Autosomal-recessive cerebellar ataxias

Handbook of Clinical Neurology, Vol. 147 (3rd series) Neurogenetics, Part I D.H. Geschwind, H.L. Paulson, and C. Klein, Editors https://doi.org/10.1016/B978-0-444-63233-3.00013-0 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 13

Autosomal-recessive cerebellar ataxias BRENT L. FOGEL* Program in Neurogenetics, Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States

Abstract The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.

HISTORIC PERSPECTIVES ON THE RECESSIVE ATAXIAS Familial disorders causing ataxia with a recessive inheritance pattern have been well described in the literature for some time. One of the most widely used initial classification schemes for such disorders was developed in the early 1980s by Harding and divided the recessive ataxias based on whether their etiology was known (primarily these were metabolic and DNA repair disorders) or unknown, with over two-thirds of these identified as Friedreich ataxia (Harding, 1983; Klockgether and Paulson, 2011). Better methods of localizing disease genes, such as linkage analysis, led to the subsequent discovery of causative genes enabling clinical testing for disease-causing mutations, especially in frataxin, the gene found to be responsible for Friedreich ataxia. This led to expansion of these classification schemes to include molecular diagnostics and gene lists, which early on combined recessive disorders with the dominant, as so few had been identified, but ultimately led to expanded discussions on the topic as more genes became known

(Klockgether and Evert, 1998; Durr and Brice, 2000; Di Donato et al., 2001; van de Warrenburg et al., 2005; Klockgether and Paulson, 2011). To aid in diagnosis, classification schemes evolved into those based on various aspects of molecular pathogenesis (Palau and Espinos, 2006; Brusse et al., 2007; Manto and Marmolino, 2009; Vermeer et al., 2011; Hersheson et al., 2012; Sailer and Houlden, 2012; Jayadev and Bird, 2013) and more clinically based classification schemes (Fogel and Perlman, 2007, 2011; Finsterer, 2009; Fogel, 2012; Anheim et al., 2012; Mancuso et al., 2014; Beaudin et al., 2017). At present, recessive ataxias represent slightly more than 50% of all genetic ataxias with approximately 3–4 cases per 100,000 persons (Ruano et al., 2014), and our knowledge of genes which cause them is so substantial that genomic methods of diagnosis are recommended as routine (Nemeth et al., 2013; Fogel et al., 2014b). In this chapter we will take a broad approach to discussing the predominant recessive cerebellar ataxias and their molecular pathogenesis as well as provide a framework for their clinical evaluation and diagnosis. While an indepth review of each disorder is not possible in this

*Correspondence to: Brent L. Fogel, MD, PhD, David Geffen School of Medicine, University of California at Los Angeles, Department of Neurology, 695 Charles E Young Drive South, Gonda 1206, Los Angeles, CA 90095, United States. E-mail: [email protected]

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overview due to sheer numbers, selected highlights are presented with associated reviews and primary studies to guide the reader to more information. Unfortunately, space limitations prevent listing more than a few key articles for each disease and many excellent articles could not be cited. A quick word must also be said regarding disease nomenclature. Unlike the dominant ataxias, where a clear system of naming has been established and is applied to disorders chronologically as they are clinically and genetically reported (Shakkottai and Fogel, 2013), the recessive ataxias have traditionally been named individually. In more recent years, as the number of genes and diseases has grown, systematic naming schemes have been suggested and applied, leading to some disorders having a plethora of names depending on the preferred naming system used. The most widely accepted system at present uses the designation “spinocerebellar ataxia, autosomal-recessive” (SCAR) for new disorders. For convenience and practicality, this review will utilize the most common name by which a disease is known clinically for more established diseases and apply the SCAR nomenclature to those more recently identified disorders for which such a designation has been given.

gene) (Fogel and Geschwind, 2015), but there are now many examples in the literature of early dominant and late recessive presentations and there are known recessive disorders which predominantly present in adulthood (Fogel and Perlman, 2007, 2011; Anheim et al., 2012; Fogel, 2012). Therefore, like the clinical examination, age of onset should only be utilized to help guide further diagnostic evaluation. Distinguishing between a dominant and recessive condition within a family can be most helpful early on, but this may not be possible in smaller families or for patients with limited family histories due to adoption or estrangement, for example. Key features suggesting a recessive disorder include the presence of affected siblings, unaffected parents, and disease in both males and females (Fogel and Geschwind, 2015). Consanguinity, if present, is also suggestive but not essential and depends on carrier frequency in the population of origin (Fogel and Geschwind, 2015). In rare situations involving populations with extremely high carrier frequencies, a pseudodominant pattern of inheritance can be seen in the absence of inbreeding (Fogel and Geschwind, 2015).

CLINICAL PHENOTYPING AND HETEROGENEITY AMONG THE RECESSIVE ATAXIAS:

For the purposes of this review, only disorders that cause cerebellar ataxia as a primary clinical feature will be considered. It is important to note, however, that many metabolic disorders and most mitochondrial disorders include features of cerebellar ataxia (OMIM, [accessed March 2017]) and therefore may need to be considered in appropriate patients. It is also important to note that there are many genetic disorders which do not typically present with cerebellar ataxia, or include it as a minor feature only (OMIM, [accessed March 2017]), that may show variant presentations in rare cases with profound cerebellar ataxia (Fogel et al., 2014b). Distinguishing such disorders from the more common genetic ataxias can be done but requires genomic diagnostic evaluation (Fogel et al., 2014b), which will be discussed in detail below. The general organization of the recessive ataxias presented here is based on age of onset, which, as previously mentioned, can be variable but provides a framework for discussing the typical presentation of disease in most individuals. Friedreich ataxia, the most common recessive ataxia and the initial clinical consideration in almost all cases, is discussed separately in the most detail.

Ataxia, or the loss of balance and coordination in the absence of muscle weakness, can be associated with dysfunction of the cerebellum, or the proprioceptive and/or vestibular systems (Fogel and Perlman, 2011). Neurodegenerative disorders affecting the cerebellum, including the recessive ataxias, can often involve more than one of these pathways (Fogel and Perlman, 2011). It is therefore critical that each patient receive a thorough clinical examination and history, including a detailed family history. Phenotypically, although many of the recessive ataxias have unique features which may be distinguishing if present, in general there is a high degree of phenotypic overlap which can make rendering a precise diagnosis based on clinical findings alone difficult, if not impossible (Fogel and Perlman, 2007, 2011; Anheim et al., 2012; Fogel, 2012). Often, the recessive ataxias present with polyneuropathy (and a corresponding sensory ataxia) and are more likely to present with involvement outside the nervous system than the dominant disorders (Fogel and Perlman, 2007, 2011; Anheim et al., 2012; Fogel, 2012). Age of onset has often been used as a means of distinguishing between dominant and recessive conditions, given the tendency for earlier onset in the recessive disorders (typically due to loss of function of the affected

GENETIC CLASSIFICATION OF THE RECESSIVE ATAXIAS

Class I: Friedreich ataxia Friedreich ataxia (Fig. 13.1) is the most common of the autosomal-recessive ataxias, currently estimated at approximately 50% of cases, and also the most common

AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIAS

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A Disease: Friedreich Ataxia (FRDA) Locus: 9q21.11 Gene: FXN (1996) Protein: Frataxin Function: Mitochondrial Iron Metabolism

Cerebellar Ataxia

B Scoliosis Cardiomyopathy GAA repeat expansion Normal: < 40 Disease: 66 to >1500

C Posterior Columns Diabetes

Lateral Corticospinal Tracts

Polyneuropathy

Fig. 13.1. Friedreich ataxia. (A) The genomic organization of the frataxin gene is shown with the pathogenic GAA repeat expansion highlighted. (B) Clinical features associated with Friedreich ataxia. (C) Illustrated view of the pathologic changes occurring in the spinal cord of patients with Friedreich ataxia.

