Pediatric Neurogenetics Zheng (Jane) Fan, MD Medical Genetics Fellow UNC-CH 04/2006.
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Transcript of Pediatric Neurogenetics Zheng (Jane) Fan, MD Medical Genetics Fellow UNC-CH 04/2006.
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:– 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
– 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
Neuronal migration
Six layers cortex
Normal Brain development
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 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
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)
Spectrum of lissencephaly with LIS1 mutation
Lissencephaly and heterotopia with DCX mutation
Cobblestone lissencephaly
Heterotopia
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
Developmental Delay/Autism
• 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), 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
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
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
– 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), Ataxia-telangiectasia (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 {Dejerine-
Sottas 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
• Dystrophinopathies• Congenital muscular dystrophies • Congenital Myopathies • Congenital presentations of adult dystrophies
– Myotonic dystrophy
• Mitochondrial myopathies • Myasthenic syndromes (neuromuscular junction)
DystrophinopathiesDuchenne 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 – 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
• 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
– 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
Congenital myopathiesSelected syndromes
• 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– 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
Nemaline (rod)
Centronuclear
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 co-
exist 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
+ - - - +
Onset 0 to 3 days post natal
Birth Birth to 1 year
> 1 year More in Orientals
Congenital
Weakness Generalized Ocular ± Generalized
Respiratory Generalized
Ocular ± Generalized
Generalized
Time course
Remission 1 to 6 weeks
Fixed weakness
Fatal early, or Improvement > 2 years
Improvement over years
Static
Family history
± Other sibs Mother Untreated
Often Usual Rare Other sibs Mother Untreated
Anti-AChR antibodies
Most - - 50% More in Orientals
+ vs Fetal AChR
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/caseNA/pb9.htm