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proposed a classication of inherited ataxias based on clinical data and genetic information obtained from the family history and genealogical pedigree. This author distinguished congenital disorders associated with non-progressive ataxia, ataxic disorders with known metabolic cause or defective DNA repair, and ataxic disorders of unknown etiology, most of them following a progressive evolution rate. The latter group included early-onset cerebellar ataxias that usually begin before the age of 25years (most of them with autosomal recessive inheritance, and currently referred to autosomal recessive cerebellar ataxias or ARCAs; some patients may express symptoms after the age of 25 but usually before

40) and late-onset cerebellar ataxias (onset usually after 25 years), which includes autosomal-dominant cerebellar ataxias (ADCAs), periodic autosomal-dominant ataxias (episodic ataxias, EA), and idiopathic late-onset cerebellar ataxias (ILOCA). In addition, hereditary ataxias also include the group of mitochondrial diseases expressing ataxic symptoms and the rare X-linked disorders. This classication has been modied by gene discovery and the use of molecular genetic diagnosis in clinical practice (Perlman 2022; Manto et al.

2020; Witek et al. 2021). Since the discovery of the rst

ataxia- associated genes SCA1 (spinocerebellar ataxia type 1) and FXN (Friedreich ataxia) in the 1990s, the genetic denition of an ataxia has moved from the inheritance pattern criterion towards the gene characterization and single-gene and genomic testing of the causative gene mutation. However, clinical criteria remain relevant to orient the diagnosis of patient with ataxia. An overview of phenotypes and genetics of cerebellar ataxias can be seen at the Washington University Neuromuscular Disease Center website (http://neuromuscu-

lar.wustl.edu/ataxia/aindex.html) and GeneReviews website

(Perlman 2022).

Electrophysiological studies, neuro-otology tests, neuroophthalmology tests, neuroimaging (e.g., magnetic resonance imaging—MRI), and cardiac studies are relevant on diagnosis to dene the altered neural structures and heart involvement. Biochemical and metabolic biomarkers and, more recently, genetic testing of phenotype-oriented genes or the search for gene mutations by next generation sequencing (e.g., exome or genome sequencing, but also a panel of ataxic genes) may be necessary to conrm clinical diagnosis, to perform a proper differential diagnosis and to provide genetic counseling to patients and families.

From a didactic and practical point of view, in this chapter, we approach the diagnosis of cerebellar ataxias based on the clinical phenotype (including age of onset), and genetic criteria of Harding (1983, 1993). First, we discuss ataxia disorders from a genetic perspective, taking into account both the inheritance pattern and the causative genetic genes, and the pathogenic mechanisms of the disease, considering the biological pathways in which the disease genes are involved. In a second approach, we discuss the classication of ataxia

disorders based on clinical criteria that include the age of onset and progression of the disease. We are distinguishing between hereditary ataxias and symptomatic or acquired ataxia (Anheim etal. 2012; Dürr 2010; Mancuso etal. 2014; Palau and Espinós 2006).

79.2 Inheritance andGenetics

The hereditary ataxias are caused by mutations mainly in the nuclear genome (nDNA) but also in the mitochondrial genome (mtDNA); therefore, depending on the involved genes and pathogenic variants, the disease can be inherited in an autosomal recessive, autosomal-dominant, X-linked or mitochondrial (maternal) manner (Witek etal. 2021). In the last years, genomic studies have allowed the increase of gene discovery in hereditary ataxias, so updating is a difcult task. In the GeneReviews overview on hereditary ataxias based on the type of inheritance, Perlman (2022, https://www.ncbi.

nlm.nih.gov/books/NBK1138/) summarizes the molecular

genetics characteristics, and clinical and phenotype features of the different ataxias. The ve categories are (1) autosomal recessive cerebellar ataxias (ARCA), which include 57 genes/loci, most notably because prevalence Friedreich’s ataxia, ataxia- telangiectasia, ataxias with oculomotor apraxia by AOA1 and AOA2, Niemann-Pick type C (NPC1), spastic ataxia Charlevoix-Saguenay type (SACS or SPAX6), and SYNE1- related cerebellar ataxia; (2) autosomal-dominant cerebellar ataxias (ADCA), which include spinocerebellar (SCA) conditions from SCA1 to SCA48, dentaterubral-pallidoluysian atrophy (DRPLA), and other conditions such as GRID2- related spinocerebellar ataxia; (3) episodic-dominant ataxias (EA), including nine forms associated with genes/ loci EA-1 to EA-9, episodic ataxia with neonatal epilepsy, and CAPOS syndrome due to mutations in ATP1A3; (4) cerebellar ataxias linked to the X chromosome, with 7 clinical entities; among them, there is the adult form of the fragile X chromosome- associated ataxia/tremor syndrome (FXTAS) that affects both men and women who carry a repeated expansion of 50–200 CGG in the FMR-1 gene (Jacquemont etal. 2003) (this is the gene that causes fragile X syndrome in patients with a complete expansion greater than 200 CGG repeats; (5) spastic ataxias, six forms of ataxias in which patients also have spasticity along with cerebellar symptoms; interestingly SPG7, which encodes the mitochondrial metalloprotease paraplegin, may be expressed with spasticity, ataxia, or a combination of both, (Coarelli etal. 2019). In addition, it is worth noting the progressive ataxias that are sometimes associated with mutations in mitochondrial DNA (mtDNA), such as the MERRF, Kearns-Sayre syndromes, and NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa). It should also be noted that there are many genes that regulate mitochondrial function of which pathogenic

