Pediatric Neurogenetics

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Pediatric Neurogenetics

• Zheng (Jane) Fan, MD
• Medical Genetics Fellow
• UNC-CH
• 04/2006

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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

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Outlines

• Basics of human genetics
• Pediatric Neurogenetics
• Classification
• Common disorders

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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)

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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.

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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)

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Inheritance Pattern

• Mendalian inheritance
• Autosomal resessive - AR
• Autosomal dominant -AD
• X-linked disorders (most recessive, can be
  dominant)
• Non-Mendalian inheritance
• Genomic imprinting
• Trinucleotide repeat disorders
• AD with incomplete penetrance
• Mitochondrial inheritance
• X-inactivation related disorders
• Modifier Genes
• Complex trait

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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

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1. CNS

• A. Cerebral cortical disorders
• 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

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Normal Brain development
Neuronal migration
Six layers cortex
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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
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Disorder of segmentation Schizencephaly

• Types the cleft can be open-lipped 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
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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

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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

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Disorders of cell proliferation

• Microcephaly
• Microcephaly vera term for genetic form
• Mostly lt 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

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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

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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)

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Heterotopia
Spectrum of lissencephaly with LIS1 mutation
Cobblestone lissencephaly
Lissencephaly and heterotopia with DCX mutation
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1. CNS

• A. Cerebral cortical disorders
• 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

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Developmental Delay/Autism

• Heterogeneous groups
• Inborn errors of metabolism
• Chromosomal anomalies
• Genetic syndromes
• Others

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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.

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Genetic disorders with autistic features

• Syndromes
  Fragile X syndrome,
  tuberous sclerosis, Angelman syndrome, 15q
  duplication, Down syndrome, MECP2 related
  disorders (Rett syndrome), Smith-Magenis
  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
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1. CNS

• A. Cerebral cortical disorders
• 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

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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

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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.
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1. CNS

• A. Cerebral cortical disorders
• 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

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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
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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),
  Ataxia-telangiectasia (ATM gene) and others.
• X-linked hereditary ataxias
• single family is described

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Prevalence of SCA subtypes around the world
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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

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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
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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
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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
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3. Hereditary polyneuropathy-CMT

• Charcot-Marie-Tooth disease (CMT) Hereditary
  sensory and motor neuropathy (HSMN)
• IncidenceHereditary 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
  Dejerine-Sottas disease (DSD) (AD or AR)
• CMT4 demyelinating neuropathy (AR)

-- Curr Opin Neurol. 2005 Apr, Ryan MM, Ouvrier R.
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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)

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4. Muscles and neuromuscular junction

• Dystrophinopathies
• Congenital muscular dystrophies
• Congenital Myopathies
• Congenital presentations of adult dystrophies
• Myotonic dystrophy
• Mitochondrial myopathies
• Myasthenic syndromes (neuromuscular junction)

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DystrophinopathiesDuchenne and Becker muscular
dysphophies

• Diagnosis
• Progressive symmetric muscle weakness,
  proximalgtdistal
• 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
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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 lt13yo, 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

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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
• Weakness Diffuse
• Contractures
• CNS involvement Common in severe forms of CMD
• Disorders of myelin or neuronal migration

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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.

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Selected syndromes of congenital muscular
dystrophies

• Fukuyama Fukutin 9q31, common in Japan, rare in
  western, severe, often death lt11yo
• Integrin a-7 deficient, laminin receptor, on
  12q13, most nl intelligence
• Merosin (laminin a2-chain) deficient, spectrum of
  severity, nl congnition
• Normal merosin "Pure" formal nl CNS, nl
  cognition, merosin present
• 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-Mannosyltransferas
  e 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

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Congenital myopathiesSelected syndromes
Centronuclear

• Centronuclear (myotubular) myopathy
• X-linked, AD or AR
• Myotubular family
• Spectrum of severity, can present at birth
• Nemaline (rod) myopathy
• Onset congenital (90) to adult
• a-Actin a-tropomyosin 3 (TPM3)
• AD, AR or sporadic
• Central core disease /- malignant hyperthermia
• AD or AR
• gt20 mutations found, related to Ryanodine
  receptor mutations (Calcium release channel)

Nemaline (rod)
Central core
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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

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Congenital myotonic dystrophy -DM1

• Congenital MD, Largest of triplet repeats of
  any MD syndrome (gt 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.

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Mitochondrial disorders

• Mitochondrial genome 16.5 kb, circular, two
  complimentary strands
• Maternally inherited
• Heteroplasmy the wide type and mutant type
  co-exist intracellularly
• Mutation types large-scale rearrangements
  (deletion or duplications) and point mutations
• Energy powerhouse

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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.

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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.

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Childhood myasthenia gravis
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Neuroanatomy tools
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Normal Anatomy in 3-D with MRI/PET

• Interactive website
• gt150 slides
• Modalities T1, T2, PET or combined
• Pointer shows structure

http//www.med.harvard.edu/AANLIB/cases/caseNA/pb9
.htm