1 / 50

Pediatric Neurogenetics

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

nodin
Download Presentation

Pediatric Neurogenetics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pediatric Neurogenetics Zheng (Jane) Fan, MD Medical Genetics Fellow UNC-CH 04/2006

  2. 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

  3. Outlines • Basics of human genetics • Pediatric Neurogenetics • Classification • Common disorders

  4. 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)

  5. 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.

  6. 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)

  7. 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

  8. 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

  9. 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

  10. Normal Brain development Neuronal migration Six layers cortex

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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)

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

  19. 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

  20. Developmental Delay/Autism • Heterogeneous groups • Inborn errors of metabolism • Chromosomal anomalies • Genetic syndromes • Others

  21. 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.

  22. 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

  23. 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

  24. 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

  25. 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.

  26. 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

  27. 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

  28. 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

  29. Prevalence of SCA subtypes around the world

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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.

  35. 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)

  36. 4. Muscles and neuromuscular junction • Dystrophinopathies • Congenital muscular dystrophies • Congenital Myopathies • Congenital presentations of adult dystrophies • Myotonic dystrophy • Mitochondrial myopathies • Myasthenic syndromes (neuromuscular junction)

  37. 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

  38. 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

  39. 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

  40. 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.

  41. 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

  42. Centronuclear 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) Nemaline (rod) Central core

  43. 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

  44. 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.

  45. 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

  46. 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.

  47. 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.

  48. Childhood myasthenia gravis

  49. Neuroanatomy tools

  50. 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

More Related