cortex 44 (2008) 54–67 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/cortex Research report Cerebellar cognitive affective syndrome without global mental retardation in two relatives with Gillespie syndrome Peter Mariëna,b,c,*, Raf Brounsa,b, Sebastiaan Engelborghsa,b, Peggy Wackeniera,b, Jo Verhoevend, Berten Ceulemanse and Peter P. De Deyna,b a Department of Neurology, ZNA Middelheim General Hospital, Antwerp, Belgium Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Belgium c Department of Linguistics, Vrije Universiteit Brussel, Belgium d Department of Language and Communication Science, City University London, UK e Department of Neurology–Child Neurology, University Hospital Antwerp, Belgium b article info abstract Article history: Although previous studies of Gillespie syndrome have systematically reported a general- Received 22 September 2005 ized delay of cognitive development (mental retardation or oligophrenia), psychometric Reviewed 23 November 2005 data to substantiate this view are strikingly absent. In the present study two first degree Revised 27 November 2005 relatives (mother and daughter) with Gillespie syndrome were neuropsychologically inves- Accepted 19 December 2005 tigated. Aside from a marked asymmetry in the Wechsler-IQ profile, consisting of signifi- Action editor Jordan Grafman cantly better results on the verbal [Verbal IQ (VIQ)] than on the nonverbal part Published online 17 November 2007 [Performance IQ (PIQ)] of the test, cognitive and behavioral assessments revealed a pattern of abnormalities that closely resembles the ‘‘cerebellar cognitive and affective syndrome’’ Keywords: (CeCAS) (Schmahmann and Sherman, 1998). Aside from prefrontal dysexecutive dysfunc- Gillespie syndrome tions such as disturbed cognitive planning and set-shifting, parietal lobe involvement Cognition was reflected by impaired visuo-spatial memory and visuo-spatial disorganization in con- Cerebellum structional tasks. Within the linguistic domain involvement of the prefrontal and temporal Partial aniridia language regions was indicated by impaired letter fluency, incidences of agrammatism, Ataxia apraxia of speech and disrupted language dynamics. With regard to mood and behavior, a number of personality and affective characteristics were found that are typically associated with prefrontal lobe damage and dysfunction of limbic related regions in the cingulate and parahippocampal gyri. Disinhibited symptoms characterized behavior and affect of the mother while the daughter displayed a variety of inhibited symptoms. As a result, behavioral and cognitive findings in these patients do not support the prevailing view of a global mental retardation as a cardinal feature of Gillespie syndrome but primarily reflect cerebellar induced neurobehavioral dysfunctions following disruption of the cerebrocerebellar anatomical circuitry. ª 2007 Published by Elsevier Masson Srl. * Corresponding author. Department of Neurology, ZNA Middelheim General Hospital, Lindendreef 1, B-2020 Antwerp, Belgium. E-mail address: peter.marien5@telenet.be (P. Mariën). 0010-9452/$ – see front matter ª 2007 Published by Elsevier Masson Srl. doi:10.1016/j.cortex.2005.12.001 cortex 44 (2008) 54–67 1. Introduction In 1965 Frederick D. Gillespie described a new syndrome consisting of partial aniridia, congenital nonprogressive cerebellar ataxia and global mental retardation in a 19-year-old adolescent and his 22-year-old sister. As both the parents and the two siblings of these primary relatives were asymptomatic, Gillespie concluded that the condition was transmitted in an autosomal recessive manner. To our knowledge, this syndrome has been documented in only 16 additional cases [Crawfurd et al., 1979 (n ¼ 3); Dollfus et al., 1998; François et al., 1984 (n ¼ 2); Kieslich et al., 2001 (n ¼ 1); Lechtenberg and Ferretti, 1981 (n ¼ 1); Nelson et al., 1997 (n ¼ 2); Nevin and Lim, 1990 (n ¼ 1); Sarsfield, 1971 (n ¼ 1); Verhulst et al., 1993 (n ¼ 2); Wittig et al., 1988 (n ¼ 2)] (Table 1). Although most reports are consistent with an autosomal recessive pattern of inheritance, the genetic substrate remains to be elucidated. Two families with an affected parent and child (Crawfurd et al., 1979; Verhulst et al., 1993) have raised the possibility of an autosomal dominant inheritance in at least some cases. In contrast to patients with complete aniridia (Jordan et al., 1992) mutations in the PAX6 gene have not been detected in Gillespie syndrome (Glaser et al., 1994; Dollfus et al., 1998). Recently, Dollfus et al. (1998) reported a de novo balanced translocation of chromosome X and 11 [t(X;11)(p22.32;p12)] in an 8-month-old girl. These findings, however, were not confirmed by the study of Kieslich et al. (2001) in which karyotyping and molecular biological investigations of the PAX6 gene and the search for a de novo translocation of chromosome X and 11 revealed no abnormalities. Notwithstanding some variability in the neurological expression of the syndrome, motor delay, hypotonia and nonprogressive ataxia constitute typical characteristics. At the cognitive level, a generalized developmental delay of different degrees has been invariably reported (mental retardation or oligophrenia). In the second edition of Pryse-Phillips’ Companion to Clinical Neurology (Pryse-Phillips, 2003) the available clinical knowledge in the literature is quite well reflected in the description: ‘A congenital cerebellar ataxic syndrome due to cerebellar and brainstem hypoplasia. Associated features include dilated pupils due to partial aniridia, delayed milestones, and mental retardation’. However, formal neuropsychological evidence to substantiate global mental retardation is strikingly absent (Table 1). No studies have formally investigated cognitive skills, apart from the study of Sarsfield (1971) and Crawfurd et al. (1979) in which general intelligence was broadly measured by means of the Merrill Palmer and the Standard Progressive Matrices (SPM), respectively. As a result, little is known about the cognitive characteristics of Gillespie syndrome. In the majority of cases, neuroimaging studies have shown cerebellar hypoplasia, particularly affecting the vermis (Table 1). In a few patients, magnetic resonance imaging (MRI) has demonstrated more extensive structural alterations such as diffuse white matter changes, diffuse atrophy of the cerebral hemispheres and brainstem and frontal cortical atrophy (Nelson et al., 1997; Dollfus et al., 1998; Kieslich et al., 2001). Given the observation that: (1) the neurobehavioral and cognitive characteristics of patients with Gillespie syndrome have not been sufficiently studied before and (2) this genetic 55 syndrome affects the cerebellum, the aim of the present study was (1) to report for the first time the cognitive data from two representative cases with Gillespie syndrome, reported before as the first pedigree with an affected mother and daughter (Verhulst et al., 1993), and (2) to investigate whether recent insights into the cognitive and affective role of the cerebellum may corroborate the pathophysiological explanation of the neurobehavioral symptoms of both patients. 