genetic ataxia overall, being present in 1:29,000–50,000 people, with a carrier frequency of 1:85–100 in the white population due to a founder effect of the related gene mutation (Delatycki and Corben, 2012; Collins, 2013; Ruano et al., 2014). Clinically patients present in adolescence with progressive limb and gait ataxia, typically leading to wheelchair dependence in about 10 years, dysarthria, dysphagia, and polyneuropathy affecting the posterior columns and lateral corticospinal tract with associated areflexia and sensory loss (Fig. 13.1) (Marmolino, 2011; Delatycki and Corben, 2012; Collins, 2013; Parkinson et al., 2013). Important nonneurologic features include hypertrophic cardiomyopathy, scoliosis in nearly 80% of patients, and glucose intolerance or diabetes in up to approximately 30% of patients (Marmolino, 2011; Delatycki and Corben, 2012; Collins, 2013; Parkinson et al., 2013). Less frequent findings include reduced hearing, mild executive dysfunction, and central sleep apnea (Marmolino, 2011; Delatycki and Corben, 2012; Collins, 2013; Parkinson et al., 2013). Magnetic resonance imaging of the brain typically shows atrophy of the spinal cord while atrophy of the cerebellum occurs later in disease (Anheim et al., 2010; Collins, 2013; Parkinson et al., 2013). Complicating the diagnostic picture is the fact that as many as 25% of patients show variant phenotypes, which can include late-onset forms (Parkinson et al., 2013).

The gene responsible for Friedreich ataxia, FXN, is located on chromosome 9 and encodes the protein frataxin (Fig. 13.1) (Marmolino, 2011; Collins, 2013). Up to 98% of patients with Friedreich ataxia carry homozygous GAA nucleotide repeat expansions, from typically less than 40 repeats to 600–900 or more, within the first intron of the FXN gene (Fig. 13.1) (Marmolino, 2011; Collins, 2013). Genotype–phenotype correlations are seen between the size of the repeat expansions and several clinical features, including age of onset (Marmolino, 2011). In contrast to the dominant genetic disorders, where repeat expansion is a common cause (Shakkottai and Fogel, 2013), Friedreich ataxia is the only recessive ataxia caused by this mechanism. This noncoding repeat expansion reduces FXN gene expression by multiple proposed mechanisms, including structural inhibition of transcription, alteration of normal epigenetic patterns, and/or by increasing the formation of RNA/DNA hybrids (R-loops) which impair transcription of the gene, thereby silencing the affected allele (Marmolino, 2011; EvansGalea et al., 2014; Groh et al., 2014). Patients lacking homozygous repeat expansions have compound heterozygous expansions combined with a point mutation or deletion in the second allele (Marmolino, 2011; Collins, 2013), thought to inactivate the protein. Frataxin is a mitochondrial protein involved in cellular iron metabolism, including the biogenesis of iron– sulfur clusters important in electron transport and

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DNA repair/replication, among other functions. Frataxin deficiency leads to mitochondrial iron accumulation, although the precise pathophysiology leading to neuronal death is still under investigation (Evans-Galea et al., 2014; Martelli and Puccio, 2014; Chen et al., 2016). Models of Friedreich ataxia used to investigate pathogenesis include patient-derived cell lines and induced pluripotent stem cell-derived neural progenitors as well as various animal models, predominantly mice (Marmolino, 2011; Perdomini et al., 2013; Bird et al., 2014). Currently treatment is symptomatic and, due to the level of disability incurred over time, the cost of care can be significant to patients and families (Polek et al., 2013). Drugs under various clinical stages of investigation for the treatment of Friedreich ataxia include iron chelators such as deferiprone (Pandolfo et al., 2014), epigenetic modification therapies to increase transcription such as histone deacetylase inhibitors (Gottesfeld et al., 2013; Soragni et al., 2014), and antioxidants, including idebenone (Meier et al., 2012; Perlman, 2012; Collins, 2013). Experimental therapies under early research investigation include stem cell transplant and/or gene therapy (Evans-Galea et al., 2014; Tajiri et al., 2014), which has shown some early successes in animal models (Perdomini et al., 2014; Sarsero et al., 2014); however, there remains no effective pharmacologic therapy available (Corben et al., 2014; Aranca et al., 2016; Kearney et al., 2016).

Class II: early-onset recessive ataxias In general, the early-onset recessive ataxias are characterized by childhood onset of disease, often before the age of 5 years. Consistent with the traditional outlook on recessive conditions as disorders of childhood, this is the largest category of disorders represented in this review (Table 13.1). It is, however, important to recognize that early onset is still not universal for all presentations of each disease, only the most typical cases, and some individuals may manifest symptoms later (or earlier) than most. This variability in age of onset illustrates the need for unbiased methods of genetic testing such as the genomic methods discussed later. For the purposes of this review, we will focus on the classic forms of these disorders.

DISORDERS OF GENOMIC OR MITOCHONDRIAL DNA METABOLISM

The first gene identified of the early-onset recessive ataxias was that responsible for ataxia-telangiectasia (AT), which is likely the second most common recessive ataxia, with a prevalence as high as 1 per 100,000 persons (Hoche et al., 2012; Ruano et al., 2014). AT is caused by mutation of the ATM gene (Table 13.1), which is

involved in the DNA damage response to double-strand breaks and in cell cycle damage checkpoint regulation to prevent genomic instability (Fig. 13.2) (Ambrose and Gatti, 2013). Clinically, AT presents with progressive ataxia starting between ages 1 and 4 as well as a constellation of associated features, including oculomotor apraxia, conjunctival telangiectasias, extrapyramidal movements such as chorea or dystonia, elevated serum alpha-fetoprotein, and immunodeficiency with an increased risk of developing leukemia and lymphomas (Gatti, 2010; Hoche et al., 2012). Female carriers also show increased risk of breast cancer (Gatti, 2010; Hoche et al., 2012). Adult-onset forms of this disorder are also not uncommon (Gatti, 2010). Although AT has specific features that can be clinically distinguished from Friedreich ataxia in typical cases, a number of other recessive disorders show phenotypic overlap (discussed below) and therefore complicate differential diagnosis, particularly in cases with later onset. One such example is AT-like disorder, caused by mutation of MRE11A (Table 13.1), which functions in the sensing of doublestranded DNA breaks (Fig. 13.2) (Stracker et al., 2013). Mutations prevent the activation of ATM (Regal et al., 2013), producing a clinically similar phenotype to AT, although lacking elevation in alpha-fetoprotein (Gatti, 2010). With regard to the mitochondrial genome, mutation of the mitochondrial helicase twinkle (encoded by C10ORF2) (Table 13.1), which is essential for mitochondrial DNA replication (Milenkovic et al., 2013), causes a severe infantile-onset spinocerebellar ataxia due to subsequent mitochondrial dysfunction (Fig. 13.2) (Hakonen et al., 2008). Most recently, SCAR23, an early-onset condition presenting with ataxia, intellectual disability, and epilepsy, was shown to be caused by mutation of the TDP2 gene (Table 13.1), which encodes a phosphodiesterase required for repair of abortive transient double-strand breaks that arise during the normal function of topoisomerase II during gene transcription (Fig. 13.2) (GomezHerreros et al., 2014).

