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Neuropathology of Ataxias MDS-ES Neuropathology of Movement Disorders online course December 2020 Neuropathology of ataxias Javier Alegre-Abarrategui MD DPhil FRCPath Consultant Neuropathologist and Clinical Lecturer, Imperial College London Director of Neuropathology, Imperial College Brain Bank Function of the cerebellum DESCENDING SYSTEMS Upper Motor Neurons Motor Cortex BASAL GANGLIA Planning, initiating, directing Gating initiation movement CEREBELLUM Brainstem centres Sensory motor coordination Basic movements and posture Local circuit neurons Lower motor neurons Reflex coordination SKELETAL MUSCLE Inputs of the cerebellum Cerebral cortex Cerebral cortex Pons Cerebellum Vestibular Inferior Spinal Granule cells nuclei olive cord Purkinje cells Pons Vestibular nuclei Inferior olive Nucleus dorsalis of Clarke Outputs of the cerebellum Cerebral cortex Cerebellar cortex Thalamus Deep nuclei Dentate nuclei Vestibular Inferior Thalamus Red nuclei olive nucleus Purkinje cells Cerebral cortex Normal cerebellum Cerebellar cortical atrophy Climbing fibres SCA 5, 6, 11, 26 Partially SCA8 Olivopontocerebellar atrophy (cerebellipetal atrophy) Dentatorubral atrophy (cerebellifugal atrophy) Climbing fibres Mossy fibres DRPLA SCA3 Plus ascending FRDA tracts SC and Clarke’s FRDA also dorsal ganglia MSA, SCA 1,2,7 Olive and pons also in SCA3 Focal lesion: stroke, brain tumour, sarcoidosis Toxic: ethanol, antiepileptics, lithium, heavy metals Infectious or postinfectious cerebellitis Sporadic Endocrine Head injury Immune-mediated cerebellar ataxia (paraneoplastic or not) Sporadic degenerative ataxias Cerebellar ataxia MSA criteria (Neurology. 2008;71:670–676) Idiopathic late onset cerebellar ataxia (ILOCA) >50y ILOCA with cerebellar-plus syndrome No Hereditary <50y Consider Friedreich's ataxia (FRDA) Modified from Current Opinion in Neurology22(4):419-429, August 2009. Paraneoplastic cerebellar degeneration Underlying Antibody type Clinical picture cancer Anti-Yo Breast, gynaecological SCLC, sarcoma, Anti-Hu Encephalomyelitis neuroblastoma Limbic encephalitis Sensory neuronopathy Autonomic dysfunction Anti-Ri Opsoclonus–myoclonus Neuroblastoma, breast, gynaecological Brainstem encephalitis Anti-Tr Hodgkin’s lymphoma Anti-CV2 (CMRP) Polyneuropathy Thymoma, SCLC, tumours of testis Anti-Ma Limbic encephalitis Breast Brainstem encephalitis Opsoclonus–myoclonus Anti-PCA2 Limbic encephalitis SCLC Lambert–Eaton syndrome Autonomic and motor neuropathy Episodic Episodic ataxia Pure cerebellar syndrome Dominant No Spinocerebellar ataxias (SCAs) SCA 5, 6, 11, 26 Cerebellar ataxia-plus (OPCA: SCA 1,2,7) Consider: Ataxia with deficiency in vitamin E (AVED) - Blood smear Hereditary Abetalipoproteinaemia (ABL) cerebellar - Vitamin E Cerebrotendinous xanthomatosis (CTX) ataxia - Cholesterol Recessive FRDA Refsum's disease - Cholestanol Ataxia with oculomotor apraxia (AOA)1-2 - Phytanic acid - Alpha-fetoprotein Early onset cerebellar ataxia with retained reflexes (EOCARR) - Immunological AR spastic ataxia of Charlevoix-Saguenay (ARSACS) Mitochondrial recessive ataxia syndrome (MIRAS) Ataxia telangiectasia/ATLD SCA with axonal neuropathy (SCAN1) X-linked Mitochondrial Late-onset Tay-Sachs disease (LOTSD) Ataxic variant of ALD (AVALD) Fragile-X tremor ataxia syndrome (FXTAS) Main episodic ataxias Episodic ataxia Phenotype Onset Triggering Mutation/locus EA1 Interictal myokymia Early childhood Physical exertion KCNA1 (12q13) Emotional stress Startle CACNA1A EA2 Interictal nystagmus Childhood or adolescence Exertion (19p13) Rarely in adulthood Stress Alcohol EA3 Episodic vertigo, tinnitus, and ataxia Linked to 1q42 No baseline deficit EA4 Episodic vertigo Late-onset Interictal nystagmus No response to acetazolamide EA6 Attacks of hemiplegia and migraine EA7 Seizures Before the age of 20 Exertion 19q13 Attacks of vertigo, weakness, and slurring Excitement Disease Gene Pathogenic Type ADCA DRPLA ATN1 or DRPLA CAG >49-88 HD HTT CAG >36-250 SBMA AR CAG >38-62 SCA1 ATXN1 CAG >49-88 I subclass I OPCA SCA2 ATXN2 CAG >32 I subclass I OPCA SCA3/MJD ATXN1 CAG >55-86 I subclass I SCA6 CACNA1A CAG >20-33 III Polyglutamine SCA7 ATXN7 CAG >37-306 II OPCA SCA17 TBP CAG >47-63 I subclass I SCA12 PPP2R2B CAG >55-78 I subclass II I: ataxia-plus FXS FMR1 CGG >230 Subclass I: Polyglutamine FXTAS FMR1 CGG 55-200 Subclass II: non-coding CAG, FRAXE AFF2 or FMR2 CCG >200 dysfunction RNA splicing FRDA FXN or X25 GAA >100 Subclass III: dels, missense, HDL2 JPH3 CTG/CAG >41 nonsense DM1 DMPK CTG >50 Trinucleotide repeat disorders II: pigmentary maculopathy SCA8 OSCA or ATXN8OS CTG >110 I subclass II III: pure cerebellar Nonpolyglutamine SCA10 ATXN10 ATTCT >800 I subclass II SCA4 Unknown I SCA5 SPTBN2 Inframe del / missense III SCA11 TTBK2 Frameshifts III SCA13 