exons), SNP (single
nucleotide polymorphism) chip (Affimetrix etc)
• Others
– Methylation study (commonly for imprinting
disorders), linkage analysis, parental testing (finger
printing)
Inheritance Pattern
• Mendalian inheritance:
– Autosomal resessive - AR
– Autosomal dominant -AD
– X-linked disorders (most recessive, can be dominant)
• Non-Mendalian inheritance:
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Genomic imprinting
Trinucleotide repeat disorders
AD with incomplete penetrance
Mitochondrial inheritance
X-inactivation related disorders
Modifier Genes
Complex trait
Classification of
Neurogenetics
• Localization based
– 1. CNS: Cerebral cortical, basal ganglia
disorders and cerebellum
– 2. Spinal cord and anterior horn cell disorders
– 3. PNS: Peripheral nerve disorders
– 4. Muscle disorders and neuromuscular
junction
– 5. Many disorders affect more than one
localization sites
– Others
1. CNS
• A. Cerebral cortical disorders
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Cortical dysplasias/Neuronal migration disorder
Developmental delay/Autism
Epilepsy
Dementia (adult)
• B. Basal ganglia disorders: movement dso
– Pediatric:, Dystonia and Wilson dsz
– Adult: Huntington dsz, Parkinson dsz, and PKAN (Pantothenate
Kinase-associated neurodegeneration) used to be called
Hallervorden-Spatz disease
• C. Disorders mainly affect cerebellum
– Ataxia syndromes
Normal Brain development
Neuronal migration
Six layers cortex
A. Cortical dysplasia
• Segmentation: Schizencephaly
• Prosencephalon cleavage: holoproencephaly,
septo-optic dysplasia and agenesis of corpus
callosum
• Neuronal and glial proliferation: microcephaly,
megalencephaly and hemimegalencephaly
• Neuronal differentiation: Tuberous sclerosis
• Neuronal migration: Lissencephaly,
polymicrogyria and heterotopia
Brain & Development ( 2004 ) Clark GD
Disorder of segmentation:
Schizencephaly
• Types: the cleft can be openlipped or close-lipped
• Unilateral or bilateral
• When it is severe malformation,
almost always associate with
epilepsy, mental retardation and
spastic cerebral palsy.
• Severe familiar cases: mutation
in EMX2, a transcriptional
regulator
Open-lipped
Close-lipped
Disorders of prosencephalon
(forebrain) cleavage
• Holoprosencephaly
– Spectrum: alobar, semilobar and lobar
– Genetically heterogeneous group
• Chromosomal aberration: trisomy 13, etc
• Single gene: Sonic hedgehog, HPE1-4, PACHED, ZIC2, SIX3
– Maternal exposure: retinoic acid, diabetes, CMV
• Septo-optic dysplasia
– Up to 60% pts with endocrine dysfunction (hypothalamic
dysfunction)
– Minority: mutation in HESX1 gene, transcriptional regulator gene
• Agenesis of corpus callosum (ACC)
– Single gene: SLC12A6 (AR) is responsible for ACC and
neuropathy
– A/w syndromes: Miller-Dieker S., Walker-Warbrug S., and
Zellweger S
Holoprosencephaly (HPE)
• HPE: the developing
forebrain fails to
divide into two
separate hemispheres
and ventricles
• Wide spectrum of
phenotypes: almost
normal to severely
impaired
• Single central incisor
can be a clue
Disorders of cell proliferation
• Microcephaly
– Microcephaly vera: term for genetic form
– Mostly < 4SD, with MR, hypotonia, and seizures
– Linked to multiple locations, no single gene identified
yet, can be AD, AR or X-linked
• Megalencephaly (big brain volume) and
hemimegalencephaly
– Hemimegalencephaly may be a/w linear sebaceous
nevus syndrome (50%) and hypomelanosis of Ito
– No single gene identified
Disorders of differentiation
• Tuberous sclerosis
– Clinically: hamartomas of the subependymal
layer (subependymal nodules), areas of cortical
migration abnormalities (tubers) and the
development of giant-cell astrocytomas (5% TS
pts). Epilepsy is a prominent feature.