2. Case reports 2.1. Case SVP SVP is 34-year-old right-handed native Dutch-speaking woman who has suffered from nonprogressive ataxic disturbances, bilaterally dilatated pupils with photophobia and learning difficulties since early childhood. Due to a delay in scholastic achievements she was referred to special education after the first grade of primary school. In 1988 – at the age of 18 – she was placed in sheltered employment. Both her parents as well as her two brothers were not affected. In 1993 – at the age of 23 – she and her two and a half year old daughter were diagnosed with Gillespie syndrome. At that time, ophthalmological investigations showed normal eye movements and normal velocity of saccades and saccadic pursuit in both the horizontal and vertical plane. A fine vertical upbeating nystagmus with the greatest amplitude upon rightward gaze was present. Slitlamp examination revealed a bilaterally underdeveloped iris. The pupillary diameter of both eyes was 8 mm without response to light or convergence (Fig. 1A). No pupillary reaction was found to phenylephrine 10% and pilocarpine 4%. Fundoscopy was normal. Pattern reversal visual evoked potential (VEP) stimulation showed a prolonged latency P100 with a normal amplitude for the right eye and a prolonged P100 latency with a subnormal amplitude for the left eye. Photopic and scotopic stimulations elicited a normal electroretinography (ERG) response. No deletion on chromosome 11p was found and molecular analysis (Southern blot analysis and polymerase chain reaction – PCR) did not show any rearrangements. Point mutations were not excluded. Neurological examination revealed marked, mainly truncal, ataxia and saccadic speech, suggestive for involvement of the vermis. The neurological examination in 2004 showed distinct midline cerebellar dysfunction presenting as truncal ataxia and gait ataxia rendering tandem gait impossible. Appendicular ataxia was less pronounced but could also be demonstrated by ataxic and slightly dysmetric finger-to-nose and heel-to-shin tests and the presence of dysdiadochokinesis. Mild cerebellar tremor was present as well. Besides the neuro-ophthalmological features described above, no other abnormality was found. Brain MRI demonstrated cerebellar hypoplasia most prominently affecting the cerebellar vermis (Fig. 2A and B). 2.2. Case SW As the only child of SVP, SW was hospitalized in 1993 at the age of two and a half because of developmental psychomotor 56 Table 1 – Case description summary results Reference Gillespie (1965) Gender/age/ generation F/22y/1st M/19y/1st Relationship Consanguity Sister of M – Brother of F – Ataxia, unable to walk alone Ataxia, unsteadiness of gait Slight hypotonia, ataxia, intention tremor, mask like facial expression, disturbed balance and gait Up to 9m: apathetic; at 5y: Merrill Palmer IQ ¼ 71, slow, indistinct and fragmented speech, consonant substitutions – Moderate degree of mental subnormality (age 3.3), mild MR, SPM ¼ 7th centile, Mill Hill ¼ 25th centile Mildly subnormal and dysarthric – At 5m: delay in social responsiveness; at 18m: social and verbal development (¼10m level) in advance of motor development (¼7m level) – Hypotonia, prominent titubation, chorea-athetotic movements of fingers, ataxia, increased tendon reflexes, downgoing plantar reflexes MR, developmental level at 8–10m, no meaningful words, no verbal comprehension CT: large 4th ventricle, quadrigeminal plate cistern and prepontine cistern; poor development of cerebellar structures, especially about the inferior vermis, pontine hypoplasia Pronounced, generalized hypotonia, ataxia (dysmetria, incoordination, intention tremor, lack of equilibrium) Severe hypotonia, ataxia Psychomotor retardation (oligophrenia), apathy, speech consisted of a few isolated words CT: skull and base cisterns enlargement Psychomotor retardation, defective speech Large subarachnoidal space above vermis CT: hypoplasia of cerebellum, particularly the vermis CT: hypoplasia of cerebellum, particularly the vermis F/19y/1st Sister of M1, Mother of M2 – Gross intention tremor, ataxia, hyperreflexia M1/17y/1st Younger brother of F – Son of F – Fits at 5m, tremor, ataxia, unsteadiness of gait Ataxia, hypotonia Lechtenberg and Ferretti (1981) F/18m/1st François et al. (1984) F1/5y/1st Sister of F2 ? F2/3y/1st Sister of F1 ? M1/8y 9m/1st Brother of M2 Diffuse ataxia Moderate MR M2/6y 8m/1st Brother of M1 Diffuse cerebellar ataxia Severe scholastic delay, considerable learning difficulties – – cortex 44 (2008) 54–67 Crawfurd et al. (1979) Wittig et al. (1988) Neuroimaging – M/2y/1st – Cognitive and behavioral symptoms MR, behavioral problems, severe dysarthria, poor stereognosis MR, inability to attend school, severe dysarthria, child-like actions Sarsfield (1971) M2/5m/2nd – Neurological symptoms Nevin and Lim (1990) F/5y/1st Verhulst et al. (1993) F1/23y/1st F2/2y 6m/2nd Nelson et al. (1997) F/4y 7m/1st M/3w/1st – Abnormal speech with prominent scanning, psychomotor delay After age 2: CT: normal ventricles; CT at age 3: enlarged basal cistern, prominent folia of the cerebellum, dilated 4th ventricle Mother of F2 Hypotonia, ataxia Mental capacities below normal Daughter of F1 Hypotonia, ataxia, slight tremor of the hands Psychomotor and cognitive delay, limited speech (a few words) MRI: cerebellar vermis hypoplasia CT: cerebellar vermis hypoplasia Hypotonia, ataxia, intention tremor Profound hypotonia, ataxia, Very dysarthric CT at 11m: normal At 5y 2m: marked developmental delay, very dysarthric, less than 10 recognisable words CT at 3w: diffuse low density changes throughout the entire WM, particularly in the frontal regions MRI at 11w and 2y: diffuse WM changes, diffuse atrophy cerebral hemispheres, cerebellum, brainstem – First cousins Dollfus et al. (1998) F/4m/1st – Discrete nystagmus, moderate axial hypotony At 8m: developmental delay and mild MR MRI at 4m: hypoplasia inferior cerebellar vermis, frontal cortical atrophy, thin corpus callosum Kieslich et al. (2001) F/8y/1st – Hypotonia, ataxia Dysarthria, MR MRI: slight atrophy, cerebellar atrophy, vermis hypoplasia cortex 44 (2008) 54–67 Hypotonia, marked ataxia, absence of ankle reflexes, intention tremor M: Male; F: female; 1st: first generation; 2nd: second generation; –: absent; w: weeks; m: months; y: years; ?: not recorded; MR: mental retardation; SPM: standard progressive matrices and WM: white matter. 