79 Genetics andDierential Diagnosis ofCerebellar Ataxias

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mutation can lead to autosomal recessive forms of ataxia. This is the case of POLG-related ataxia neuropathy spectrum (Schulte etal. 2009).

The Online Mendelian Inheritance in Man (OMIM, www.

omim.org) catalog of phenotypes and genes offers another

way to identify the hereditary ataxias. The OMIM contains phenotypic entries for most of the large groups of inherited ataxias. There is an entry for the following clinical-genetic series: (1) progressive ADCA under the name of spinocerebellar ataxias (SCA), which is how the different gene loci of 45 clinical-genetic forms are called (https://www.omim.org/

phenotypicSeries/PS164400); (2) episodic ataxias, with

autosomal-dominant inheritance, which include the nine EA nosology categories (https://www.omim.org/phenotypic-

Series/PS160120); (3) ARCA is recognized as spinocerebel-

lar ataxias with recessive inheritance and includes 29 entries series (https://www.omim.org/phenotypicSeries/PS213200); however, the most frequent forms such as Friedreich ataxia, ataxia-telangiectasia or ataxia with oculomotor apraxia 1 are not included in the phenotypic series; (4) spastic ataxia, with different Mendelian segregations (https://www.omim.org/

phenotypicSeries/PS108600); and (5) there are also specic

entries for some forms of congenital ataxias such as cerebellar ataxias with intellectual disabilities: Cerebellar ataxia, mental retardation, and dysequilibrium, which have four entries (http://omim.org/phenotypicSeries/PS224050) or Joubert syndrome with agenesis or hypoplasia of the cerebellar vermis with 38 entries (https://www.omim.org/phenotyp-

icSeries/PS213300). This is not the case, however, for the

X-linked ataxias.

As with most of the genetic disorders, many ataxias are caused by point mutations of the DNA sequence in the proper gene. Such mutations may insert a new nucleotide or delete a nucleotide in the sequence (indels variants) or substituting one nucleotide for another. Depending on the localization within the gene, the point mutations may replace one amino acid in the protein with another (missense mutation), introduce a premature stop codon (nonsense mutation), alter the triplet or codon reading (frameshift), affect splicing between exon and intron by altering an existing splice site, affect splicing by activating a cryptic splice site, or involve the promoter or another cis-acting regulatory sequence. However, there is a peculiar type of mutation that affects many inherited ataxias, dynamic expansion mutations of a single- tandem

repeat (Depienne and Mandel 2021), often a trinucleotide (Orr and Zoghbi 2007). This is the case for spinocerebellar ataxias (ADCA) due to the expansion of a CAG triplet repeat within an exon of several genes, the GAA trinucleotide repeat within the rst intron in the FXN gene in Friederich’s ataxia, the AAGGG pentanucleotide repeat expansion in RFC1-related disorders (see Cortese etal. 2020), or the CGG trinucleotide in the 5’-UTR region of the FMR-1 gene, associated with FXTAS.This type of mutation largely explains the genetic anticipation phenomenon observed in dominant ataxias, either autosomal or X-linked, when the expansion exceeds a certain threshold of repetitions, which is gene and disease specic. In the case of the FMR-1 gene, genetic anticipation is observed in families segregating with the fragile X chromosome syndrome, which is expressed as intellectual disability. A schematic of the genes associated with neurodegenerative disorders, including cerebellar ataxias and the respective dynamic microsatellite expansions, is shown in Fig.79.1.