– Genes: TSC1 (encodes for Hamartin, on 9q34)
and TSC2 (encodes for Tuberin, on 16p13.3)
– Both are AD
Neuronal migration disorders
• Lissencephaly (smooth brain)
– Classic lissencephaly: LIS1 gene, a/w Miller-Dieker
syndrome
– X-linked lissencephaly: DCX (doublecortin)
– Lisencephaly with cerebellar hypoplasia: REELIN gene
– Cobble stone lissencephaly, a/w Walker-Warburg
syndrome, muscle-eye-brain syndrome. Can also a/w
Fukuyama muscular dystrophy (fukutin gene).
• Polymicrogyria (many small gyri), a/w genetic or
chromosomal dso, such as Zellweger syndrome.
• Heterotopias (collections of normal-appearing
neurons in abnormal location), DCX
(doublecortin)
Heterotopia
Spectrum of lissencephaly with LIS1 mutation
Cobblestone
lissencephaly
Lissencephaly and heterotopia with DCX mutation
1. CNS
• A. Cerebral cortical disorders
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Cortical dysplasias/Neuronal migration disorder
Developmental delay/Autism
Epilepsy
Dementia (adult)
• B. Basal ganglia disorders: movement dso
– Pediatric:, Dystonia and Wilson dsz
– Adult: Huntington dsz, Parkinson dsz, and PKAN (Pantothenate
Kinase-associated neurodegeneration) used to be called
Hallervorden-Spatz disease
• C. Disorders mainly affect cerebellum
– Ataxia syndromes
Developmental Delay/Autism
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Heterogeneous groups
Inborn errors of metabolism
Chromosomal anomalies
Genetic syndromes
Others
Autism
• No single gene identified for autism
• Most syndromes are associated with
atypical autistic features
• Chromosomal aberrations are associated
with mental retardation.
• Submicroscopic chromosomal arrangements
• Can be associated with specific genetic
syndromes.
Genetic disorders with autistic
features
• Syndromes:
Fragile X syndrome, tuberous sclerosis, Angelman
syndrome, 15q duplication, Down syndrome,
MECP2 related disorders (Rett syndrome), SmithMagenis syndrome, 22q13 deletion, Cohen
syndrome, and Smith-Lemli-Opitz syndrome, etc.
• Inborn errors of metabolism:
PKU, adenylosuccinate lyase deficiency,
Sanfilippo syndrome (MPS III), etc.
J Autism Dev Disorder (2005) Feb, Cohen D et al
1. CNS
• A. Cerebral cortical disorders
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Cortical dysplasias/Neuronal migration disorder
Developmental delay/Autism
Epilepsy
Dementia (adult)
• B. Basal ganglia disorders: movement dso
– Pediatric:, Dystonia and Wilson dsz
– Adult: Huntington dsz, Parkinson dsz, and PKAN (Pantothenate
Kinase-associated neurodegeneration) used to be called
Hallervorden-Spatz disease
• C. Disorders mainly affect cerebellum
– Ataxia syndromes
Epilepsy - etiology
• Genetic epilepsy: next slide for details
• Chromosomal abnormalities
– Angelman syndrome, 4p deletion syndrome,
and ring chromosome 20
• Abnormal cortical development
– Focal cortical dysplasia: heterotopia,
schizencephaly, hemimegalencephaly etc.
– Neurocutaneous syndrome: tuberous sclerosis,
Sturge-Weber syndrome
Genetic epilepsy
• Most are iron channel related single gene disorders.
• Idiopathic generalized epilepsies
– Cl- channel: CLCN2, GABA receptors (GABRA1 and
GABRG20 and Ca++ channel (EFHC1 gene) are reported
• Familiar autosomal dominant epilepsies
– Benign familial neonatal-infantile convulsions: K+ channels
genes (KCNQ3 and KCNQ2) and Na+ channel gene (SCN2A)
– Autosomal dominant nocturnal frontal lobe epilepsy is a/w
nicotinic acetylcholine receptor genes (CHRNA4 and
CHRNB2)
– Autosomal dominant partial epilepsy with auditory features:
LGI1-epitempin (leucine-rich glioma-inactivated 1 gene)
Lancet. (2006) Feb, Epilepsy in children, Guerrini R.