57 58 cortex 44 (2008) 54–67 Fig. 1 – Partial aniridia in two primary relatives with Gillespie syndrome: (A) SVP and (B) SW. problems. Pregnancy, delivery and birth weight were normal and medical history was unremarkable. Biometric parameters such as weight, length and fronto-occipital circumference were normal. The girl could sit without assistance but crawling and standing were impossible. A delay in fine motor activity was observed. The clinical neurological examination further revealed ataxic symptoms more pronounced in sitting and standing position, a slight tremor affecting both hands especially during volitional movements and a basic hypotonia with hyporeflexia. The Bayley Scales of Infant Development (Bayley, 1969) indicated a developmental delay of 7 months. Ophthalmologic examination showed widely dilated pupils with no reaction to light or convergence. The pupillary diameter was 8 mm bilaterally (Fig. 1B). No reaction was found to phenylephrine 1% and pilocarpine 2%. Eye movements were normal but a saccadic pursuit was present in both the horizontal and vertical directions. Fundoscopy was normal. Pattern reversal VEP and flash VEP stimulations showed a normal P100 latency with a normal amplitude for the right eye and a prolonged P100 latency for the left eye. Photopic and Fig. 2 – Brain MRI parasagittal T1-weighted and axial fluid-attenuated inversion-recovery (FLAIR) slices (A–D) demonstrate marked cerebellar hypoplasia, especially involving the cerebellar vermis in SVP (A and B) and SW (C and D). cortex 44 (2008) 54–67 scotopic stimulations elicited a normal ERG response. A computerized tomography (CT) scan of the brain demonstrated cerebellar vermis hypoplasia. Chromosomal examination showed a normal karyotype and no deletion on chromosome 11p was found. As in the mother, molecular studies of the PAX6 gene did not demonstrate any rearrangements. However, point mutations were not excluded. In 2004, at the age of 13, the neurological examination was dominated by unchanged neuro-ophthalmological abnormalities and cerebellar dysfunction. Postural instability, widebased gait with unsteadiness and irregular steps, ataxia, dysdiadochokinesis and dysmetria in the four extremities characterized the neurological tableau. MRI of the brain showed cerebellar hypoplasia with pronounced hypoplasia of the vermis (Fig. 2C and D). 3. Neurocognitive investigations Eleven years after having been diagnosed with Gillespie syndrome, both patients were for the first time extensively examined by means of standard cognitive tests. The neuropsychological test battery consisted of the Mini Mental State Examination (MMSE) (Folstein et al., 1975), the Wechsler Adult Intelligence Scale (WAIS) (Wechsler, 1970), the Wechsler Intelligence Scale for Children-III (WISC-III) (Wechsler, 2002), the Snijders-Oomen nonverbal intelligence test (SON-R) (Tellegen et al., 1998), the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1987), the 15 words test of the PI-batterij voor neuropsychologisch onderzoek bij kinderen (PINOK) (Vieijra et al., 1992), memory and praxis subtests of the Hierarchic Dementia Scale (HDS) (Cole and Dastoor, 1987), the Stroop Colour-word test (Golden, 1978; Lezak, 1995), the Trail Making Test, the Wisconsin Card Sorting Test (WCST) (Heaton et al., 1993), the Rey–Osterrieth Figure (Osterrieth, 1944), the Judgment of Line Orientation test (JLO) (Benton et al., 1983), Hooper Visual Organization Test (HVOT) (Hooper, 1983) and the Birmingham Object Recognition Battery (BORB) (Riddoch and Humphreys, 1993). Handedness was formally assessed by means of the Edinburgh Inventory (Oldfield, 1971). The neurolinguistic test battery consisted of several subtests of the Boston Diagnostic Aphasia Examination (BDAE) (Goodglass and Kaplan, 1983), the Aachener Aphasie Test (AAT) (Graetz et al., 1992), the Token Test (De Renzi and Vignolo, 1962), the Boston Naming Test (BNT) (Kaplan et al., 1983; Mariën et al., 1998), and a semantic and phonological verbal fluency task (1 min generation of names of animals, means of transport, vegetables, clothes and words starting with phoneme [f], [a] and [s]) (unpublished norms). 3.1. Cognitive findings SVP A strong right hand preference (laterality quotient of þ100) was formally confirmed by means of the Edinburgh Handedness Inventory (Oldfield, 1971). As shown in Table 2, the WAIS revealed a global IQ (GIQ) of 82. A significant discrepancy of 22 IQ-points was found between the verbal (VIQ ¼ 94) and performance level [PIQ ¼ 72; 1.8 standard deviation (SD)]. At the verbal level, all subtest scores were normal. By contrast, only the subtest ‘picture 59 completion’ scored within the normal range at the performance level. Scaled scores of 2 or below 2 SD were obtained for ‘digit symbol substitution’, ‘picture arrangement’ and ‘object assembly’. As reflected by a severely distorted copy of the Rey– Osterrieth Figure (Fig. 3A), the copying tasks of the BORB and the drawing and constructional subtests of the HDS, test performances did not improve when no time limits were imposed. Therefore, disrupted performances on these tasks were not attributable to the motor demands of the tasks. The ability to conceptually rearrange pictures was impaired as well (HVOT ¼ 2.2 SD). The score on the SON-R patterns matched a mean age equivalent of 6 years and 10 months. In marked contrast with these findings, examination of visual object identification and visual semantics was entirely normal (BNT and BORB). The WMS-R profile was characterized by a discrepancy of 22 points between the verbal and nonverbal memory index. The verbal memory index was normal (¼89) but visual memory tasks led to a deficient result (index ¼ 67; 2.2 SD). As demonstrated by the WCST, frontal planning and problem solving were severely defective (<percentile 1). A score below percentile 5 on the Stroop Colour-word test indicated that the ability to inhibit a competing and more automatic response set was disrupted. Visual search and sequencing (Trail Making Test) were also deficient. From a neurobehavioral point of view, inappropriate laughing, Witzelsücht, impulsiveness, disinhibited verbal reactions and abusive language (cursing, foul language, and four letter words) frequently occurred during the examination and the patient behaved euphorically. At the linguistic level, oral and written comprehension (BDAE and AAT), visual confrontational naming (BNT), semantic word fluency and oral reading were normal. The phonological verbal fluency task (phonemes [f], [a], [s]), however, yielded a defective result (n ¼ 16; 2.0 SD). No intrusions or perseverations occurred. Linguistic analysis of a 5-min spontaneous speech sample, obtained via video-taped interviews, revealed a normal articulation rate of 3.99 syllables/sec (normal range for Dutch between 3.98 and 4.23; Verhoeven et al., 2004). Voice quality as well as intonation and prosody were normal and pauses were realized correctly. Spontaneous speech was generally characterized by a somewhat labored articulation particularly in the alveolar region with strikingly little jaw movement. The latter gave rise to a relatively closed articulatory setting. In addition, there were a number of inconsistent phonetic errors. Consonants as well as vowels were sometimes deleted or substituted (e.g. [d] realized as glottal stop [?], the velar fricative [X] as a velar plosive [k]). In addition, consonant clusters were sometimes reduced (e.g. [nd] pronounced as [d]). In general the patient’s speech did not show the characteristics that are typical for ataxic dysarthria particularly with respect to slow speech rate, monotonous intonation, prolonged phonemes and prolonged intervals between phonemes. Due to sporadic omission of function words, conjugated verbs and pronouns, spontaneous speech contained a number of agrammatic sentence constructions resulting in a telegrammatic style. The patient, for instance, deleted the personal pronoun, auxiliary and article in the sentence ‘I was hospitalized for 4 months’ (‘Vier maanden in ziekenhuis gelegen’ 60 cortex 44 (2008) 54–67 Table 2 – Neurocognitive test results for patient SVP Neurocognitive tests Score/maximum (scaled score) Percentile Mean 1 SD MMSE 29/30 29 1.3 Intelligence Wechsler GIQ Wechsler VIQ Information Comprehension Arithmetics Similarities Vocabulary 82 94 4/22 (4) 12/28 (4) 6/16 (5) 8/26 (4) 27/60 (5) 27 38 46 38 54 100 100 5 5 5 5 5 15 15 1.5 1.5 1.5 1.5 1.5 Wechsler PIQ Digit symbol substitution Picture completion Block design Picture arrangement Object assembly 72 26/115 (1) 8/20 (5) 6/26 (3) 4/20 (2) 6/82 (1) 4 42 14 8 3 100 5 5 5 5 5 15 1.5 1.5 1.5 1.5 1.5 Memory WMS-R Visual memory index Verbal memory index Global memory index Information Orientation Mental control Logical memory (A þ B) Visual paired associates (I–III) Verbal paired associates (I–III) Visual reproduction Digit span forward Digit span backward Visual memory span forward Visual memory span backward 67 83 76 6/6 7/7 5/6 26/43 6/18 10/24 26/41 7/12 4/12 6/14 6/12 100 100 100 15 15 15 51 26 12 20 11 10 19 33–34 Delayed recall index Logical memory (A þ B) Visual paired associates Verbal paired associates Visual reproduction 60 18/43 1/6 4/8 17/41 HDS Memory: Biographic: item 17 10/10 10 0 Rey–Osterrieth Figure –/36 25 3 46/60 52.8 3.7 47 15 11 10 11 1 0 59.7 13.27 16 8 3 5 1 0 42.6 13.01 Language BNT Verbal fluency Semantic generation (total) Animals, 1 min Transportation, 1 min Vegetables, 1 min Clothing, 1 min Total number of perseverations Total number of intrusions Phonological generation (total) Phoneme F, 1 min Phoneme A, 1 min Phoneme S, 1 min Total number of perseverations Total number of intrusions 31 100 22 7 31 15 61 cortex 44 (2008) 54–67 Table 2 (continued) Neurocognitive tests Score/maximum (scaled score) Percentile Mean 1 SD Executive functioning Wisconsin Card Sorting Stroop Colour-word test Card I Card II Card III 2/128 <1 5 6500 8100 11600 10 10 25 4800 6300 9900 Trail making Part A Part B 6400 11300 <10 15 32 63 10 Praxis Rey–Osterrieth Figure HDS ideational: it. 5 HDS ideomotor: it. 3 HDS drawing: it. 15 HDS constructional: it. 12 SON-R patterns –/36 10/10 10/10 8/10 8/10 14/16a 35 9.79 9.94 9.81 10 3 0.17 0.23 0.52 0 20/20 24/30 30/32 15/30 19.3 25.3 29.9 26 2.3 5 Impaired 27/30 25/30 23/30 33/40 24/25 25/25 25/32 32/32 27/32 26.9 27.3 24.8 35.1 23.3 21.6 27.0 30 27.5 1.6 2.4 2.6 4.0 2.0 2.6 2.2 2.2 2.4 Visual perception Right–left orientation – Form A JLO Visual form discrimination HVOT BORB Copying Length match task – A Size match task – A Orientation match task – A Position of gap match task – A Minimal feature match Foreshortened match Object decision Item match Association match a Mean age equivalent ¼ 6 years 10 months. instead of ‘Ik heb vier maanden in het ziekenhuis gelegen’). Dictation and spontaneous writing contained no spelling errors but were characterized by motor dysgraphia consisting of overall increased letter size, poor motor execution and erratic spatial trajectory related to the inadequate control of movement direction, force, speed, and amplitude (Fig. 4). 3.2. Cognitive findings SW At the age of two and a half years, SW was neuropsychologically investigated for the first time by means of the Bayley Scales of Infant Development (Bayley, 1969). In addition to a developmental delay of 7 months, a strikingly disharmonic distribution of test results was found. In marked contrast to age appropriate scores at the verbal level, a severe delay in the nonverbal domain was recorded. Pathological scores, matching an age level of 18 months, were obtained on the subtests assessing motor–praxic skills. It was noted by the examiners that ataxic symptoms affected speed and accuracy of motor performances. However, even when no time limits were imposed the patient did not succeed to solve visuoconstructive tasks at the most basic levels. More extensive cognitive investigations were carried out in 2004 at the age of 13 (Table 3). As reflected by a laterality quotient of þ100, the Edinburgh Handedness Inventory (Oldfield, 1971) indicated a strong and consistent right hand preference. The WISC-III revealed a global intelligence level of 69 with a significant discrepancy of 32 IQ-points between the normal verbal (VIQ ¼ 87) and pathological PIQ (PIQ ¼ 55; 3 SD). Except for the subtest ‘digit span’ (>2 SD) normal results were obtained for all verbal subtests of the WISC-III. At the performance level, however, defective scaled scores (below percentile 5) were found for all but one subtest (mazes). The subtests ‘digit symbol substitution’, ‘object assembly’ and ‘symbol comparison’ scored below –2 SD. In addition to a pathological result on the visuo-constructive tasks of the WISC-III, a variety of constructional and drawing tasks with no time limits similarly showed disrupted performances (HDS item 12 and 15; SON-R patterns; copy of the Rey–Osterrieth Figure (Fig. 3B); BORB test 1). In addition to a pathological result on digit span tasks (working memory), verbal learning (15 words of the PINOK) was also disturbed. Results on the Stroop Colour-word test, the Trail Making Test and the WCST were severely distorted. At the level of mood and behavior the patient made an apathetic impression with a marked lack of initiative and spontaneity. Affect was clearly flattened. 