Gene discovery of ataxia disorders is very useful for diagnosis and genetic counseling. It is also relevant to classify disorders based on biological proles along with clinical features. Additionally, understanding the genetic basis of hereditary ataxias allows to dene specic pathways involved in the cellular pathophysiology of ataxias and searching for molecular druggable targets and new pharmacological or biological therapies. For instance, in the case of autosomal recessive cerebellar ataxias, gene and function discoveries indicate four major clusters of shared molecular themes that may become important for translational approaches (Synofzik and Németh 2018; Synofzik etal. 2019; Vermeer etal. 2011). They are (1) mitochondrial homeostasis that are altered in diseases caused by mutations in nuclear genes encoding mitochondrial proteins (e.g., FXN in Friedreich’s ataxia, POLG-related ataxia disorders, COQ8A in cerebellar ataxias associated with CoQ deciency, SPG7-related disorders such as spastic paraparesis and spastic ataxia); (2) DNA damage repair (e.g., ATM in ataxia-telangiectasia, APTX in AOA1, SETX in AOA2); (3) metabolic disorders such as those involving complex lipid metabolism (e.g., CYP27A1 in cerebrotendinous xanthomatosis, GBA1 in Gaucher disease, PHYH and PEX7 in Refsum disease, NPC1 in Niemann-Pick type C1); and (4) cilial disorders, with special mention to Joubert syndrome (JBS) and related disorders.

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EPM1

(CCCCGC

CCCGCG)

C9 ALS/FTD

(GGGGCC)n

start

HDL2

(CTG)n

codon

5’ 3’

(CGG)n

FMR1:

(CAG)n

SCA12

• FXS

• FXTAS

AFF2

intron

(GAA)n

FRDA

(CCTG)n

DM2

(GGCCTG)n

SCA36

(AAGGG)n

CANVAS/

RFC1

OPMD

(GCG)

(polyalanines)

(CAG)n

HD SCA1 SCA2 SCA3/MJD SCA6 SCA7 SCA17 DRPLA

(polyglutamines)

intron exon 3’UTR 5’UTR

(CTG)n

FECD

stop

codon

(ATTCT)n

SCA10

(TGGAA)n

SCA31

(CTG)

DM1

SCA8

Fig. 79.1 Dynamic mutations by expansion of microsatellite sequences. ALS/FTD amyotrophic lateral sclerosis/fronto-temporal dementia; CANVAS cerebellar ataxia, neuropathy, and vestibular areexia syndrome (RFC1 gene); DM1 myotonic dystrophy type 1; DM2 myotonic dystrophy type 2; DRPLA dentatorubral-pallidoluysian atrophy; EPM1 progressive myoclonic epilepsy 1A; FECD Fuchs corneal endothelial dystrophy; FMR-1 gene on chromosome Xq28 (CGG

79.3 Clinical Phenotypes andAge at Onset

Based on the age at onset, we recognize four major categories: very early onset in infancy and young children (under 2years), childhood to early adulthood, and late onset after the age of 25years. There is not a perfect division among each age category, but it is realistic to take into account several considerations: (1) congenital ataxias are generally non- progressive and are an unusual group of neurological disorders (delayed motor development, very early-onset cerebellar ataxia, hypotonia, and cognitive impairment), with a heterogeneous clinical and genetic presentation, often misdiagnosed as cerebral palsy (Raslan etal. 2021); (2) most of very early-onset ataxias in children under 2years used to be a developmental defect that segregate as an auto-

expansion associated with fragile X syndrome (FXS) and fragile X tremor/ataxia syndrome FXTAS); AFF2 (FMR2) gene: intellectual developmental disorder X-linked 109 on chromosome Xq28 (fragile X syndrome type FRAXE); FRDA Friedreich ataxia; MJD Joseph disease; SCA spinocerebellar ataxia; HD Huntington disease; HDL2 Huntington disease-like 2; OPMD oculopharyngeal muscular dystrophy

Machado-

somal recessive trait; (3) chronic early-onset ataxias in childhood, adolescence and young adults under 25 years (rarely after 40years) may be acquired or hereditary with autosomal recessive, maternal inheritance or rarely X-linked inheritance, and include progressive degenerative ataxias, inherited metabolic diseases, and mitochondrial disorders; (4) late-onset ataxias after the age of 25years may be hereditary, usually segregating as an autosomal-dominant trait (less frequently as autosomal recessive and X-linked traits), symptomatic as the consequence of different primary acquired causes, or idiopathic. Among these idiopathic lateonset cerebellar ataxias, the cerebellar type (OPCA variant) of multiple system atrophy (MSA) is an important diagnosis (Klockgether 2010). A working diagram for differential diagnosis is proposed in Fig.79.2.