KCNC3 Missenses I subclass III SCA14 PRKCG Missenses I subclass III SCA15/16 ITPR1 Exon dels / missenses I subclass III SCA19/22 KCND3 Missenses I subclass III SCA23 PDYN Missenses I subclass III SCA26 EEF2 Missense III SCA27 FGF14 Missense and frameshift I subclass III SCA28 AFG3L2 Missense I subclass III SCA35 TGM6 Missense and inframe mut I SCA38 ELOVL5 Missense III SCA42 CACNA1G Missense I subclass III Trinucleotide repeat disorders – general remarks • Instability of repeat length leading to expansion in following generation : “anticipation” – particularly paternal • In polyQ disorders the repeat length inversely correlates with age of onset +/- speed of progression and clinical presentation • Only 50-80% variability in age of onset attributable to CAG repeat length: modulated by nonmutated genes for example heat shock proteins. • No correlation in the case of SCA8 Ataxia neuropathology – general remarks • Total brain weight usually normal (except SCA with very long repeat length, DRPLA and FXTAS) • Hindbrain (cerebellum + brainstem) normally should be 11-12% of total brain weight • Degeneration is often more severe in the anterior >posterior vermis (archicerebellum) • Always sample several levels of SC and dorsal ganglia • Sample fibroblast for cultures and freeze CSF • Observe the skull in the mortuary room, as DRPLA typically thickening of the skull IHC in ataxia – general remarks • Retraction of Purkinje cell dendritic tree - Calbindin IHC • Axonal torpedoes and empty baskets - Bielschowsky or Sevier-Munger • Grumose degeneration – SNAP25 IHC • Proteinaceaous aggregation – Ub, p62, 1C2 IHC • Morphologies: granular cytoplasmic, condensed cytoplasmic, diffuse nuclear, condensed intranuclear, axonal inclusions PolyQ inclusions in SCA2 Images courtesy of O. Ansorge IHC in ataxia – some peculiarities • SCA6: Large filamentous cytoplasmic aggregates do not stain with 1C2 Ub inclusions in SCA6, anterior horn Images courtesy of O. Ansorge Control SCA6 SCA3 / MJD OPCA Dentatorubral Normal cerebellum Pure cortical atrophy Modified from Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders – with permission SCA2 SCA6 SCA3 / MJD Cerebellar cortex Neurofilament P/non-P Dentate nucleus Cresyl violet SNAP-25 OPCA Modified from Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders – with permission SCA2 SCA6 SCA3 / MJD Basis pontis Neurofilament (non-P) Inferior olive Neurofilament (non-P) Thoracic SC MBP Modified from Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders – with permission Pathogenesis inherited ataxias •Loss of function •Gain of function Protein aggregation • Inclusion bodies are the rule in PolyQ diseases • Length of polyQ tract predict aggregation propensity and cellular toxicity in vitro • Effects may be enhanced by alteration of protein clearance, both UPS and autophagy and cause downstream mitochondrial dysfunction • Prion-like protein propagation and transfer between cells • Disconnection of inclusion formation and neurodegeneration • Purkinje cells, a main apparent disease target, usually no/minor inclusions • Distribution of aggregates does not correlate with severity of degeneration, with inclusions abundant in areas with no/minor degeneration (e.g. basis pontis in SCA3) AD SCA – shared mechanisms • Alteration of regulation of transcription or RNA processing leading to alterations in gene expression • Direct interaction of mutant protein with promoter, repressors and splicing factors • Sequestration of splicing factors by repeat-containing (untranslated) RNA • Incorporation into polyribosomes • Alteration of transcription (remodelling of chromatin, regulators of transcription, direct mutation of transcription factors) • Alteration of synaptic transmission • Neurotransmitters (e.g. decreased glutamate reuptake) • Ionic signalling pathways (e.g. direct mutation of K+ or Ca++ channels or indirect effects) • Dysregulation of gene transcription or translation proteins necessary for regulation of ions and neurotransmitters Disease Gene Pathogenic Type ADCA DRPLA ATN1 or DRPLA CAG >49-88 HD HTT CAG >36-250 SBMA AR CAG >38-62 SCA1 ATXN1 CAG >49-88 I subclass I OPCA SCA2 ATXN2 CAG >32 I subclass I OPCA SCA3/MJD ATXN1 CAG >55-86 I subclass I SCA6 CACNA1A CAG >20-33 III Polyglutamine SCA7 ATXN7 CAG >37-306 II OPCA SCA17 TBP CAG >47-63 I subclass I SCA12 PPP2R2B CAG >55-78 I subclass II I: ataxia-plus FXS FMR1 CGG >230 Subclass I: Polyglutamine FXTAS FMR1 CGG 55-200 Subclass II: non-coding CAG, FRAXE AFF2 or FMR2 CCG >200 dysfunction RNA splicing FRDA FXN or X25 GAA >100 Subclass III: dels, missense, HDL2 JPH3 CTG/CAG >41 nonsense DM1 DMPK CTG >50 Trinucleotide repeat disorders II: pigmentary maculopathy SCA8 OSCA or ATXN8OS CTG >110 I subclass II III: pure cerebellar Nonpolyglutamine
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