62 cortex 44 (2008) 54–67 Fig. 3 – Copies of the Rey Complex figure: on the left produced by SVP (A) and on the right by SW (B). Aside from slight ataxic speech symptoms, neurolinguistic investigations revealed a marked dissociation between spontaneous and imposed oral language. Since the girl only produced very short verbal responses in conversations and interviews, no sufficient data were obtained to allow formal analysis of spontaneous or conversational speech. Even when strongly encouraged, the girl was not able to tell a story, to report about her hobbies or to describe a scene displayed on a picture (Cookie Theft Picture – BDAE). Linguistic/phonetic analysis of a few short utterances showed a somewhat slowed down articulation rate (2.54 syllables/sec, normal range: between 3.98 and 4.23; Verhoeven et al., 2004), normal voice quality and a slightly labored articulation in the alveolar region. The intonation was characterized by the frequent use of a rising intonation pattern at the end of utterances, which leaves a very hesitant perceptual impression. There were no imprecise articulations of consonants and in only one instance, the reduction of a consonant cluster was witnessed whereby [mp] was simplified to [p]. Unlike the mother, she has a very scrapy uvular-r. At the linguistic level, it was striking that all the answers to questions were very short and the use of one-word sentences prevailed. Formal investigation of visual confrontational naming (BNT), repetition of words and sentences (AAT) and semantic word fluency were, however, normal. On the phonological verbal fluency task she performed in the severely defective range (2.3 SD). Fig. 4 – Handwriting sample from SVP (A) [Samantha is een meisje (Samantha is a girl)] and SW (B) [Een appel is fruit (An apple is fruit)] demonstrating the characteristic features of megalographia, including overall increased letter size, poor motor execution and erratic spatial trajectory related to the inadequate control of movement direction, force, speed, and amplitude. 63 cortex 44 (2008) 54–67 Table 3 – Neurocognitive test results patient SW Neurocognitive tests Intelligence Wechsler GIQ Wechsler VIQ Information Comprehension Digit span Arithmetics Similarities Vocabulary Wechsler PIQ Digit symbol substitution Picture completion Block design Picture arrangement Object assembly Symbol comparison Mazes Memory PINOK–15 Words Trial I Trial II Trial III Trial VI Trial V Total score HDS Memory: Biographic: item 17 Rey–Osterrieth Figure Language BNT Verbal fluency Semantic generation Animals, 1 min Transportation, 1 min Vegetables, 1 min Clothing, 1 min Total number of perseverations Total number of intrusions Phonological generation Phoneme F, 1 min Phoneme A, 1 min Phoneme S, 1 min Total number perseverations Total number intrusions Executive functioning Wisconsin Card Sorting Stroop Colour-word test Card I Card II Card III Trail making Part A Part B Praxis Rey-Osterrieth Figure HDS ideational: it. 5 HDS ideomotor: it. 3 HDS drawing: it. 15 HDS constructional: it. 12 SON-R patterns Score/maximum (scaled score) Percentile Mean 1 SD 69 87 19/31 (8) 26/38 (8) 8/30 (3) 19/34 (7) 18/36 (9) 38/70 (8) 100 100 (10) (10) (10) (10) (10) (10) 15 15 3.5 3.5 3.5 3.5 3.5 3.5 55 31/119 (3) 16/30 (4) 29/69 (4) 16/64 (4) 9/44 (1) 16/45 (3) 20/28 (8) 100 (10) (10) (10) (10) (10) (10) (10) 15 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3/15 7/15 5/15 8/15 7/15 30/75 1 47 10/10 –/36 10 25 0 3 47/60 45.23 3.85 47 15 9 6 4 0 1 59.7 13.27 12 3 5 4 0 0 42.6 13.01 1/128 5 8900 12400 25200 <1 <1 <1 4800 6300 9900 2700 6200 2 1 1500 2800 –/36 10/10 10/10 8/10 8/10 11/16a 35 9.79 9.94 9.81 10 3 0.17 0.23 0.52 0 (continued on next page) 64 cortex 44 (2008) 54–67 Table 3 (continued) Neurocognitive tests Score/maximum (scaled score) Visual Perception Judgment of Line Orientation Visual form discrimination Hooper VOT BORB Copying Length match task – A Size match task – A Orientation match task – A Position of gap match task – A Minimal feature match Foreshortened match Object decision Item match Association match Percentile Mean 1 SD 16/30 30/32 19/30 22.7 29.9 23.1 4.2 3.3 Impaired 26/30 24/30 25/30 30/40 24/25 22/25 26/32 32/32 27/30 26.9 27.3 24.8 35.1 23.3 21.6 27.0 30 27.5 1.6 2.4 2.6 4.0 2.0 2.6 2.2 2.2 2.4 a Mean age equivalent ¼ 5 years and 7 months. Within 1 min time she could only name three words beginning with phoneme [f], five words with phoneme [a] and four words with phoneme [s]. No perseverations or intrusions occurred. 4. Discussion Both primary relatives with early onset nonprogressive cerebellar ataxia, partial aniridia and a developmental psychomotor delay present the clinical characteristics consistent with Gillespie syndrome. Although global mental retardation has been considered as a cardinal feature since the first description of the syndrome, the psychometric data obtained in our patients do not corroborate this view. As reflected by the Wechsler-IQ results, both patients had an unusual large VIQ–PIQ discrepancy with a normal verbal and significantly depressed PIQ. Except for the fact that the daughter (SW) obtained a deviant result on digit span tasks, both patients obtained normal scores on the verbal subtests of the Wechsler scales. By contrast, both patients obtained deviant results on the performance subtests assessing psychomotor speed and concentration (digit symbol substitution), constructional praxis (object assembly) and visual search (symbol comparison). This disharmonic distribution of the Wechsler-IQ data is not consistent with a diagnosis of global mental retardation but rather indicates more selectively affected cognitive skills. Indeed, in both patients, additional neurocognitive investigations disclosed a constellation of symptoms resembling the ‘‘cerebellar cognitive and affective syndrome’’ (CeCAS) (Schmahmann and Sherman, 1998). The core features of this syndrome so far reported in patients with acquired cerebellar lesions consist of (1) disturbances of executive function, (2) impaired spatial cognition, (3) linguistic deficits and (4) personality disorders. 