79 Genetics andDierential Diagnosis ofCerebellar Ataxias

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Diagnosis Features of Cerebellar Ataxia

525

Age at Onset vs. Inheritance matrix

[with some examples of disease]

Extension and Evolution

Age at Disease Onset

Infancy

(<2 yr)

SCAR18 Rare Arts syndrome LS UC defects CS

Early-onset

(EO<25 yr)

FRDA EO_SCAs SCAX4 MELAS, MERFF AVED, CTX AT

Late-onset (LO>25 yr)

LO_FRDA SCAs, EAs FXTAS MELAS (<40yr), KSS Rare Rare

Cerebellar localization

•focal

• non focal. diffuse

Progression rate

(nonprogressive)

Hereditary:

•AR

•AD

•X-linked

•mitochondrial

•metabolic

•DNA repair

Congenital

JBS Gillespie XLAS/A Not DCMA Not

•acute, rapid

Non genetic:

•symptomatic

Mode of Inheritance

•idiopathic

Viral cerebellar

encephalitis

Rare

Paraneoplastic cerebellar

degeneration

Cerebellar MSA

•chronic, slowly progressive

•chronic, stationary

clinical/neurological examination – electrophysiology – neuroimaging – biochemistry – genetic testing

Fig. 79.2 Diagram of clinical diagnostic criteria in cerebellar ataxias. The drawing is designed in an attempt to integrate age at onset with other clinical criteria in a working process. As wide overlapping exists in cerebellar ataxias, the authors are aware that reality is more complex. AD autosomal dominant; AR autosomal recessive; AT ataxia telangiectasia; AVED isolated ataxia with vitamin E deciency; DCMA dilated cardiomyopathy with ataxia (3-methylglutaconic aciduria, 3-MGC);

EO early onset; LO late onset; CTX cerebrotendinous xanthomatosis; CS Cockayne syndrome; EAs episodic ataxias; FRDA Friedreich ataxia;

FXTAS fragile X with tremor/ataxia syndrome; JBS Joubert syndrome; KSS Kearn-Sayre syndrome; LS Leigh syndrome; MELAS mitochon-

drial encephalopathy, lactic acidosis, and stroke-like episodes; MERFF myotonic epilepsy with ragged-red bers; SCAs spinocerebellar ataxias; SCAR18 spinocerebellar ataxia, autosomal recessive 18; SCAX4 spinocerebellar ataxia, x-linked 4; UC defects urea cycle disorders; XLAS/A X-linked ataxia syndrome with anemia. Mitochondrial inheritance refers to disorders involving mitochondrial DNA genes that affect oxidative phosphorylation

79.4 Congenital Ataxias

Congenital ataxias present with hypotonia, delay of motor milestones and non-progressive cerebellar ataxia associated with cerebellar malformation or cerebellar hypoplasia or pontocerebellar hypoplasia. There are a large number of clinical pictures and syndromes (Perlman 2022; Mancuso etal.

2014; Raslan etal. 2021). Most of them are autosomal reces-

sive but a few are autosomal dominant or X-linked. Joubert syndrome is a clinically and genetically heterogeneous group of disorders (more than 38 genes) involving primary cilia, characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic ‘molar tooth sign,’ and accompanying neurologic symptoms: ataxia, intellectual disability, oculomotor apraxia, dysregulation of breathing pattern, and developmental delay. Among other rare disorders with cere-

bellar hypoplasia, it can be mentioned Gillespie syndrome characterized by iris hypoplasia and cognitive impairment. Specic structural pattern of cerebellar malformation can be observed in cases of rhombencephalosynapsis, macrocerebellum, pontine tegmental cap dysplasia, and cerebellar dysplasia. Within the heterogeneous group of cerebellar malformations, the Dandy Walker malformation stands out, dened by an upward-rotating hypoplastic vermis, an enlarged fourth ventricle, and an enlarged posterior fossa. Most patients with Dandy Walker syndrome are sporadic, although some mutations have also been described. Pontocerebellar hypoplasia (PCH) is a heterogeneous group of congenital ataxias characterized by cerebellar and brainstem hypoplasia, recognizing 13 genetic types. Its natural history is variable and can have a progressive or nonprogressive course. Patients may show varying degrees of

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dysmorphic features, microcephaly, optic atrophy, spasticity, epilepsy, and movement disorders. Typical MRI ndings include cerebellar and pons hypoplasia, frequently associated with the ‘dragony’ sign.

79.5 Cerebellar Ataxias inInfancy andYoung Children (<2years)

Most of these are autosomal recessive, but a few are X-linked. Autosomal recessive ataxias include ataxia with epilepsy and intellectual disability, carbohydrate-decient glycoprotein syndrome type 1c, opsoclonus-myoclonus-ataxia, ataxiaoculomotor apraxia plus cerebellar atrophy (SCAR18), cerebro- renal syndrome (Birk-Landau-Perez syndrome), Cayman ataxia, ataxia deafness (Lichtenstein-Knorr syndrome, SCAR19), Salla disease, or the X-linked disorders associated with ataxia such as connatal PelizaeusMerzbacher, Arts syndrome, mental retardationmicrocephaly- epilepsy-ataxia (Angelman-like syndrome), spinocerebellar ataxia and sideroblastic anemia, and Rett syndrome. Metabolic ataxias in infancy include Hartnup disorder, argininosuccinic acidemia, citrullinemia, and biotinidase deciency (Fogel and Perlman 2007).