DISORDERS OF SIGNAL TRANSDUCTION Impairment of intracellular signaling leads to cerebellar ataxia in a number of diverse diseases. Cayman ataxia, found in an isolated population on Grand Cayman Island, is due to mutation of the ATCAY gene (Table 13.1) (Bomar et al., 2003). Although postulated to be involved in signal transduction (Fig. 13.2), the molecular pathogenesis of ATCAY mutation is not yet established; however, its murine ortholog appears to share a conserved function and its mutation also causes ataxia (Sikora et al., 2012), raising hope that elucidation is not far off. GRID2, a gene involved in signal transduction and

Table 13.1 Early-onset autosomal-recessive ataxias Disease

Abbreviation

Locus

Gene

Year

Protein

Function

Clinical

Ataxia telangiectasia (OMIM 208900)

AT

11q22.3

ATM

1995

Ataxia-telangiectasia mutated

DNA repair

Malignancy Oculomotor apraxia Telangiectasias

Ataxia telangiectasialike disorder (OMIM 604391)

ATLD

11q21

MRE11A

1999

Meiotic recombination-11

DNA repair

Oculomotor apraxia

Autosomal-recessive ataxia of CharlevoixSaguenay (OMIM 270550)

ARSACS

13q12

SACS

2000

Sacsin

Protein folding and/or quality control, mitochondrial morphology

Polyneuropathy Pyramidal signs

Cayman ataxia (OMIM 601238)

CA

19p13.3

ATCAY

2003

Caytaxin

Signal transduction

Psychiatric symptoms Pure cerebellar

Infantile-onset spinocerebellar ataxia (OMIM 271245)

IOSCA

10q24

C10ORF2

2005

Twinkle, twinky

Mitochondrial DNA metabolism

Extrapyramidal signs Polyneuropathy

Marinesco–Sj€ogren syndrome (OMIM 248800)

MSS

5q31

SIL1

2005

BiP-associated protein

Protein folding and/or quality control

Cataracts Intellectual disability Myopathy

Spinocerebellar ataxia autosomal-recessive, type 9 (OMIM 612016)

SCAR9

1q42.13

ADCK3

2008

aarF domain-containing kinase-3

CoQ10 synthesis, mitochondrial metabolism

Epilepsy Intellectual disability Pure cerebellar

Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (OMIM 224050)

CAMRQ

9p24

VLDLR

2008

Very-low-density lipoprotein receptor

Signal transduction

Intellectual disability Quadrupedal gait

Continued

Table 13.1 Continued Disease

Abbreviation

(OMIM 613227) (OMIM 610185) (OMIM 615268)

Locus

Gene

Year

Protein

8q12.1 17p13.3 13q12.13

CA8 WDR81 ATP8A2

2009 2011 2013

Carbonic anhydrase VIII WD repeat domain 81 ATPase, aminophospholipid transporter, class I, type 8A, member 2

8q21.1

PEX2

2011

Peroxin 2

1p36.32 11p11.2

PEX10 PEX16

2010 2010

Peroxin 10 Peroxin 16

Function

Clinical

Peroxisomal metabolism

Pure cerebellar

Peroxin-associated ataxias (OMIM 170993) (OMIM 602859) (OMIM 603360)

PEX

Spinocerebellar ataxia autosomal-recessive, type 15 (OMIM 615705)

SCAR15

3q29

KIAA0226

2010

Rundataxin

Autophagosome function and/or endocytic trafficking

Epilepsy Intellectual disability

Spinocerebellar ataxia autosomal-recessive, type 13 (OMIM 614831)

SCAR13

6q24.3

GRM1

2012

Glutamate receptor, metabotropic 1

Signal transduction

Congenital ataxia Intellectual disability

Spinocerebellar ataxia autosomal-recessive, type 14 (OMIM 615386)

SCAR14

11q13.2

SPTBN2

2012

Spectrin, beta, non-erythrocytic 2

Neuronal membrane structure, signal transduction

Intellectual disability Allelic with SCA5

GBA2 ataxia (OMIM 609471)

GBA2

9p13.3

GBA2

2013

Beta-glucosidase 2

Membrane lipid metabolism

Polyneuropathy Pyramidal signs Allelic with SPG46

Spinocerebellar ataxia autosomal-recessive, type 7 (OMIM 609270)

SCAR7

11p15.4

TPP1

2013

Tripeptidyl peptidase I

Lysosomal metabolism

Polyneuropathy Pyramidal signs Allelic with CLN2

Polyneuropathy Cataracts Pyramidal signs

Spinocerebellar ataxia autosomal-recessive, type 18 (OMIM 616204)

SCAR18

4q22.1

GRID2

2013

Glutamate receptor, ionotropic, delta 2

Signal transduction

Intellectual disability Oculomotor apraxia Pyramidal signs

Spinocerebellar ataxia autosomal-recessive, type 12 (OMIM 614322)

SCAR12

16q23.1

WWOX

2014

WW domain containing oxidoreductase

Tumor suppressor gene, signal transduction

Epilepsy Intellectual disability

PNPLA6 ataxia (OMIM 215470)

PNPLA6

19p13.2

PNPLA6

2014

Patatin-like phospholipase domain containing 6

Lipid metabolism

Chorioretinal dystrophy Hypogonadism Pyramidal signs Allelic with SPG39

Spinocerebellar ataxia autosomal-recessive, type 19 (OMIM 616291)

SCAR19

1p36.11

SLC9A1

2014

Solute carrier family 9, subfamily A, member 1

Cell metabolism, pH regulation

Deafness Polyneuropathy

Spinocerebellar ataxia autosomal-recessive, type 17 (OMIM 616127)

SCAR17

10q24.31

CWF19L1

2014

CWF19-like 1, cell cycle control

Cell cycle regulation?

Congenital ataxia Intellectual disability

Spinocerebellar ataxia autosomal-recessive, type 20 (OMIM 616354)

SCAR20

6q14.3

SNX14

2014

Sorting nexin 14

Lysosomal metabolism, autophagy

Deafness Dysmorphic facies Intellectual disability Macrocephaly

Spinocerebellar ataxia autosomal-recessive, type 21 (OMIM 616719)

SCAR21

11q13.1

SCYL1

2015

SCY1-like pseudokinase 1

Golgi metabolism

Liver failure Polyneuropathy

Spinocerebellar ataxia autosomal-recessive, type 23 (OMIM 616949)

SCAR23

6p22.3

TDP2

2014

Tyrosyl-DNA phosphodiesterase 2

DNA repair

Epilepsy Intellectual disability

Spinocerebellar ataxia autosomal-recessive, type 24 (OMIM 617133)

SCAR24

3q22.1

UBA5

2016

Ubiquitin-like modifier activating enzyme 5

Protein quality control

Cataracts

CoQ, coenzyme Q; OMIM, Online Mendelian Inheritance in Man.

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B.L. FOGEL Endosomes & Membrane Vesicles Vesicle Trafficking

Lysosome Lysosomal Metabolism HEXA Peroxisomal SNX14 Metabolism TPP1 AMACR PEX16 Peroxisome PEX2 PHYH PEX7 PEX10 DNA Transcription

Protein Translation

RNA RNA Processing

GBA2 Cell Membrane MTTP PNPLA6 & Intracellular Signaling TTPA

Protein Quality Control RNF216 SIL1 STUB1 UBA5

DNA DNA Repair/Genome Stability APTX SETX TDP1 ATM MRE11A TDP2 PNKP XRCC1

KIAA0226 SYT14

Lipid & Lipoprotein Metabolism

Signal Transduction ABHD12 PIK3R5 Other/Unknown Cellular ANO10 SPTBN2 Metabolism/Functions ATCAY VLDLR CWF19L1 SYNE1 ATP8A2 WDR81 SCYL1 VWA3B CA8 WWOX SLC9A1 Mitochondrial GRID2 Other Iron Metabolism Mitochondrial GRM1 FXN Metabolism DNA ADCK3 Repair/Replication CYP27A1 C10ORF2 MARS2 POLG SACS

ER

Nucleus

Mitochondria

Fig. 13.2. Subcellular localization and pathogenesis of the recessive ataxias. A neuron is depicted with structures and subcellular organelles labeled in black. Cellular and metabolic functions disrupted in disease pathogenesis for the various ataxias are indicated in white. Recessive ataxia genes are indicated in red with abbreviations corresponding to those used in Figure 13.1 and Tables 13.1–13.3. ER, endoplasmic reticulum.