4.1. Neurocognitive performance Neuropsychological test results of both patients evidenced disruption of frontal-mediated executive processes and impairment of spatial cognition subserved by the parietal lobe. Pathological scores were obtained on psychometric tests measuring cognitive planning, set-shifting, visuo-spatial organization and visuo-spatial memory. In addition, working memory was clearly distorted in patient SW. Within this group of deficits, the deficiently organized drawings (copyings and drawings from memory) and disrupted performance on constructional tasks revealed visuo-constructional apraxia. This phenomenon could not be explained by motor control disturbances since both patients showed only mild motor coordination problems and a slight cerebellar tremor. That constructional disturbances are likely to result from a higher level planning and organization disorder was also indicated by the findings on an experimental figure copy task that required no motor actions from the patients. Markedly impaired ability to appreciate the structural components of the figures and many unsuccessful attempts to plan the copies of the figures characterized the patients’ performance when they verbally instructed the examiner during the execution of these tasks. Visual object identification and visual semantics were normal in both patients (BORB and BNT). The sparing of visual feature detection, subserved by the inferotemporal areas, is consistent with the anatomical evidence showing that these object pathway functions are not interconnected with the cerebellum and as a result do not make part of the cerebrocerebellar system (Schmahmann and Pandya, 1997). 4.2. Neurolinguistic performance Within the verbal domain, a complex of nonmotor language symptoms also revealed disruption of frontal-mediated executive functions. Firstly, letter fluency was severely impaired while both patients obtained normal results on semantic category fluency. This finding is consistent with a large number of clinical and experimental studies demonstrating high sensitivity of controlled word association tasks to prefrontal lobe dysfunction of the language dominant hemisphere (Parks et al., 1988; Perret, 1974; Ramier and Hecaen, 1970; Ruff et al., 1994). In addition, recent clinical and experimental research has convincingly shown that the contralateral cerebellum is crucially involved in verbal fluency tasks as well (Leggio cortex 44 (2008) 54–67 et al., 1995, 2000). Treating the dysarthria score as a covariate with the total verbal output for the phonological and semantic verbal fluency tasks, Leggio et al. (2000) demonstrated that verbal fluency deficits could not be attributed to motor speech impairments. The authors interpreted the difference in cerebellar effects between phonological and semantic verbal fluency along the view of the role of the cerebellum in planning, strategy formation, and learning of procedures. They conceived that cerebellar damage affects phonological processes to a greater extent than semantic processes because phonological tasks depend on unusual novel and less automized searching strategies than semantic tasks. Secondly, formal analysis of the spontaneous speech samples of our patients showed: (1) incidences of agrammatism and mild apraxia of speech (AoS) in SVP and (2) severely disrupted language dynamics in SW. During the past two decades, agrammatism – a syntax disorder classically attributed to damage of the prefrontal language area – has been recorded in patients with focal lesions of the right cerebellum (Fabbro et al., 2000, 2004; Gasparini et al., 1999; Mariën et al., 1996, 2000; Riva and Giorgi, 2000; Silveri et al., 1994; Zettin et al., 1997). Given the structural integrity of the supratentorial language areas as evidenced by MRI, the grammatical errors in SVP’s speech indicate functional involvement of the right cerebellar hemisphere. Semiological analysis of the spontaneous speech samples of SVP additionally disclosed a number of inconsistent phonetic errors typical of AoS (unpredictable consonant cluster reductions and deletions and substitutions of consonants and vowels). AoS, classically defined as a selective impairment of speech movements following the inability to properly and smoothly convert phonological knowledge into verbal–motor commands (Rosenbek, 1999) typically follows damage of the supratentorial motor speech areas (Lebrun, 1990; Hillis et al., 2004). However, on the basis of some striking semiological similarities with ataxic dysarthria, Mariën et al. (2006) and Mariën and Verhoeven (2007) recently hypothesized that the disruption of articulatory planning and speech timing processes in AoS may reflect functional disruption of a close connection between supra- and infra-tentorial regions. Clinical recovery of the apraxic speech symptoms in their two patients with a left hemisphere ischemic stroke was reflected on single photon emission computerized tomography (SPECT) scan by a remission of perfusional defects in the right cerebellar hemisphere. SVP’s speech errors add to the view that the cerebellum may be directly implicated in the orchestration of speech movements. Neurolinguistic assessments of SW’s language functions disclosed a marked dissociation between affected propositional speech and well-preserved, externally guided language in nominative, repetition and comprehension tasks. Despite normal confrontational naming and phonological and syntactic skills, self-generated speech was severely reduced, adynamic and fragmented. This pattern of disrupted self-generated speech typologically resembles Luria’s ‘dynamic aphasia’ (Luria and Tsvetkova, 1967). The anatomical substrate of this language disorder involves either of two distinct prefrontal areas of the language dominant hemisphere: the area anterior and/or superior to Broca’s area and the territory supplied by the left anterior cerebral artery. In addition to these loci, disrupted language dynamics have been recorded in patients 65 with focal lesions of the right cerebellar hemisphere. In the absence of neuroradiological evidence for a structural lesion in the left prefrontal language areas, Mariën et al. (1996, 2000) reported prefrontal aphasic symptoms, among which a significant reduction of spontaneous speech output, in a right-handed patient with focal ischemic damage in the vascular territory of the right superior cerebellar artery. The hypothetical causative role of the right cerebellar lesion on the contralateral prefrontal aphasic symptoms was supported by positive SPECT findings, revealing focal hypoperfusions in the clinically suspected supratentorial language areas. During longitudinal follow-up the regression of crossed cortical and subcortical left hemisphere diaschisis, demonstrated by SPECT, paralleled language improvement. 