79.6 Cerebellar Ataxias inChildhood, Adolescence, andYoung Adulthood

In childhood and young patients, viral cerebellar encephalitis is the most frequent cause of acute ataxia. By contrast, progressive ataxia suggests an inherited ataxia likely with autosomal recessive inheritance, which may be suspected when the disease affects two or more affected sibs or there is consanguinity (pseudodominant pattern also suggest recessive inheritance) in the genealogical information provided by parents or relatives. Friedreich ataxia (FRDA) is the most frequent autosomal recessive cerebellar ataxia in Caucasians. FRDA is a sensory and cerebellar ataxia with characteristic clinical phenotype expressing both peripheral sensory neuropathy and spinocerebellar syndrome with signs of posterior columns dysfunction and dentate nucleus neuropathology, dysarthria, heart disease, diabetes mellitus or glucose intolerance, and skeletal deformities. Genetic testing of FXN gene provides denite diagnosis by demonstration of homozygosity of two GAA expanded alleles (98% of patients) (Dürr etal. 1997), compound heterozygosity of one expanded allele and one point mutation (2% of patients) (De Castro etal. 2000) or, the recently described patient carrying two bialleic missense point mutations (Candayan et al. 2020). Based on prevalence, other ARCAs to be considered are ataxia with ocular apraxia (AOA types 1, 2, 3 and 4), isolated

vitamin E deciency (AVED), abetalipoproteinemia (ABL), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), POLG-related ataxias (include mitochondrial recessive ataxia syndrome—MIRAS, and sensory ataxic neuropathy, dysarthria and ophthalmoparesis—SANDO), cerebrotendinous xanthomatosis (CTX), autosomal recessive cerebellar ataxia 2 (ARCA2 or SCAR9), MarinescoSjögren syndrome (MSS), cerebellar ataxia with coenzyme Q (CoQ) deciency (Anheim etal. 2012; Fogel and Perlman

2007; Palau and Espinós 2006; Vermeer etal. 2011; Synofzik

and Németh 2018; Gana and Valente 2020), and Peripheral neuropathy—Hearing loss—Ataxia with cerebellar atrophy—Retinitis pigmentosa—Cataract (PHARC) (Fiskerstrand etal. 2009). Both vitamin E and CoQ deciencies could be the consequence of gene mutations or secondary to acquired disorders such as disorders associated with malabsorption syndrome in case of vitamin E deciency.

Among ataxias caused by defects in DNA repair are ataxia-telangiectasia (AT)—the second most frequent ARCA type–, ataxia-telangiectasia-like disorder 1, Cockayne syndrome (CS), xeroderma pigmentosum (XP), and spinocerebellar ataxia with axonal neuropathy (SCAN1). Cockayne syndrome and xeroderma pigmentosum show locus genetic heterogeneity and may be diagnosed during infancy. AOA1 and AOA2 pathogenesis also involve DNA repair defects. AOA1 is the most ARCA form in Japan and Portugal.

Inherited metabolic diseases with enzymatic biochemical defects may also present with intermittent or progressive ataxia. In some disorders, ataxia is a frequent sign but in others it is not relevant in the clinical picture. Most are autosomal recessive traits but X-linked inheritance may occur as well. Metabolic ataxias usually begin in infancy or childhood. Metabolic ataxias in the childhood period (2–12years) include carnitine acetyltransferase deciency, X-linked ornithine transcarbamilase deciency and other defects of the urea cycle, Niemann-Pick type C disease, infantile Refsum disease, and ataxia with selective vitamin E deciency (AVED) caused by mutations in the TTPA gene. Clinical metabolic entities in adolescence and adulthood are abetalipoproteinemia, hypobetalipoproteinemia, α-methylacyl- CoA racemase deciency, cerebrotendinous xanthomatosis, gamma-glutamyl cysteine synthetase deciency, adolescent or young adult Refsum disease, and Wilson disease.

Mitochondrial oxidative phosphorylation (OXPHOS) provides energy to most of the organs and tissues. Ataxia is one of the major neurological symptoms of OXPHOS defects due to mutations in the mitochondrial DNA, which become symptomatic in childhood or young adulthood. Examples manifesting with ataxia include MELAS syndrome (mitochondrial myopathy, encephalopathy, lactacidosis, stroke syndrome), MERRF (myoclonic epilepsy with ragged-red

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bers), NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), and KSS (Kearns-Sayre syndrome) (Fogel and Perlman 2007).

