Neurogenetics, Part I

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• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780444632333
• eBook ISBN: 9780444632357
• Topic: Biological Sciences
• Subtopic: Genetics in Medicine
• Index: Biological Sciences

Genetic methodologies are having a significant impact on the study of neurological and psychiatric disorders. Using genetic science, researchers have identified over 200 genes that cause or contribute to neurological disorders. Still an evolving field of study, defining the relationship between genes and neurological and psychiatric disorders is evolving rapidly and expected to grow in scope as more disorders are linked to specific genetic markers. Part I covers basic genetic concepts and recurring biological themes, and begins the discussion of movement disorders and neurodevelopmental disorders, leading the way for Part II to cover a combination of neurological, neuromuscular, cerebrovascular, and psychiatric disorders. This volume in the Handbook of Clinical Neurology will provide a comprehensive introduction and reference on neurogenetics for the clinical practitioner and the research neurologist.- Presents a comprehensive coverage of neurogenetics- Details the latest science and impact on our understanding of neurological psychiatric disorders- Provides a focused reference for clinical practitioners and the neuroscience/neurogenetics research community

Section III: Movement disorders

Chapter 12

Autosomal-dominant cerebellar ataxias

Andrew Mundwiler^1,2; Vikram G. Shakkottai^3,* ¹ Department of Neurosciences, Spectrum Health, Grand Rapids, MI, United States
² College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
³ Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^* Correspondence to: Vikram Shakkottai, MD, PhD, 4009 BSRB, 109 Zina Pitcher Place, Ann Arbor MI 48109, United States. Tel: + 1-734-615-6891 email address: [email protected]

Abstract

Spinocerebellar ataxias (SCAs) are a genetically diverse group of dominantly inherited disorders that share clinical features that result from dysfunction and degeneration of the cerebellum and its associated pathways. Although nearly 40 genes are currently recognized to result in SCA, shared mechanisms for disease pathogenesis exist among subsets of the SCAs. The most common SCAs result from a glutamine-encoding CAG repeat in the respective disease genes. This chapter discusses the varied genetic etiology of SCA and attempts to categorize these disorders based on shared mechanisms of disease. We also summarize evaluation and management for the SCAs.

Keywords

spinocerebellar ataxia; autosomal dominant cerebellar ataxias; cerebellum; polyglutamine; CAG repeat; SCA

Introduction

The autosomal-dominant cerebellar ataxias (ADCAs), currently known primarily by the designation spinocerebellar ataxia (SCA), are a heterogeneous group of degenerative disorders characterized by dysfunction of the cerebellum and brainstem as well as their associated pathways and connections. All patients with SCAs exhibit cerebellar ataxia. Other symptoms and signs are variable and disease-specific, including extrapyramidal features, long tract signs, peripheral neuropathy, cognitive decline, and seizures (Table 12.1). The polyglutamine ataxias, including SCA1, SCA2, and SCA3, are progressive disorders and lead to shortened lifespan (Durr, 2010). Several other autosomal-dominant ataxias lead to significant morbidity but are not associated with early death. The first widely accepted systematic classification of dominantly inherited ataxias was proposed in 1993 by Harding. This scheme included ADCA type I, in which cerebellar ataxia is variably associated with other neurologic features, including dysfunction of the central and/or peripheral nervous system; SCAs 1, 2, and 3 all represent type I, and are among the most common SCAs. In ADCA type II, ataxia is associated with a pigmentary retinopathy; SCA7 is the only ADCA belonging to type II. ADCA type III is characterized by relatively pure cerebellar ataxia, of which SCA6 is the most common. Although this classification currently has limited clinical utility, it remains useful to classify the ADCAs into those typically presenting with relatively pure ataxia and those accompanied by other neurologic symptoms and signs.

Table 12.1

Summary of clinical features, genes, and molecular pathogenesis of autosomal-dominant ataxias