4.3. Affective and behavioral features With regard to mood and behavior, the two personality types classically attributed to damage of the prefrontal lobe were observed in both patients. Disinhibited symptoms generally linked to orbitofrontal dysfunction were present in SVP. Impulsiveness, inappropriate behavior, facetiousness, mild euphoria and foul language characterized SVP’s behavior and affect. By contrast, SW displayed a variety of inhibited, pseudodepressed symptoms among which apathy, lethargy, blunting of affect, little spontaneity of behavior, unconcern, and little overt emotion. These symptoms are classically attributed to dorsofrontal dysfunction. During the past two decades, similar configurations of affective and behavioral symptoms have been documented in an increasing number of etiologically different patients with cerebellar damage particularly involving the posterior lobe of the cerebellum and the vermis which cause disruption of the cerebellar limbic (apathetic patients) and temporal (euphoric patients) circuitry (Courchesne et al., 1988; Pollack et al., 1995; Schmahmann and Sherman, 1998; Levinsohn et al., 2000; Riva and Giorgi, 2000; Schmahmann, 2000; Van Harskamp et al., 2005). 5. Conclusions This study of the neuropsychological, neurolinguistic and behavioral characteristics of two primary relatives with Gillespie syndrome did not disclose globally affected cognitive skills but a variety of selective verbal, nonverbal, behavioral and affective impairments matching a diagnosis of CeCAS. Based on a substantial amount of anatomical, experimental and clinical evidence, Schmahmann and Sherman (1998) related CeCAS in patients with focal cerebellar lesions to acute and often transient disruption of the associative cerebrocerebellar circuitry as reflected by crossed cerebello-cerebral diaschisis. According to this view, cognitive and behavioral dysfunctions within CeCAS may result from temporarily functional depression of the reciprocal pathways that connect the cerebellum with the limbic circuitry and the prefrontal, temporal and parietal association cortices. In accordance with this view, the behavioral and cognitive symptoms constituting CeCAS in our patients with marked cerebellar hypoplasia evoke essentially 66 cortex 44 (2008) 54–67 all the cerebrocerebellar circuitry that has been postulated to contribute to the deficits in emotional and cognitive processing. In addition, the findings in our patients show that a congenital disorder affecting the cerebellum in its anatomical and functional integrity might lead to full-blown CeCAS. In contrast to CeCAS following acquired cerebellum damage, the findings in this congenital variant corroborate the view that congenital cerebellar disorders may be associated with permanent behavioral and cognitive impairments (Guzetta et al., 1993; Steinlin et al., 1998, 1999). Insufficient maturation and underdevelopment of the neural circuitry connecting the cerebellum with the supratentorial association areas might account for the persistent nature of the cognitive and affective deficits in patients with congenital cerebellar disorders. Acknowledgements We are grateful to Mrs. Diane Verbruggen for the editorial assistance. This study was supported by grant G.0209.05 of the Fund for Scientific Research – Flanders (F.W.O. – Vlaanderen). SE is a postdoctoral fellow of F.W.O. – Vlaanderen. references Bayley N. Bayley Scales of Infant Development. Manual. New York: Psychological Corporation, 1969. Benton AL, deS Hamsher K, Varney NR, and Spreen O. Contributions to Neuropsychological Assessment: a Clinical Manual. New York: Oxford University Press, 1983. Cole MG and Dastoor D. A new hierarchic approach to the measurement of dementia. Psychosomatics, 28: 298–305, 1987. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, and Jernigan TL. Hypoplasia of cerebellar vermal lobeulus VI and VII in autism. New England Journal of Medicine, 318: 1349–1354, 1988. Crawfurd MD, Harcourt RB, and Shaw PA. Non-progressive cerebellar ataxia, aplasia of pupillary zone of iris, and mental subnormality (Gillespie’s syndrome) affecting 3 members of a non-consanguineous family in 2 generations. Journal of Medical Genetics, 16: 373–378, 1979. De Renzi E and Vignolo LA. The token test: a sensitive test to detect receptive disturbances in aphasia. Brain, 85: 665–678, 1962. Dollfus H, Joanny-Flinois O, Doco-Fenzy M, Veyre L, JoannyFlinois L, Khoury M, Jonveaux P, Abitbol M, and Dufier J-L. Gillespie syndrome phenotype with a t(X;11)(p22.32;p12) de novo translocation. American Journal of Ophthalmology, 125: 397–399, 1998. Fabbro F, Moretti R, and Bava A. Language impairments in patients with cerebellar lesions. Journal of Neurolinguistics, 13: 173–188, 2000. Fabbro F, Tavano A, Corti S, Bresolin N, De Fabritiis P, and Borgatti R. Long-term neuropsychological deficits after cerebellar infarctions in two young adult twins. Neuropsychologia, 42: 536–545, 2004. Folstein M, Folstein S, and McHugh P. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12: 189–198, 1975. François J, Lentini F, and De Rouck F. Gillespie’s syndrome (incomplete aniridia, cerebellar ataxia and oligophrenia. Ophthalmic Paediatrics and Genetics, 4: 29–32, 1984. Gasparini M, Di Piero V, Ciccarelli O, Cacioppo MM, Pantano P, and Lenzi GL. Linguistic impairment after right cerebellar stroke: a case report. European Journal of Neurology, 6: 353–356, 1999. Gillespie FD. Aniridia, cerebellar ataxia, and oligophrenia in siblings. Archives of Ophthalmology, 73: 338–341, 1965. Glaser T, Ton CCT, Mueller R, Petzl-Erler ML, Oliver C, Nevin NC, Housman DE, and Maas RL. Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation). Genomics, 19: 145–148, 1994. Golden JC. Stroop Color and Word Test. Chicago, IL: Stoelting Co, 1978. Goodglass H and Kaplan E. The Assessment of Aphasia and Related Disorders. Philadelphia: Lea and Febiger, 1983. Graetz P, De Bleser R, and Willmes K. De Akense Afasie Test. Lisse: Swets & Zeitlinger, 1992. Guzetta F, Mercuri E, Bonanno S, Longo M, and Spano M. Autosomal recessive congenital cerebellar atrophy. A clinical and neuropsychological study. Brain and Development, 15: 439– 445, 1993. Heaton RK, Chelune GJ, Talley JL, Kay GG, and Curtis G. Wisconsin Card Sorting Test (WCST) Manual Revised and Expanded. Odessa, FL: Psychological Assessment Resources, 1993. Hillis AE, Work M, Barker PB, Jacobs MA, Breese EL, and Maurer K. Re-examining the brain regions crucial for orchestrating speech articulation. Brain, 127: 1479–1487, 2004. Hooper HE. Hooper Visual Organisation Test. Los Angeles: Western Psychological Services, 1983. Jordan T, Hanson I, Zaletyev D, Hodgson S, Prosser J, Seawright A, Hastie N, and van Heyningen V. The human PAX6 gene is mutated in two patients with aniridia. Nature Genetics, 1: 328–332, 1992. Kaplan E, Goodglass H, and Weintraub S. The Boston Naming Test. Philadelphia: Lea and Febiger, 1983. Kieslich M, Vanselow K, Wildhardt G, Gebhardt B, Weis R, and Böhles H. Gegenwärtige Grenzen der molekularbiologischen Diagnostik bei Gillespie-Syndrom. Klinische Pädiatrie, 213: 47–49, 2001. Lebrun Y. Apraxia of speech: a critical review. Journal of Neurolinguistics, 5: 379–406, 1990. Lechtenberg R and Ferretti C. Ataxia with aniridia of Gillespie: a case report. Neurology, 31: 95–97, 1981. Leggio MG, Silveri MC, Petrosini L, and Molinari M. Phonological grouping is specifically affected in cerebellar patients: a verbal fluency study. Journal of Neurology, Neurosurgery, and Psychiatry, 69: 102–106, 2000. Leggio MG, Solida A, Silveri MC, Gainotti G, and Molinari M. Verbal fluency impairments in patients with cerebellar lesions. Society for Neuroscience Abstracts, 21: 917, 1995. Levinsohn L, Cronin-Golomb A, and Schmahmann JD. Neuropsychological consequences of cerebellar tumor resection in children: Cerebellar cognitive affective syndrome in a paediatric population. Brain, 123: 1041–1050, 2000. Lezak MD. Neuropsychological Assessment. 