The Childhood Ataxia and Cerebellar Group of the

European Paediatric Neurology Society (Brandsma et al.

2019) provides a diagnostic algorithm for patients with

early-onset cerebellar ataxia. Along with clinical suspicion and genetic testing for FRDA, imaging and laboratory criteria for differential diagnosis include brain MRI, blood analysis, and biochemical and metabolic biomarkers (e.g., plasma vitamin E, alpha-fetoprotein), and genome testing by NGS technologies.

79.7 Late-Onset Cerebellar Ataxias

A primary cause may be found in cerebellar ataxia with onset after the age of 25years. The etiology may be genetic or symptomatic because a gene mutation or an acquired disorder that is expressed with ataxia. However, the cause is not evident in several sporadic patients, for which idiopathic late-onset cerebellar ataxia is the working diagnosis.

While symptomatic ataxia may appear in infancy and childhood (cerebellar tumors, metabolic deciencies and immunological disease—e.g., opsoclonus/myoclonus syndrome), they are more frequent in adult individuals. Symptomatic ataxias in adulthood may be caused by vascular disease, hypoxia, mass lesion (neoplasm, abscess, sarcoid nodules), cervico-occipital hinge anomalies, hypothyroidism, hypoparathyroidism, vitamin deciency (B1, B12, E), immune disease (acute cerebellar ataxia, paraneoplastic cerebellar degeneration, celiac disease, anti-GAD ataxia, multiple sclerosis, Bickerstaff encephalitis, Miller-Fisher syndrome), infections (acute cerebellar encephalitis, meningitis, HIV, Whipple’s disease, Creutzfeldt-Jakob disease), drugs (e.g., ethanol, phenytoin, 5-uorouracil), metals (lead, mercury, manganese, bismuth), toxics (toluene, methyl bromide, triorthocresyl phosphate), toxins (buckthorn fruit), paroxysmal causes (epilepsy, migraine, fever, heat stroke), and other systemic disorders (amyloid).

Most of the late-onset ataxias segregate as autosomaldominant cerebellar ataxias (ADCAs) (Dürr 2010). Two major groups are recognized: spinocerebellar ataxias (SCAs) with 45 dened genes/loci, and nine episodic ataxias (EAs) plus CAPOS syndrome. The CAG trinucleotide expansion is the major mutation in the most common forms of spinocerebellar ataxia, i.e., SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and DRPLA (dentatorubral-pallidoluysian atrophy). Other nucleotide expansions are observed in SCA8 (CTG), SCA10 (ATTCT), SCA31 (TGGAA), SCA36 (intronic GGCCTG) (Fig.79.1), and SCA37 (pentanucleotide ATTTC repeat insertion in non-coding region) (Seixas etal. 2017). The phenotypic classication by Harding (1993)

that categorized three clinical groups of ADCAs may be useful to perform an accurate genetic testing. ADCA type I refers to ataxia plus impairment of other neuronal systems, ADCA type II is ataxia plus retinal degeneration, and ADCA type III is described as pure cerebellar ataxias. For ADCA type I, the rst genes to be tested are SCA1, SCA2, and SCA3. ADCA type II is exclusively associated with SCA7 mutations. Finally, for ADCA type III, SCA6 and SCA12 should be the rst genes to be analyzed. The most frequent types of episodic ataxias are due to mutations in ion channels: EA-1 manifests without vertigo and is associated with interictal myokymia, and EA-2 manifests with vertigo and is associated with interictal nystagmus, and in these patients, acetazolamide often dramatically stops the spells.

The eld of autosomal-dominant ataxias is recently expanded to other phenotypes. One example is the STUB1related disorders, which include the autosomal-dominant spinocerebellar ataxia SCA48in which patients suffer from signicant cognitive impairment expressed as cerebellar cognitive-affective syndrome (CCAS) in addition to ataxia (Genis etal. 2018). CCAS patients have difculties with executive function, affect regulation, linguistic processing, and spatial cognition (Hoche et al. 2018). Interestingly, STUB1-related ataxias are relatively frequent (7%) among dominantly inherited cerebellar ataxias (Roux etal. 2020) and was originally described as autosomal recessive cerebellar ataxia SCAR16 (Shi et al. 2013; Synofzik et al.

2014).