long known to cause cerebellar ataxia in mice, was recently associated with a human recessive ataxia phenotype primarily featuring intellectual disability, pyramidal signs, and eye movement abnormalities, including oculomotor apraxia (SCAR18, Table 13.1, Fig. 13.2) (Hills et al., 2013; Utine et al., 2013; Van Schil et al., 2015). In contrast to most of the other disorders in this category, which are due to mutation of single genes, the phenotype of cerebellar ataxia, mental retardation (intellectual disability), and dysequilibrium syndrome (CAMRQ) is caused by mutation in one of four genes: VLDLR (Ozcelik et al., 2008), CA8 (Turkmen et al., 2009), WDR81 (Gulsuner et al., 2011), or ATP8A2 (Table 13.1) (Onat et al., 2013). Although the cerebellar ataxia is congenital and nonprogressive, and therefore atypical of other disorders listed in the class, it is so clinically profound as to warrant inclusion here; for example, in all these disorders, individuals can be found in which the ataxia is so marked they adopt a striking quadrupedal gait for ambulation (Ozcelik et al., 2008; Turkmen et al., 2009; Gulsuner et al., 2011; Onat et al., 2013). Various lines of evidence implicate disruption of cellular signaling pathways in the pathogenesis of this phenotype (Fig. 13.2) (Ozcelik et al., 2008; Turkmen et al., 2009; Gulsuner et al., 2011; Onat et al., 2013; Kizhakkedath et al., 2014). Recently, a number of new genes have been identified as causing cerebellar ataxia likely by disruption of

pathways of intracellular signaling (Fig. 13.2). SCAR12, which presents with epilepsy and intellectual disability, was recently found to be associated with mutation of the tumor suppressor gene WWOX (Table 13.1) and similar phenotypes are seen in animal models (Mallaret et al., 2014). SCAR13, is due to mutation of GRM1 which encodes the glutamate receptor mGluR1 involved in cerebellar formation and synaptogenesis (Table 13.1, Fig. 13.2) (Guergueltcheva et al., 2012). Mutations in this gene cause ataxia in mice (Conti et al., 2006; Sachs et al., 2007) and dogs (Zeng et al., 2011) and antibodies against the protein can be associated with acquired cerebellar ataxia due to paraneoplastic disease (Levite, 2014). SCAR14 is an early-onset ataxia associated with intellectual disability recently found to be caused by recessive mutations in the SPTBN2 gene (Table 13.1) (Lise et al., 2012), which is already known to cause a dominant pure cerebellar ataxia phenotype termed spinocerebellar ataxia type 5 (Cho and Fogel, 2013; Shakkottai and Fogel, 2013), illustrating how dramatic phenotypic differences can occur through variable expression of the same gene (e.g., loss of function versus haploinsufficiency).

DISORDERS OF ORGANELLE FUNCTION Mutation of the lysosomal enzyme encoded by TPP1 causes SCAR7, a slowly progressive recessive ataxia

AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIAS with pyramidal signs and polyneuropathy, and also causes the much more severe fatal disease neuronal ceroid lipofuscinosis type 2, which also includes ataxia in its clinical presentation (Table 13.1, Fig. 13.2) (Sun et al., 2013). SCAR9 is caused by mutation of the ADCK3 gene which is involved in mitochondrial metabolism via the synthesis of coenzyme Q10 and whose deficiency results in variable ataxia phenotypes, often including epilepsy and intellectual disability (Table 13.1, Fig. 13.2) (Mollet et al., 2008; Horvath et al., 2012; Mignot et al., 2013). Unfortunately, unlike some other deficiency disorders mentioned later, individuals with SCAR9 do not generally respond well to replacement via coenzyme Q10 supplementation (Horvath et al., 2012; Desbats et al., 2015). Autosomal-recessive ataxia of Charlevoix-Saguenay (or ARSACS), typically featuring pyramidal signs and polyneuropathy, is caused by mutation of the SACS gene (Table 13.1). Originally identified as a rare, geographically localized disorder, continued molecular genetic efforts have expanded the SACS gene size, the diversity of clinical presentations, and the worldwide prevalence of its mutations (Takiyama, 2007; Vermeer et al., 2008; Baets et al., 2010; Duquette et al., 2013; Synofzik et al., 2013; Thiffault et al., 2013; Pilliod et al., 2015). Sacsin, the product of the SACS gene, had been predicted to play a role in protein quality control; however, more recent work supports a model where the underlying pathogenesis is due to cytoskeletal alterations affecting mitochondrial morphology and function (Fig. 13.2) (Criscuolo et al., 2015; Lariviere et al., 2015; Pilliod et al., 2015). The most commonly seen form of a peroxisomal disorder with recessive ataxia is Refsum disease, which is discussed below with adolescent-onset conditions. However, it must be mentioned that mutations in certain peroxisomal biogenesis proteins (which typically cause Zellweger spectrum phenotypes) have been reported to rarely present as early-onset ataxic disorders, further illustrating the need for a systematic and unbiased approach to diagnosis given such unexpected phenotypic variability. To date mutations in PEX2 (Sevin et al., 2011), PEX10 (Regal et al., 2010), and PEX16 (Ebberink et al., 2010) have been reported (Table 13.1, Fig. 13.2). This also highlights the importance of utilizing serum biomarkers for diagnosis in circumstances where genetic testing options are limited (see below). SCAR20 results from mutation of the SNX14 gene (Table 13.1) and is characterized by cerebellar ataxia, intellectual disability, sensorineural hearing loss, macrocephaly, and facial dysmorphisms (Thomas et al., 2014; Akizu et al., 2015). SNX14 is thought to play a role in the normal function of lysosomes leading to disruption of

195

normal autophagy mechanisms (Fig. 13.2) (Thomas et al., 2014; Akizu et al., 2015). SCAR21, a recently identified disorder, presents in infancy with ataxia, peripheral neuropathy, and acute liver failure caused by mutation of the SCYL1 gene (Table 13.1), involved in the function of the Golgi apparatus and possibly in transport between the Golgi and the endoplasmic reticulum (Fig. 13.2) (Schmidt et al., 2015).

DISORDERS OF PROTEIN QUALITY CONTROL Disruption of protein quality control appears to underlie Marinesco–Sj€ogren syndrome, mostly due to private SIL1 mutations in rare families (Table 13.1), and clinically characterized by ataxia, myopathy, cataracts, and intellectual disability (Krieger et al., 2013; Ezgu et al., 2014). Cell culture and murine studies have shown that SIL1 is a molecular chaperone that plays important roles in muscle and brain, including neuronal migration and axon development (Fig. 13.2) (Inaguma et al., 2014; Roos et al., 2014). Mutation of the UBA5 gene (Table 13.1) causes SCAR24, a childhood-onset ataxia associated with early cataracts (Duan et al., 2016). UBA5 encodes a ubiquitinactivating enzyme (Fig. 13.2) whose function appears important in the development of this disease as a similar phenotype was observed in a knockdown Drosophila model (Duan et al., 2016).

DISORDERS OF LIPID AND LIPOPROTEIN METABOLISM GBA2, which encodes an enzyme important in lipid metabolism (Korschen et al., 2013) and previously known to cause SPG46, a rare complicated hereditary spastic paraparesis (Table 13.1, Fig. 13.2) (Citterio et al., 2014), was recently shown to cause spastic ataxia (Hammer et al., 2013), providing an illustration of how disorders with a spectrum of phenotypic variability can be classified into separate diagnostic categories depending on the relative severity of one key symptom over another. Further proving this point, PNPLA6, which expresses an enzyme also involved in lipid metabolism and previously identified in patients with the hereditary spastic paraparesis SPG39, was recently shown to exhibit a broad phenotypic spectrum of ataxia with varying degrees of chorioretinal dystrophy, hypogonadotropic hypogonadism, and pyramidal signs (Table 13.1, Fig. 13.2) (Synofzik et al., 2014a; Synofzik and Zuchner, 2014).