Name	Symptoms/signs^a	Locus	Gene	Protein/mutation^b	Normal function
SCA1	Pyramidal signs Extrapyramidal signs Amyotrophy Ophthalmoparesis	6p23	ATXN1	Ataxin-1 CAG repeats, 41–81 (normal 25–36)	Gene transcription and RNA splicing
SCA2	Slow saccades Extrapyramidal signs Peripheral neuropathy Ophthalmoplegia Pyramidal signs Dementia (rare)	12p24	ATXN2	Ataxin-2 CAG repeats, 35–59 (normal 15–24)	RNA processing
SCA3 (MJD)	Pyramidal signs Amyotrophy Exophthalmos Extrapyramidal signs Ophthalmoparesis	14q24.3-q31	ATXN3	Ataxin-3 CAG repeats, 62–82 (normal 13–36)	Deubiquitinating enzyme
SCA4	Sensory axonal neuropathy Pyramidal signs	16q22.1	Unknown but distinct from SCA31	Unknown	Unknown
SCA5	Pure cerebellar ataxia (late onset) Pyramidal signs (early onset)	11q13	SPTBN2	β III Spectrin	Scaffolding protein involved in glutamate signaling
SCA6	Pure cerebellar ataxia Late onset, usually > 50 years	19p13.2	CACNA1A	Cav2.1 CAG repeats, 21–30 (normal 6–17)	Calcium channel important in Purkinje cells
SCA7	Pigmentary macular degeneration Ophthalmoplegia Pyramidal signs	3p21.1-p12	ATXN7	Ataxin-7 CAG repeats, 38–130 (normal 7–17)	Gene transcription
SCA8	Pyramidal signs Diminished vibratory sense Spastic and ataxic dysarthria	13q21.33	ATXN8OS/ ATXN8	CAG/CTG repeats, 80–250 (normal 15–50) Toxic mRNA Pure polyglutamine protein	Unknown
SCA9	Extrapyramidal signs Ophthalmoplegia Posterior-column dysfunction Pyramidal tract signs Central demyelination (one patient)	Unknown	Unknown	Unknown	Unknown
SCA10	Seizures Cognitive/neuropsychiatric impairment Polyneuropathy Pyramidal signs	22q13.31	ATXN10	Ataxin-10 Intronic ATTCT repeats, 800–4500 (normal 10–32)	Involved in neuron survival, neuron differentiation, and neuritogenesis
SCA11	Pure cerebellar ataxia	15q15.2	TTBK2	Tau tubulin kinase-2	Serine-threonine kinase Regulates ciliogenesis
SCA12	Upper-extremity tremor Mild/absent gait dysfunction Hyperreflexia	5q32	PPP2R2B	Protein phosphatase PP2A CAG repeats in 5’-UTR 51–78 (normal 7–32)	Serine-threonine phosphatase Negative control of cell growth and division
SCA13	Intellectual disability (in French pedigree) Pure cerebellar ataxia (in Filipino pedigree)	19q13.3-13.4	KCNC3	Kv3.3	Potassium channel involved in regulating Purkinje cell excitability
SCA14	Pure cerebellar ataxia Rare chorea and cognitive deficits	19q13.4	PRKCG	Protein kinase C gamma	Neuronal serine-threonine protein kinase
SCA15/SCA16	Pure cerebellar ataxia Rare tremor or cognitive impairment	3p26.1	ITPR1	Inosital 1,4,5-triphosphate receptor	Intracellular calcium channel Regulation of neuronal excitability
SCA17/HDL4	Chorea Dementia Extrapyramidal features Hyperreflexia Psychiatric symptoms	6q27	TBP	TATA box-binding protein CAG repeats, 46–63 (normal 25–42)	Gene transcription
SCA18/SMNA	Posterior-column dysfunction Amyotrophy Early onset, usually < 20 years Hyporeflexia	7q22-q32	Unknown	Unknown	Unknown
SCA19/SCA22	Pure cerebellar ataxia Cognitive impairment Myoclonus Postural tremor	1p13.3	KCND3	Kv4.3	Potassium channel involved in regulating neuronal excitability
SCA20	Spasmodic dysphonia or spasmodic coughing Palatal tremor	11p11.2-q13.3	Unknown	Gene duplication	Unknown
SCA21	Early onset Cognitive impairment Akinesia Resting tremor Rigidity Dysgraphia Hyporeflexia Postural tremor	7p21.3-p15.1	Unknown	Unknown	Unknown
SCA23	Late onset, usually > 50 years Decreased vibratory sense	20p13	PDYN	Prodynorphin	Processed to form opioid peptides that bind to kappa-type opioid receptors
SCA25	Areflexia Peripheral sensory neuropathy	2p21-p15	Unknown	Unknown	Unknown
SCA26	Pure cerebellar ataxia	19p13.3	Unknown	Unknown	Unknown
SCA27	Orofacial dyskinesia Cognitive impairment Tremor	13q34	FGF14	Fibroblast growth factor 14	Interacts with voltage-gated sodium channels Regulates Purkinje neuron excitability
SCA28	Early onset, usually < 20 years Hyperreflexia Ophtha...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Handbook of Clinical Neurology 3rd Series
• Foreword
• Preface
• Contributors
• Section I: Basic genetic concepts
• Section II: Recurring biological themes in neurogenetics
• Section III: Movement disorders
• Section IV: Neurodevelopmental disorders
• Index