Non-autosomal-dominant inherited ataxias may present in individuals older than 25 years. Among them are also ataxia-laryngeal abductor paralysis-motor neuropathy and cerebelloparenchymal disorder II (CPD II) and V (CPD V). The fragile X tremor/ataxia syndrome (FXTAS) is a frequent ataxic syndrome in adults and elderly people and is due to short but abnormal CGG expansions in the FMR-1 gene classically associated with fragile X intellectual disability syndrome. Rarely, mitochondrial (e.g., cerebellar ataxia, deafness, and narcolepsy syndrome) and metabolic ataxias (e.g., hypobetalipoproteinemia, gamma-glutamyl cysteine synthetase deciency) may become symptomatic in individuals older than 25years. In this way, it is very important to recognize that FRDA may express rst symptoms in adult individuals older than 40years. A recently recognized recessive disorder in adults is the RFC1-related disorder caused by bialleic AAGGG pentanucleotide expansion on chromosome 4p14 (Cortese et al. 2019). The disease spectrum encompasses from typical cerebellar ataxia of the extremities and gait, non-length-dependent sensory neuronopathy, vestibular areexia syndrome (CANVAS) (Szmulewicz etal.

2011; Cortese et al. 2020b) to more limited phenotypes

involving predominantly or exclusively one of the systems involved in balance control, autonomic dysfunction or cough (Cortese etal. 2020a).

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Overview ofAtaxia inChildhood

https://t.me/medicina_free

EugenBoltshauser

Abstract

In children, a wide number of hereditary or acquired diseases may cause ataxia. The prevalence varies signicantly in causes between pediatric and adult ataxia. Pediatric ataxia may be classied as acute, progressive, non-progressive, intermittent, and episodic. Cerebellar dysfunction is the leading cause of pediatric ataxia, while sensory and vestibular ataxias are less common in children. In congenital ataxias, developmental delays and cognitive impairment are often clinically dominating. A careful clinical history and neurological examination are essential in classifying pediatric ataxia based on the course of symptoms and involved systems and narrowing the differential diagnosis. Neuroimaging plays a key role in the further work-up of pediatric ataxia and may be diagnostic or lead to further targeted investigations. Genetic testing plays an increasing role but does not replace history taking, clinical reasoning, and imaging interpretation, and the diagnostic yield is still rather low.

Keywords

Ataxia · Children · Cerebellum · Acute · Progressive · Non-progressive · Cerebellar malformation · Joubert syndrome

Ataxia is a relatively common disorder in children. Childhood ataxia may have a genetic cause or be acquired. The duration and dynamic of symptoms vary greatly and allow the classication of ataxia as acute, non-progressive, progressive, episodic, or intermittent. Additionally, pediatric ataxia may be categorized by the affected system (e.g., cerebellum, sensory, and vestibular) or etiology (e.g., inammation, intoxication, and infectious). In children, cerebellar dysfunctions

E. Boltshauser (*) Division of Pediatric Neurology (Emeritus), University Children’s Hospital, Zurich, Switzerland

cause the majority of ataxia cases (Boltshauser and Schmahmann 2012).

In this chapter, we discuss some general information about the work-up of pediatric ataxia and review the most common causes of pediatric ataxia. We classify pediatric ataxia according to the duration and dynamic of symptoms and affected systems. We refer to other chapters in this volume dealing with “Differential diagnosis of cerebellar ataxia on the basis of age at onset,” “Autosomal recessive ataxias,” and “Imaging of malformations of the hindbrain.”

80.1 Diagnostic Work-Up

A careful clinical history is essential. The age of the child and nature of symptoms suggest different etiologies. The temporal course of symptoms allows classifying ataxia as acute, non-progressive, progressive, episodic, or intermittent. Taking the clinical history requires knowledge about the potential differential diagnoses.

The neurological examination should include cerebellar functions and other systems to reveal additional ndings (“ataxia plus”). The neurological examination should be seen within the context of the age of the child. In young children, much of the neurological examination comes from observation. A brief general examination may provide somatic clues such as organomegaly or cardiac involvement.

Further investigations including neuroimaging, different laboratory assays, genetic analysis, electroencephalography, and nerve conduction study may be needed. Magnetic resonance imaging (MRI) plays a key role in the diagnostic workup of ataxic children. MRI may provide the nal diagnosis in cerebellar malformations or narrow signicantly the differential diagnosis in neurometabolic disorders. As for history taking, interpretation of imaging requires knowledge, according to the manner of speaking “You look for what you know” and “What you see depends on how you look.” High- quality image acquisition and interpretation is a prerequisite.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_80

531

532

https://t.me/medicina_free

E. Boltshauser

80.2 Acute Ataxia

In acute ataxia, symptoms develop over a few hours or a few (1–2) days (Poretti etal. 2013). Acute postinfectious cerebellar ataxia (APCA) is the most common form. The onset of symptoms follows a (mostly viral) infection. APCA is a selflimiting, pure cerebellar dysfunction with an excellent prognosis without treatment. The diagnosis is made clinically and neuroimaging is usually not indicated.