1. CNS
• A. Cerebral cortical disorders
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–
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Cortical dysplasias/Neuronal migration disorder
Developmental delay/Autism
Epilepsy
Dementia (adult)
• B. Basal ganglia disorders: movement dso
– Pediatric:, Dystonia and Wilson dsz
– Adult: Huntington dsz, Parkinson dsz, and PKAN (Pantothenate
Kinase-associated neurodegeneration) used to be called
Hallervorden-Spatz disease
• C. Disorders mainly affect cerebellum
– Ataxia syndromes
Hereditary ataxias
• Clinical: progressive incoordination of gait
and often poor coordination of hands,
speech, and eye movements.
• Pathology: dysfunction of cerebellum and
its associated systems (spinal cord and
peripheral nerves)
• Onset age: childhood (common) to
adulthood
Genetests.org, Bird T, updated April 2006
Hereditary ataxias
Classified by inheritance
• Autosomal dominant cerebellar ataxias (ADCA)
– Most are SCAs (spinocerebellar ataxias). All are
trinucleotide repeat expansion disorders with
anticipation.
– Genes: ATXN genes, SCA genes (at least 28 to date)
and others
– DRPLA (also called Haw River syndrome)
• Autosomal recessive hereditary ataxias
– Friedreich ataxia (FXN gene: Frataxin), Ataxiatelangiectasia (ATM gene) and others.
• X-linked hereditary ataxias:
– single family is described
Prevalence of SCA subtypes around
the world
2. Spinal cord and anterior horn cell
disorders
• Spinal cord disorders
– Hereditary spastic paraplegias (HSPs)
• Anterior horn cell disorders
– Spinal muscular atrophies (SMAs)
– Kennedy's disease (X-linked spinal-bulbar
muscular atrophy, adult onset)
– Amyotrophic lateral sclerosis (ALS), adult
onset, familial subgroup: SOD1 mutation
Hereditary spastic paraplegias (HSPs)
• Clinical: insidiously progressive lower extremity
weakness and spasticity. Onset varies from early
childhood to adulthood.
• Neuropath: Axonal degeneration (corticospinal
tracts)
• Classified as uncomplicated (pure) and
complicated (complex). Complicated is a/w other
neurological symptoms: seizures, MR, etc.
• Clinical presentation Can overlap with other
hereditary syndromes
• Genetics: many genes (SPG1-29, SAX1, PLP1,
etc) identified (up to 2004), list is expanding.
• Inheritance: AD (most common), AR and X-linked
Genetests.org, updated Oct 2004
Anterior horn motor neuron disease:
SMAs (Spinal muscular atrophies)
• Clinical: Motor weakness. Tongue fasciculation in
an alert weak baby is highly suggestive.
• Classification is based on age of onset (spectrum
of phenotype):
– SMA 0 (proposed name) (prenatal onset) = Congenital
SMA with arthrogryposis
– SMA I (0-6m) = Werdnig-Hoffmann syndrome
– SMA II (after 6mo) and SMA III (after 10m, with
ability to walk) = Kugelberg-Weland syndrome
– SMAIV (adult onset) = later onset SMA
• Pathology: Loss of the anterior horn motor
neurons in the spinal cord and the brain stem
nuclei
Genereviews.org, Prior T, April 2006 and www.neuro.wustl.edu/neuromuscular
Genetics of SMA
• Genetics: AR
• Two closely related genes,
SMN1 (= telomeric SMN)
and SMN2 (= centromeric
SMN)
• SMN1 and SMN2, adjacent
to each other on 5q
– SMN1 and SMN2 only differ
by 5 base pairs
– SMN1 is the primary disease
causing gene
– SMN2 is a modifier gene
Congenital SMA with arthrogryposis
3. Hereditary polyneuropathy-CMT
• Charcot-Marie-Tooth disease (CMT) =
Hereditary sensory and motor neuropathy
(HSMN)
• Incidence:Hereditary neuropathies: ~30 per
100,000
• Most common: CMT 1A: 10.5 per 100,000
• Heterogeneous inherited polyneuropathies
• Classification: complex and changing
– CMT1: demyelinating neuropathy (AD or X-linked)
– CMT2: axonal neuropathy (most AD, minority AR)
– CMT3: severe demyelinating neuropathy {DejerineSottas disease (DSD)} (AD or AR)
– CMT4: demyelinating neuropathy (AR)
-- Curr Opin Neurol. 2005 Apr, Ryan MM, Ouvrier R.