3rd ed. New York: Oxford University Press, 1995. Luria A and Tsvetkova L. Towards the mechanisms of ‘dynamic aphasia’. Acta Neurologica et Psychiatriatrica Belgica, 67: 1045–1057, 1967. Mariën P, Engelborghs S, Pickut BA, and De Deyn PP. Aphasia following cerebellar damage: Fact or fallacy? Journal of Neurolinguistics, 13: 145–171, 2000. Mariën P, Mampaey E, Vervaet A, Saerens J, and De Deyn PP. Normative data for the Boston Naming Test in native Dutch-speaking Belgian elderly. Brain and Language, 65: 447– 467, 1998. cortex 44 (2008) 54–67 Mariën P, Saerens J, Nanhoe R, Moens E, Nagels G, Pickut BA, Dierckx RA, and De Deyn PP. Cerebellar induced aphasia: case report of cerebellar induced prefrontal aphasic language phenomena supported by SPECT findings. Journal of the Neurological Sciences, 144: 34–43, 1996. Mariën P, Verhoeven J, Engelborghs S, Pickut BA, and De Deyn PP. A role for the cerebellum in motor speech planning: Evidence from Foreign accent syndrome. Clinical Neurology and Neurosurgery, 108: 518–522, 2006. Mariën P and Verhoeven J. Cerebellar involvement in motor speech planning: some further evidence from foreign accent syndrome. Folia Phoniatrica et Logopaedica, 59: 210–217, 2007. Nelson J, Flaherty M, and Grattan-Smith P. Gillespie syndrome: a report of two further cases. American Journal of Medical Genetics, 71: 134–138, 1997. Nevin NC and Lim JHK. Syndrome of partial aniridia, cerebellar ataxia, and mental retardation – Gillespie syndrome. American Journal of Medical Genetics, 35: 468–469, 1990. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia, 9: 97–113, 1971. Osterrieth PA. Le Test de Copie d’une Figure Complexe. Neuchâtel: Delachaux & Niestlé, 1944. Parks RW, Loewenstein DA, Dodrill KL, Barker WW, Yoshii F, Chang JY, Emran A, Apicalla A, Shermata WA, and Duara R. Cerebral metabolic effects of a verbal fluency test: a PET scan study. Journal of Clinical and Experimental Neuropsychology, 10: 565–575, 1988. Perret E. The left frontal lobe of man and the suppression of habitual responses on verbal categorical behavior. Neuropsychologia, 12: 323–330, 1974. Pollack I, Polinko P, Albright A, Towbin R, and Fritz C. Mutism and pseudobulbar symptoms after resection of posterior fossa tumours in children: Incidence and pathophysiology. Neurosurgery, 37: 885–893, 1995. Pryse-Phillips W. Companion to Clinical Neurology. 2nd ed. New York: Oxford University Press, 2003. Ramier A-M and Hecaen H. Role respectif des attaintes frontales et la lateralisation lésionelle dans les deficits de la ‘‘fluence verbale’’. Revue Neurologique, 123: 17–22, 1970. Riddoch MJ and Humphreys GW. Birmingham Object Recognition Battery (BORB). Hove, East Sussex: Laurence Erlbaum Associates, 1993. Riva D and Giorgi C. The cerebellum contributes to higher cognitive function during development. Brain, 123: 1051–1061, 2000. Rosenbek JC. Verbal apraxia. In Fabbro F (Ed), Concise Encyclopedia of Language Pathology. Oxford: Pergamon, 1999. Ruff RM, Allen CC, Farrow CE, Niemann H, and Wylie T. Figural fluency: Differential impairment in patients with left versus 67 right frontal lobe lesions. Archives of Clinical Neuropsychology, 9: 41–55, 1994. Sarsfield JK. The syndrome of congenital cerebellar ataxia, aniridia and mental retardation. Developmental Medicine and Child Neurology, 13: 508–511, 1971. Schmahmann JD. The role of the cerebellum in affect and psychosis. Journal of Neurolinguistics, 13: 189–214, 2000. Schmahmann JD and Pandya DN. The cerebrocerebellar system. In Schmahmann JD (Ed), International Review of Neurobiology: the Cerebellum and Cognition, vol. 41. San Diego, CA: Academic Press, 1997: 31–60. Schmahmann JD and Sherman JC. The cerebellar cognitive– affective syndrome. Brain, 121: 561–579, 1998. Silveri MC, Leggio MG, and Molinari M. The cerebellum contributes to linguistic production: a case of agrammatic speech following a right cerebellar lesion. Neurology, 44: 2047–2050, 1994. Steinlin M, Styger M, and Bolthauser E. Cognitive impairments in patients with congenital nonprogressive cerebellar ataxia. Neurology, 53: 966–973, 1999. Steinlin M, Zangger B, and Bolthauser E. Non-progressive congenital ataxia with or without cerebellar hypoplasia. Developmental Medicine and Child Neurology, 40: 148–154, 1998. Tellegen PJ, Winkel M, Wijnberg-Williams BJ, and Laros JA. Snijders-Oomen Niet-verbale Intelligentietest (SON-R). Lisse: Swets Test Publishers, 1998. Van Harskamp NJ, Rudge P, and Cipolotti L. Cognitive and social impairments in patients with superficial siderosis. Brain, 128: 1082–1092, 2005. Verhoeven J, De Pauw G, and Kloots H. Speech rate in a pluricentric language situation: a comparison between Dutch in Belgium and the Netherlands. Language and Speech, 47: 297–308, 2004. Verhulst S, Smet H, Ceulemans B, Geerts Y, and Tassignon MJ. Gillespie syndrome, partial aniridia, cerebellar ataxia, and mental retardation in mother and daughter. Bulletin Société Belge d’ Ophtalmologie, 250: 37–42, 1993. Vieijra JPM, Gerdien CJ, and König CE. PINOK: Neuropsychologisch Onderzoek bij Kinderen. Lisse: Swets & Zeitlinger, 1992. Wechsler D. Manual for the Wechsler Memory Scale-Revised. New York: Psychological Corporation, 1987. Wechsler D. Wechsler Intelligence Scale for Children. 3rd ed. London: The Psychological Corporation, 2002. Wechsler D. Handleiding WAIS Nederlandstalige bewerking. Lisse: Swets & Zeitlinger, 1970. Wittig EO, Moreira CA, Freire-Maia N, and Vianna-Morgante AM. Partial aniridia, cerebellar ataxia, and mental deficiency (Gillespie syndrome) in two brothers. American Journal of Medical Genetics, 30: 703–708, 1988. Zettin M, Cappa SF, D’Amico A, Rago R, Perino C, Perani D, and Fazio F. Agrammatic speech production after a right cerebellar haemorrhage. Neurocase, 3: 375–380, 1997.