Intoxication is the second most frequent cause and occurs most commonly in young children (accidental ingestion). Symptoms are accompanied by reduced level of consciousness of variable severity, seizures, and/or vomiting. Because a history of ingestion or exposure may not be given, a high index of suspicion is needed. Blood or urine analysis may conrm the diagnosis.

Less common causes include cerebellitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), cerebellar stroke, and opsoclonus-myoclonus syndrome (OMS). A high index of suspicion is needed to recognize OMS, a very rare autoimmune disorder characterized by opsoclonus (not consistent), ataxia/myoclonus, behavioral changes (irritability and sleep disturbances), and inconsistently associated with a neuroblastoma. Early immunemodulating treatment is the prerequisite for favorable outcome (Sheridan etal. 2020).

Acute pediatric ataxia may be caused by dysfunction of the vestibular and sensory systems. Vestibular migraine is the most common cause of acute vestibular ataxia, while acute unilateral vestibular dysfunction is rare. Acute sensory ataxia is the presenting symptom in about 15% of children with Guillain–Barré syndrome.

Table 80.1 Differential diagnosis of non-progressive cerebellar ataxia

Disease NPCA outside a

dened syndrome

Cerebellar malformations

Congenital oculomotor apraxia-type Cogan Cerebellar

disruptions

Metabolic disorders mimicking NPCA at onset

Infantile onset progressive ataxias that may mimic NPCA at onset

White matter disorders that may mimic NPCA at onset

Syndromes that may mimic NPCA at onset

Benign hereditary chorea (NKX2-1 gene) Midline tumors in the posterior fossa

Autosomal recessive inheritance (genes:

VLDLR, CA8, ZNF592, KCNJ10, NEUROD1, KIAA0226, WDR81, ATP8A2, WWOX);

several families with pedigree compatible with autosomal recessive inheritance and unknown gene

Autosomal dominant inheritance (genes: ITPR1, CAMTA1, KCNC3, CACNA1A)

X-linked (genes: ATPB3, ABCB7) Dandy–Walker malformation Joubert syndrome Rhombencephalosynapsis Cerebellar hypoplasia

Unilateral cerebellar hypoplasia Extreme prematurity L-2-Hydroxyglutaric aciduria Glutaric aciduria type 1 Congenital disorders of glycosylation Ia Congenital disorders of glycosylation Iq Pyruvate dehydrogenase deciency Glucose transporter type 1 (GLUT1)

deciency Ataxia telangiectasia Infantile-onset spinocerebellar ataxia Mitochondrial disorders Marinesco–Sjögren syndrome Vanishing white matter disease (early

childhood-onset form) Hypomyelination and congenital cataract 4H syndrome Rett syndrome Angelman syndrome

80.3 Non-progressive Ataxia

Non-progressive ataxia refers to children with early (congenital) evidence of ataxia without progression on follow-up (Table80.1). First obvious features of ataxia are preceded by hypotonia and delayed motor (and often language) milestones. Ataxia is thus not “congenital” in the strict sense. Non-progressive cerebellar ataxia (NPCA) may result from inherited (genetic) and prenatal or neonatal acquired (disruptive) causes. A Malformation is a morphologic anomaly due to an alteration of the primary developmental program caused by a genetic defect. Gene mutations causing malformations may be “de novo” or be inherited following different patterns that imply a different recurrence risk for further offspring. A Disruption is a morphologic anomaly due to the breakdown of a body structure that had a normal developmental potential. Disruptive causes include, e.g., prenatal infection and hemorrhage.

Cerebellar malformations may underlie NPCA, typical examples are Dandy–Walker malformation (DWM), and Joubert syndrome (JS). DWM is dened by (1) hypoplasia of the vermis, which is elevated and upwardly rotated and (2) dilatation of the cystic-appearing fourth ventricle. A majority of patients present before one year of age with hydrocephalus. Ataxia is present in about one half of the patients. Terms such as “Dandy-Walker variant” have been introduced to classify malformations that do not fulll the DWM criteria. These terms lack specicity, are highly confusing, and should be avoided.

JS is dened by the presence of the “molar tooth sign” (MTS), which is characterized by elongated, thickened, and horizontally orientated superior cerebellar peduncles, a deep interpeduncular fossa, and vermian hypoplasia. Children with JS present with hypotonia, ataxia, ocular motor apraxia, neonatal breathing dysregulation, and intellectual disability. Systemic involvement (renal, eye, liver, and skeleton) may

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