CMT1A and PMP22 gene
• Clinical: slow onset of weakness (ankle and knee),
age of onset: 4-25yrs.
• CMT1A represents 70-80% CMT1
• PMP22 duplication responsible for 98% CMT1A
• PMP22 point mutation cause CMT1E
• PMP22 deletion responsible for 80% Hereditary
Liability to Pressure Palsies (HNPP)
4. Muscles and neuromuscular
junction
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Dystrophinopathies
Congenital muscular dystrophies
Congenital Myopathies
Congenital presentations of adult dystrophies
– Myotonic dystrophy
• Mitochondrial myopathies
• Myasthenic syndromes (neuromuscular junction)
Dystrophinopathies
Duchenne and Becker muscular dysphophies
• Diagnosis:
– Progressive symmetric muscle weakness, proximal>distal
– Normal at birth, occasional congenital form can present with
hypotonia at birth.
– Gower maneuver: indication of proximal muscles weakness, most
common seen in DMD (Duchenne muscular dystrophy)
– Molecular genetic diagnosis is preferred
– Muscle biopsy only needed in case without molecular dx
• Treatment:
– Supportive: PT and others
– Surveillance for cardiomyopathy, respiratory failure and
orthopedic complications.
– Steroids prolong walking, q weekly dosing is most commonly
used, with reduced side affects
– Research: gene therapy
Gower maneuver
Genetics of Dystrophinopathies
(DMD and BMD)
• Clinical features
– It is the most common myopathy in children: ~ 1 in
every 3500 boys worldwide
– DMD: delayed motor milestones, mean age of dx is
~4yo (no FH), wheelchair dependency <13yo, mean
age of living 15-25yrs
– BMD: milder phenotype , alleic disorder to DMD
• Molecular genetics
– Located at Xp21
– Gene: DMD (the largest human gene, 79 exons),
protein: dystrophin (rod like protein)
– Mutation types:
• Deletion: ~65% male with DMD, ~85% male with BMD
• Duplication: ~ 6-10% DMD, ~6-10% BMD
• Point mutation/small deletion, insertion/splicing mutation:
~25-30 DMD, ~5-10% BMD
Congenital muscular dystrophies
(CMD)
• A group of inherited disorders
• Muscle weakness is present at birth
• Muscle weakness tends to be stable over time, but
complications of dystrophy become severe with time; in
contrast, weakness from dystrophinopathies is progressive.
• Clinical features
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Weakness: Diffuse
Contractures
CNS involvement: Common in severe forms of CMD
Disorders of myelin or neuronal migration
Congenital muscular dystrophies continued
• Inheritance: Autosomal recessive (AR)
• Frequency: Common cause of AR
neuromuscular disorders
• Diagnosis is based on muscle biopsy
findings traditionally
• May overlap with other conditions: LGMD
(limb girdle muscular dystrophy),
congenital myopathies, etc.