DISORDERS OF CELLULAR METABOLISM SCAR15, caused by mutation of the KIAA0226 gene (Table 13.1), is associated with epilepsy and intellectual disability (Assoum et al., 2010) and dysregulation of

196

B.L. FOGEL

endosome maturation and vesicle trafficking (Fig. 13.2) (Assoum et al., 2013). Inactivating mutations in SLC9A1 (Table 13.1), which expresses a sodium/hydrogen transporter important in pH regulation of the inner ear (Fig. 13.2), were recently associated with cerebellar ataxia and sensorineural deafness (SCAR19) (Guissart et al., 2015). SCAR17, due to mutation of the CWF19L1 gene (Table 13.1), is a nonprogressive congenital ataxia associated with intellectual disability (Burns et al., 2014). The functional role of the gene is presently unknown but various aspects of RNA metabolism, cell cycle regulation, and endosomal trafficking have been implicated (Fig. 13.2) (Burns et al., 2014).

Class III: adolescent-onset recessive ataxias As discussed for the early-onset recessive ataxias, adolescent onset represents the most common presentation of the diseases in this category with variations that can present earlier or later in individuals. One important clinical note to emphasize for disorders with typical adolescent onset is that many of the diseases in this category are phenocopies, or mimics, of the Friedreich ataxia presentation. Thus it is important to screen for Friedreich ataxia early, once the evaluation proceeds into the realm of genetic analysis, to prevent delay in diagnosis, particularly if the presentation is somewhat variant, as can be common in Friedreich cases (Collins, 2013).

DISORDERS OF GENOMIC OR MITOCHONDRIAL DNA METABOLISM

As alluded to above, a class of disorders whose clinical presentation mimics both Friedreich ataxia and AT are the disorders of ataxia with oculomotor apraxia (AOA), types 1–4, and XRCC1-AOA, presented together because of their clinical similarity. AOA1 is caused by mutation of the APTX gene (Date et al., 2001; Moreira et al., 2001) while AOA2 is caused by mutation of the SETX gene (Table 13.2) (Moreira et al., 2004). Both disorders present with cerebellar ataxia and axonal sensorimotor neuropathy; however, AOA1 presents under the age of 10 and shows elevated levels of cholesterol, low serum albumin, and normal alpha-fetoprotein while patients with AOA2 present in the teenage years and have elevated levels of alpha-fetoprotein (although usually never as high as in AT) (Date et al., 2001; Moreira et al., 2001, 2004; Anheim et al., 2009; Castellotti et al., 2011). Other clinical features associated with AOA1 include cognitive impairment and, more rarely, coenzyme Q10 deficiency (Quinzii et al., 2005; Le Ber et al., 2007; Castellotti et al., 2011). Of the two conditions, AOA2 is more common and, in some parts of the world, AOA2 may be the second most

common recessive ataxia (Le Ber et al., 2004; Anheim et al., 2009, 2010). Functionally, aprataxin (product of the APTX gene) plays a role in DNA repair as part of the DNA damage response and otherwise serves to maintain the integrity of the genome (Fig. 13.2) (Harris et al., 2009; Tumbale et al., 2014). Senataxin, the product of the SETX gene, likely functions in transcription, RNA processing, and DNA repair, but plays a primary role in the stability of the genome through the resolution of R-loops (Fig. 13.2) (Suraweera et al., 2009; SkourtiStathaki et al., 2011; Padmanabhan et al., 2012; Wagschal et al., 2012; Becherel et al., 2013; Fogel et al., 2014a; Groh et al., 2016). Recent development of a mouse model of Setx disruption has shed new light on disease pathogenesis (Becherel et al., 2013; Yeo et al., 2014, 2015) and recent studies of gene expression in both patients and mice have identified disease-specific alterations that are conserved across cell type and species and likely underlie the AOA2 phenotype (Fogel et al., 2014a; Becherel et al., 2015). Lastly, the PNKP and XRCC1 genes, whose mutation cause AOA4 (childhood-onset) and XRCC1-AOA (adult-onset) respectively (Bras et al., 2015; Hoch et al., 2017), encode additional members of the single-strand break repair complexes, along with aprataxin, suggesting a common pathway for disease pathogenesis (Hoch et al., 2017). Interestingly, PIK3R5, causative for AOA3, encodes a protein likely involved in signal transduction (Al Tassan et al., 2012), suggesting that alternate mechanisms of pathogenesis for this phenotype also exist. Another recessive disorder of DNA repair is caused by mutation of the TDP1 gene resulting in a syndrome known as spinocerebellar ataxia with axonal neuropathy and characterized by slowly progressing ataxia and sensorimotor polyneuropathy (Table 13.2, Fig. 13.2) (Fam et al., 2012). Mice with Tdp1 knockout have cerebellar atrophy and their neurons are unable to repair genomic DNA breaks due to oxidative damage (Fam et al., 2012). Within the mitochondria, mutation of POLG (Table 13.2), which encodes the DNA polymerase solely responsible for replication and repair of the mitochondrial genome (Fig. 13.2) (Wong et al., 2008; Tzoulis et al., 2014), causes DNA depletion and progressive somatic mutagenesis, leading to disease (Tzoulis et al., 2014). Clinically this manifests as a progressive ataxia associated with diverse neurologic features, including polyneuropathy, progressive external ophthalmoplegia, epilepsy, and extrapyramidal features (Wong et al., 2008; Synofzik et al., 2012) that appears to be relatively common in certain European populations (Hakonen et al., 2005; Schicks et al., 2010).

Table 13.2 Adolescent-onset autosomal-recessive ataxias Disease

Abbreviation

Locus

Gene

Year

Protein

Function

Clinical

Late-onset Tay–Sachs (OMIM 272800)

LOTS

15q23

HEXA

1986

Hexosaminidase A

Lysosomal metabolism

Extrapyramidal signs Psychiatric symptoms

Cerebrotendinous xanthomatosis (OMIM 213700)

CTX

2q35

CYP27A1

1991

Sterol 27-hydroxylase

Bile acid metabolism

Cataracts Tendon xanthomas

Abetalipoproteinemia (OMIM 200100)

ABL

4q24

MTTP

1993

Microsomal triglyceride transfer protein

Lipoprotein metabolism

Lipid malabsorption Pigmentary retinopathy

Ataxia with vitamin E deficiency (OMIM 277460)

AVED

8q12.3

TTPA

1995

Alpha-tocopherol transfer protein

Vitamin E metabolism

Pigmentary retinopathy Polyneuropathy

Refsum disease (OMIM 266500)

RD

10p13

PHYH

1997

Phytanoyl-CoA hydroxylase

Fatty acid metabolism

Anosmia Pigmentary retinopathy

6q23.3

PEX7

2003

Peroxin-7

Peroxisomal import

(OMIM 601757) Ataxia with oculomotor apraxia (OMIM 208920) (OMIM 606002)

AOA1

9p13.3

APTX

2001

Aprataxin

DNA repair

AOA2

9q34.13

SETX

2004

Senataxin

(OMIM 615217)

AOA3

17p13.1

PIK3R5

2012

(OMIM 616267)

AOA4

19q13.33

PNKP

2015

(OMIM 194360)

XRCC1-AOA

19q13.31

XRCC1

2017

Phosphoinositide-3kinase regulatory subunit 5 Polynucleotide kinase 3’-phosphatase X-ray repair crosscomplementing 1

Genome stability, DNA repair, transcription, RNA processing Signal transduction

Spinocerebellar ataxia with axonal neuropathy (OMIM 607250)

SCAN1

14q32.11

TDP1

2002

Tyrosyl-DNA phoshodiesterase-1

Oculomotor apraxia Polyneuropathy

DNA repair DNA repair DNA repair

Polyneuropathy

Continued

Table 13.2 Continued Disease

Abbreviation

Locus

Gene

Year

Protein

Function

Clinical

DNA polymerase gamma disorders (OMIM 607459)

POLG

15q25

POLG

2004

DNA polymerase gamma

Mitochondrial DNA metabolism

Epilepsy Polyneuropathy Progressive external ophthalmoplegia

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (OMIM 612674)

PHARC

20p11.21

ABHD12

2010

Abhydrolase domain containing 12

Endocannabinoid metabolism, signal transduction

Cataracts Hearing loss Polyneuropathy Pigmentary retinopathy

Spinocerebellar ataxia autosomalrecessive, type 16 (OMIM 615768)

SCAR16

16p13.3

STUB1

2013

STIP1 homology and U-box containing protein 1, E3 ubiquitin protein ligase

Protein quality control

Dementia Hypogonadism Polyneuropathy

CoA, coenzyme A; OMIM, Online Mendelian Inheritance in Man.

AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIAS

DISORDERS OF SIGNAL TRANSDUCTION Recently, mutations in ABHD12 (Table 13.2), an enzyme thought to be involved in endocannabinoid metabolism, were seen in patients with adolescent onset of polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts, a presentation similar to that seen for patients with Refsum disease (see below), except lacking anosmia (seen in all Refsum patients: Wanders et al., 2010) and having normal peroxisomal function (Fiskerstrand et al., 2010). Recent development of a mouse model mimicking the human disease suggests defects in signal transduction may underlie disease pathogenesis (Fig. 13.2) (Blankman et al., 2013).

DISORDERS OF ORGANELLE FUNCTION Among the disorders most easily confused with Friedreich ataxia is the late-onset form of Tay–Sachs disease, due to partially inactivating mutations of the HEXA gene (Table 13.2), which encodes a lysosomal enzyme responsible for degrading GM2 gangliosides (Fig. 13.2) (Montalvo et al., 2005; Neudorfer et al., 2005). Although classic forms of infantile Tay–Sachs show severe neurologic presentations with intellectual disability, blindness, and early death, patients with later onset can be much milder, with features including cerebellar ataxia, lower motor neuron involvement, axonal polyneuropathy, and psychiatric/behavioral problems, a presentation often misdiagnosed as spinocerebellar ataxia or spinal muscular atrophy (Neudorfer et al., 2005; Rozenberg et al., 2006; Shapiro et al., 2008). Psychiatric symptoms can include depression, mania, and psychosis (Neudorfer et al., 2005; Shapiro et al., 2008) and patients may be diagnosed with bipolar disorder. The disease is seen more frequently in the Ashkenazi Jewish population but can be seen in other populations worldwide as well (Montalvo et al., 2005; Neudorfer et al., 2005; Hoffman et al., 2013). Although not yet treatable, methods to enhance enzyme activity pharmacologically have met with some early success (Clarke et al., 2011; Osher et al., 2011); however, whether this affects clinical outcome has yet to be determined. Cerebrotendinous xanthomatosis, due to mutation of CYP27A1 (Table 13.2), a mitochondrial protein involved in the bile synthesis pathway (Fig. 13.2), is associated with ataxia and/or spastic paraparesis, as well as other neurologic findings, including polyneuropathy, intellectual disability, psychiatric problems, epilepsy, and extrapyramidal signs, along with systemic features, most notably tendon xanthomas and juvenile cataracts (Bjorkhem et al., 2010; Mignarri et al., 2014). In addition to mimicking Friedreich presentations, if both early cataracts and ataxia are present this may suggest a diagnosis of Marinesco–Sj€ ogren syndrome (Table 13.1) to the clinician, and biomarker

199

testing for elevated cholestanol can be helpful (Mignarri et al., 2014). Early diagnosis of this disease is critical as it is one of the treatable genetic causes of ataxia with early administration of chenodeoxycholic acid to reduce the excessive cholestanol leading to better outcomes (Bjorkhem et al., 2010; Yahalom et al., 2013). As discussed above, peroxisomal disorders can present with ataxia. Refsum disease, which commonly includes anosmia and retinitis pigmentosa, in addition to ataxia, polyneuropathy, and deafness, is due to mutation of one of two distinct genes involved in the oxidation of phytanic acid, PHYH (which encodes the enzyme and is the major cause) and, more rarely, PEX7 (which transports the enzyme into peroxisomes) (Table 13.2, Fig. 13.2) (Wierzbicki, 2007; Wanders et al., 2010). Refsum disease can be identified by high levels of phytanic acid in the blood and is treatable by dietary modification, including the avoidance of fasting, because this can lead to mobilization of body stores of phytanic acid and clinical worsening (Wierzbicki, 2007; Wanders et al., 2010).

DISORDERS OF PROTEIN QUALITY CONTROL STUB1, a gene encoding a ubiquitin ligase implicated in a protective role for various neurodegenerative diseases (Table 13.2, Fig. 13.2), has recently been found to be mutated in patients with typically adolescent-onset ataxia (SCAR16), although adult-onset cases do not appear uncommon. Variable features of disease include cognitive impairment, hypogonadotropic hypogonadism, and peripheral neuropathy (Shi et al., 2013; Depondt et al., 2014; Heimdal et al., 2014; Synofzik et al., 2014b).

DISORDERS OF LIPID AND LIPOPROTEIN METABOLISM Perhaps the most striking mimic of the Friedreich ataxia clinical phenotype is caused by ataxia with vitamin E deficiency due to mutation of the alpha-tocopherol transfer protein encoded by the TTPA gene (Table 13.2) and leading to accelerated degradation, excretion, and consequently deficient serum levels of vitamin E (Fig. 13.2) (Christopher Min, 2007; Di Donato et al., 2010). Many patients also show retinitis pigmentosa (Di Donato et al., 2010). A related disorder, termed abetalipoproteinemia, is due to the MTTP gene (Table 13.2) which produces the microsomal triglyceride transfer protein and whose mutation causes a disorder of lipoprotein assembly which results in an absence of all apolipoprotein B lipoproteins, including very-lowdensity and low-density lipoproteins and particularly chylomicrons, important for the absorption of fat-soluble vitamins, including vitamin E (Fig. 13.2) (Narcisi et al., 1995; Zamel et al., 2008). Patients present with fat malabsorption, acanthocytosis, and reduced serum cholesterol as well as low serum vitamin E, cerebellar ataxia,

200

B.L. FOGEL

and retinitis pigmentosa (Narcisi et al., 1995; Zamel et al., 2008). In both cases, treatment with vitamin replacement (and a low-fat diet for abetalipoproteinemia) can improve the neurologic outcome and should be initiated early to achieve the best possible outcome (Zamel et al., 2008; Di Donato et al., 2010).

Class IV: adult-onset recessive ataxias Although the majority of recessive disorders may have variant presentations which appear in adulthood, a few of these are exclusively found to occur at a later age and should be considered in sporadic cases. This is a much less typical presentation for recessive ataxias, with only a few diseases where this may be common, although as we discover more information with regard to phenotypic variability it is possible this category will expand further (Fogel et al., 2014b). When evaluating adultonset cases, one should also consider variant

presentations of metabolic and mitochondrial-related diseases (discussed further below) (Fogel et al., 2014b).

DISORDERS OF SIGNAL TRANSDUCTION Mutations of ANO10 (Table 13.3), which encodes a suspected calcium-activated chloride channel (Fig. 13.2) (Schreiber et al., 2015), were recently identified in adult-onset patients with recessive ataxia associated with pyramidal signs and, in some cases, lower motor neuron involvement and dementia (Vermeer et al., 2010; Chamova et al., 2012).

DISORDERS OF ORGANELLE FUNCTION Mutations in the AMACR gene (Table 13.3), involved in peroxisomal metabolism (Fig. 13.2), have been linked to late-onset recessive ataxia associated with dementia and epilepsy (Dick et al., 2011) and to presentations mimicking Refsum disease (Ferdinandusse et al., 2000), further

Table 13.3 Adult-onset autosomal-recessive ataxias Disease

Abbreviation Locus

Gene

Year Protein

SYNE1

2007 Synaptic nuclear Cerebellar subcellular Pure cerebellar envelope protein-1 architecture

Spinocerebellar ataxia SCAR8 autosomal recessive, type 8 (OMIM 610743)

6q25

Spinocerebellar ataxia SCAR10 autosomal recessive, type 10 (OMIM 613728)

3p22.1 ANO10

AMACR ataxia (OMIM 604489)

5p13

AMACR

2010 Anoctamin 10

AMACR 2011 Alpha-methylacylCoA racemase

Function

Clinical

Signal transduction

Dementia Pyramidal signs

Peroxisomal metabolism

Dementia Epilepsy

Spinocerebellar ataxia SCAR11 autosomal recessive, type 11 (OMIM 614229)

1q32.2 SYT14

2011 Synaptotagmin 14

Membrane trafficking Intellectual disability

Autosomal recessive ARSAL spastic ataxia with leukoencephalopathy (OMIM 611390)

2q33.1 MARS2

2012 Mitochondrial methionyl-tRNA synthetase 2

Mitochondrial protein Pyramidal signs synthesis

RNF216 ataxia (OMIM 212840)

7p22.1 RNF216 2013 Ring finger protein 216

Protein quality control

Dementia Hypogonadism Digenic with OTUD4?

2q11.2 VWA3B

Apoptosis

Intellectual disability

RNF216

Spinocerebellar ataxia SCAR22 autosomal recessive, type 22 (OMIM 616948)

2016 von Willebrand factor A domain containing 3B

CoA, coenzyme A; OMIM, Online Mendelian Inheritance in Man.

AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIAS emphasizing the value of peroxisomal biomarkers in the basic laboratory evaluation of sporadic cerebellar ataxia. In an impressive example of the power of molecular genetics to identify candidate disease genes, Bayat et al. (2012) performed a screen to detect neurodegenerative phenotypes in Drosophila photoreceptors which led to the finding of disease-associated mutations in the fly mitochondrial methionyl-tRNA synthetase, involved in mitochondrial protein translation. The group subsequently leveraged these findings to diagnose the molecular basis for a human disease due to mutations in the human ortholog MARS2 (Table 13.3), characterized by adult-onset spastic ataxia with leukodystrophy and showing similar mitochondrial defects as in the flies (Fig. 13.2) (Bayat et al., 2012).

DISORDERS OF PROTEIN QUALITY CONTROL Similarly to STUB1, described above, RNF216, a ubiquitin ligase, was recently shown to be mutated in families with adult-onset ataxia, hypogonadotropic hypogonadism, and dementia (Table 13.3, Fig. 13.2). Interestingly, data from one family and from genetic models of the disease in zebrafish suggest that the phenotype may be caused or worsened by digenic mutations in OTUD4, which encodes a related deubiquitinase (Margolin et al., 2013), although this has yet to be demonstrated in additional patients.

DISORDERS OF CELLULAR METABOLISM The most common of the adult-onset recessive disorders is associated with mutations of the SYNE1 gene (Table 13.3) (Dupre et al., 2007; Gros-Louis et al., 2007; Synofzik et al., 2016), thought to be involved in maintaining the cerebellar subcellular architecture (Fig. 13.2) (Zhang et al., 2001). The classic phenotype presents as a pure cerebellar ataxia (Dupre et al., 2007; Gros-Louis et al., 2007), although recent larger studies have broadly expanded the phenotype (Synofzik et al., 2016) and other mutations in the gene are associated with Emery–Dreifuss muscular dystrophy (Zhang et al., 2007). Due to the large size of this gene, comprehensive testing was initially a challenge and only recently with next-generation sequencing (see below) has it become cost-effective for routine clinical screening (Fogel et al., 2012, 2014b; Synofzik et al., 2016). With this increased ability to test, the disease has now been seen widely outside the French-Canadian population, with additional cases reported in France, Brazil, Japan, the United States, and across Europe (Gros-Louis et al., 2007; Izumi et al., 2013; Noreau et al., 2013; Fogel et al., 2014b; Synofzik et al., 2016), consistent with this disease being a worldwide disorder of higher prevalence than previously thought (Synofzik et al., 2016).

201

Additionally, mutations in SYT14 (Table 13.3), involved in synaptic membrane trafficking (Fig. 13.2), have been observed in patients with intellectual disability and late-onset development of cerebellar ataxia (Doi et al., 2011). Mutations in VWA3B (Table 13.3), a gene potentially involved in cellular apoptosis (Fig. 13.2), cause SCAR22, also initially characterized by childhoodonset intellectual disability and late-onset cerebellar ataxia (Kawarai et al., 2016).

CLINICAL EVALUATION, DIAGNOSIS, AND ADVANCES IN GENETIC TESTING: The evaluation of a patient with a suspected recessive ataxia should be performed systematically (Fig. 13.3). One of the most important clinical points that can be made concerning the ataxic patient is that genetic conditions should never be the initial focus unless there is treatment for the disorder under consideration and delay could affect outcome. Prior to the initiation of any genetic tests, acquired causes must be ruled out as these are, in many cases, treatable or modifiable and early identification is critical to minimize resulting cerebellar damage (Fogel and Perlman, 2007, 2011; Fogel, 2012; Shakkottai and Fogel, 2013). For the recessive ataxias, the one caveat is that some of these disorders (e.g., abetalipoproteinemia, ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum disease) have disease-specific treatments and if these are suspected they should be evaluated immediately so that prompt treatment can be initiated. The use of biomarker testing can be particularly useful in this regard and should be considered as clinically appropriate (Fig. 13.3). The etiologies of acquired causes of cerebellar ataxia are many, and delays in identification can have considerable impact on patient outcome (Fogel et al., 2009; Fogel, 2012) and therefore must be avoided. Although beyond the scope of the current discussion, detailed algorithms and workflows exist for diagnosing acquired causes of cerebellar ataxia (Fogel and Perlman, 2006, 2011; Klockgether, 2010; Shakkottai and Fogel, 2013) and these, or similar, strategies should be carefully utilized prior to considering genetic etiologies and related diagnostic testing. For early-onset symptoms, special consideration must be given for acquired causes of ataxic disorders of childhood (Fogel, 2012). With regard to genetic testing, all patients with suspected recessive ataxia should be screened for the Friedreich repeat expansion due to the high carrier frequency and incidence of disease as well as the broad variability of phenotypes associated with it (Fig. 13.3) (Collins, 2013). If a heterozygous expansion is detected, FXN gene sequencing can be considered but missense mutations are otherwise too rare a consideration for initial diagnostic testing. Beyond that, individual gene testing can be

202

B.L. FOGEL Clinical Evaluation Detailed History of Symptoms Comprehensive Neurological Examination Complete Family History MRI of the Brain

Most common etiologies Diagnostic Evaluation Screen for Acquired Causes of Ataxia (if < 20 years emphasis on childhood causes)

Biomarker

Change

Disease

Acanthocyes

Present

ABL

Albumin

↓

AOA1 SCAN1

α-fetoprotein

↑

AOA2 AT

Cholestanol

↑

CTX

Cholesterol

↑

AOA1 AOA2 SCAN1

Coenzyme Q10 (muscle)

↓

AOA1 SCAR9

Hexosaminidase A

↓

LOTS

Immunoglobulins

↓

AT ATLD

Lactate

↑

SCAR9

Radiosensitivity Sex hormones and gonadotropins Very long chain fatty acids (peroxisomal biomarkers) Vitamin E