Selected syndromes of congenital
muscular dystrophies
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Fukuyama: Fukutin; 9q31, common in Japan, rare in western, severe, often death
<11yo
Integrin α-7 deficient, laminin receptor, on 12q13, most nl intelligence
Merosin (laminin α2-chain) deficient, spectrum of severity, nl congnition
Normal merosin: "Pure" formal: nl CNS, nl cognition, merosin present
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CMD with Rigid spine
CMD + Respiratory failure & Muscle hypertrophy (CMD1B; MDC1B)
Ulrich: Collagen 6A2
CMD + Muscle hypertrophy
Muscle-Eye-Brain Disorders
– Santavuori (Finnish): POMGnT1(O-Mannosyltransferase 1); 1p32
– Walker-Warburg: POMT1; 9q3l, Fukutin, FKRP(Fukutin related protein)
•
Congenital muscular dystrophy with muscle hypertrophy
– Normal CNS (MDC1C): FKRP; 19q13, allelic with LGMD 2I
– Severe retardation (MDC1D): LARGE; 22q12
•
Ullrich congenital myopathy, joint contractures are very common
– COL6A1; 21q22
– COL6A2; 21q22
– COL6A3; 2q37
Centronuclear
Congenital myopathies
Selected syndromes
• Centronuclear (myotubular)
myopathy
– X-linked, AD or AR
– Myotubular family
– Spectrum of severity, can present at birth
• Nemaline (rod) myopathy
Nemaline (rod)
– Onset: congenital (90%) to adult
– α-Actin; α-tropomyosin 3 (TPM3)
– AD, AR or sporadic
• Central core disease +/- malignant
hyperthermia
– AD or AR
– >20 mutations found, related to
Ryanodine receptor mutations (Calcium
release channel)
Central core
Myotonic dystrophy
• Myotonic dystrophy (MD) is a trinucleotide repeat disease
with multi-systemic involvement: muscle (myotonia and
weakness), nerve, CNS (MR), heart (conduction
problems), eyes (cataract), etc.
• Myotonia refers to the slow/impaired relaxation of the
muscles after voluntary contraction or electrical
stimulation
• AD with anticipation
• 3 Genetic loci :
– DM 1 : 98% of families l Myotonin protein kinase (DMPK) ;
Chromosome 19q13.3; Dominant
– DM 2 (PROMM), l Zinc finger protein 9 (ZNF9) ; Chromosome
3q21; Dominant
– DM3l Chromosome 15q21-q24; Dominant
Congenital myotonic dystrophy DM1
• Congenital MD, Largest # of triplet
repeats of any MD syndrome (>
1,000), large expansion happens when
it is transmitted maternally.
• Severe hypotonia/weakness at birth,
respiratory failure is major cause of
mortality, if infant survives infancy,
weakness improve during early
childhood. MR common.
Mitochondrial disorders
• Mitochondrial genome: 16.5 kb, circular, two
complimentary strands
• Maternally inherited
• Heteroplasmy: the wide type and mutant type coexist intracellularly
• Mutation types: large-scale rearrangements
(deletion or duplications) and point mutations
• Energy powerhouse
Clinical presentation
• Multisystemic with remarkable variability
in the phenotypic presentation
• Neurological: myopathy, exercise
intolerance, ophthalmoplegia, headache,
seizures, dementia, ataxia, myoclonus, etc.
• Non-neurological: short stature, heart,
endocrine, metabolic acidosis (lactic), etc.
Diagnosis
• Biochemical: lactate, CK
• Mutation analysis: large arrangement study
for deletion/duplication, point mutation
analysis
• Muscle bx:
– Ragged red fibers: accumulated of abnormal
mitochondria under the sarcolemmal
membrane. Absent does not rule out.
Childhood myasthenia gravis
CHILDHOOD MYASTHENIA GRAVIS: TYPES
Neonatal
Congenital
Familial
Infantile
Acquired
Juvenile
Recurrent
Arthrogryposis
+
-
-
-
+
Maternal
MG
Birth
to 1 year
> 1 year
More in
Orientals
Congenital
Onset
0 to 3 days
post natal
Weakness
Ocular
Generalized ±
Generalized
Respiratory
Generalized
Ocular
± Generalized
Generalized
Time
course
Remission
Fixed
1 to 6 weeks weakness
Fatal early, or
Improvement
> 2 years
Improvement
over years
Static
Family
history
± Other
sibs
Mother
Untreated
Rare
Other sibs
Mother
Untreated
50%
More in
Orientals
+ vs
Fetal AChR
Anti-AChR
antibodies
Most
Birth
Often
Usual
-
-
Neuroanatomy tools
Normal Anatomy in 3-D with
MRI/PET
• Interactive
website
• >150 slides
• Modalities:
T1, T2, PET
or combined
• Pointer shows
structure
http://www.med.harvard.edu/AANLIB/cases/c
aseNA/pb9.htm