Present

Genetic etiologies

Basic Diagnostic: Initial Genetic Screening FRDA Genetic Testing (repeat expansion only) Other Single Gene Testing*(based on phenotype)

If negative

AT ATLD

↓

PNPLA6 RNF216 SCAR16

↑ (others variable)

AMACR PEX RD

Advanced Diagnostic: Clinical Exome Sequencing

ABL AVED

Rare Genes: Estimated <1% of Genetic Ataxia

↓

(strongly consider simultaneous evaluation of parents)

Fig. 13.3. Diagnostic evaluation of the autosomal-recessive ataxias. Diagnostic flowchart for the evaluation of a patient with suspected autosomal-recessive ataxia is shown. Disease abbreviations correspond to those used in Tables 13.1–13.3. * if indicated based on strong phenotypic and/or laboratory/biomarker indications; FRDA, Friedreich ataxia; MRI, magnetic resonance imaging.

considered for patients whose phenotype appears diagnostic based on key phenotypic features (Fig. 13.3). With the extensive availability of tests for individual genes associated with ataxia (Fogel and Geschwind, 2015), there has been a trend toward shotgun approaches to genetic testing, typically involving panels of multiple rare genes (Fogel et al., 2013). Unfortunately, because the majority of these genes cause less than 1% of all recessive genetic ataxias worldwide, the yield of positive results is often poor and extremely costly to the patient (Fogel et al., 2012, 2013). More recently, nextgeneration sequencing (Fogel and Geschwind, 2015; Fogel et al., 2016a, b) has made it possible to evaluate genetic disease on a genomewide scale at a significantly reduced cost (Coppola and Geschwind, 2012; Fogel

et al., 2014b, 2016a, b; Lee et al., 2014; Fogel and Geschwind, 2015). Next-generation sequencing can be used to create targeted gene panels that are much more extensive and cheaper than those currently in use (roughly 1/100th the cost per gene for hundreds of genes versus traditional Sanger sequencing methods) (Nemeth et al., 2013). Furthermore, for only a minimal increase in cost, the entire coding portion of the genome, termed the exome, can be clinically sequenced (approximately $5000 for 20,000 genes as of 2017) and evaluated in an unbiased manner for any potential mutations in genes associated with disease (Coppola and Geschwind, 2012; Chen et al., 2013; Fogel et al., 2014b, 2016a, b; Lee et al., 2014; Fogel and Geschwind, 2015). Although targeted next-generation panels have seen success clinically

AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIAS (Nemeth et al., 2013), it appears that great diagnostic utility can likely be gained through the use of exome sequencing, particularly in heterogeneous diseases such as ataxia (Sailer et al., 2012; Fogel et al., 2014b, 2016a, b; Gomez and Das, 2014). In the ataxias, exome sequencing has already been shown to be valuable diagnostically in multiple studies, including patients with childhood-onset ataxia (diagnosis rate 46%, 13/28 families) (Sawyer et al., 2014), childhood-onset ataxia with cerebellar atrophy (diagnosis rate 39%, 9/23 families) (Ohba et al., 2013), earlyonset ataxia (before age 20 years) (diagnosis rate 48%, 10/21 families) (Fogel et al., 2014b) and even adult-onset disease (diagnosis rate 11%, 6/55 families) (Fogel et al., 2014b). Exome sequencing may be particularly useful in familial cases (diagnosis rate 25%, 5/20 families) (Fogel et al., 2014b) and/or those childhood-onset cases with consanguineous parentage (diagnosis rate 69%, 9/13 families) (Sawyer et al., 2014) but is also extremely valuable for sporadic cases (diagnosis rate 20%, 11/56 families) (Fogel et al., 2014b). The largest study which examined a cohort of 76 patients comprised of familial, sporadic, adult, and early-onset cases found the highest yield for autosomal-recessive disorders (88%, 14/16 positive cases) (Fogel et al., 2014b). Additional recent studies have supported these general findings across familial and sporadic forms of adult or childhood-onset disease (Keogh et al., 2015; Pyle et al., 2015; Marelli et al., 2016; van de Warrenburg et al., 2016). When using exome sequencing to evaluate potential recessive disease, trio sequencing can be particularly informative by helping to address variant segregation and identify de novo mutation (Fig. 13.3) (Lee et al., 2014; Fogel et al., 2016a). Most importantly, by providing an unbiased genomic approach to genetic diagnosis, exome sequencing allows for the detection of disease presenting with variant phenotypes, including diseases that do not typically present as primary ataxic disorders, such as various leukodystrophies, hereditary spastic paraplegias, and metabolic or mitochondrial conditions (Fogel et al., 2014b, 2016a, b). Due to this high diagnostic yield, clinical exome sequencing would therefore be recommended for all ataxia patients with a negative evaluation for acquired causes and, in the case of suspected recessive disease, a negative test for Friedreich ataxia, regardless of age of onset or the presence of a family history (Fogel et al., 2014b, 2016b).

FUTURE DIRECTIONS The emergence of next-generation sequencing in the hunt for ataxia genes has had a major impact on the recessive ataxias in recent years. Targeted next-generation

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sequencing has led to the identification of several new recessive ataxia genes, including ANO10 (Vermeer et al., 2010), WDR81 (Gulsuner et al., 2011), SPTBN2 (Lise et al., 2012), and ATP8A2 (Onat et al., 2013). Exome sequencing has had an even greater impact, identifying numerous new recessive ataxias, including those caused by mutation of SYT14 (Doi et al., 2011), GRM1 (Guergueltcheva et al., 2012), GBA2 (Hammer et al., 2013), TPP1 (Sun et al., 2013), RNF216 (Margolin et al., 2013), STUB1 (Shi et al., 2013, 2014), WWOX (Mallaret et al., 2014), PNPLA6 (Synofzik et al., 2014a), SLC9A1 (Guissart et al., 2015), CWF19L1 (Burns et al., 2014), SNX14 (Thomas et al., 2014), PNKP (Bras et al., 2015), SCYL1 (Schmidt et al., 2015), TDP2 (Gomez-Herreros et al., 2014), UBA5 (Duan et al., 2016), VWA3B (Kawarai et al., 2016), and XRCC1 (Hoch et al., 2017). Given that up to half of the causative genes of cerebellar ataxia may be unknown (Fogel and Perlman, 2007, 2011), these methods likely will uncover additional ataxia genes as well as expand the landscape of mutations in known genes (Nemeth et al., 2013; Fogel et al., 2014b). Most importantly, the phenotypic variability among these disorders will become more evident. Already, recently identified genes and mutations in patients and families with recessive ataxia have merged phenotypes with previously recognized forms of hereditary spastic paraplegia (Hammer et al., 2013; Fogel et al., 2014b; Synofzik et al., 2014a), neuronal ceroid lipofuscinosis (Sun et al., 2013), and disorders of peroxisomal biogenesis (Ebberink et al., 2010; Regal et al., 2010; Sevin et al., 2011), as well as various leukodystrophies and other metabolic and mitochondrial conditions (Fogel et al., 2014b). This trend will continue as genomic methods are applied to more patients and families. As their use becomes more widespread we can expect to vastly improve the diagnosis rate and time to diagnosis for many patients, which currently can be quite extensive and delayed (Fogel et al., 2016b). Coupled with this are the continued advances in our basic understanding of the molecular pathogenesis of disease through the study of animal and cellular models and the application of new technologies to the study of patients. Although the most immediate advance in routine clinical practice will be improved diagnosis, many recent promising studies suggest that soon we may see the introduction of pathogenesis- or gene-based disease-specific treatments or disease-modifying therapies, particularly for Friedreich ataxia, a milestone previously thought unattainable but now seemingly in reach.

ACKNOWLEDGMENT This work was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094).

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