Language skills and neuropsychological performance in patients with SHH mutations and a holoprosencephaly-like phenotype

Authors

  • Giselda Santiago,

    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
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  • Dagma Venturini Marques Abramides,

    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
    2. Department of Speech Pathology, University of São Paulo, Bauru, Brazil
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  • Luciana Paula Maximino De-Vitto,

    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
    2. Department of Speech Pathology, University of São Paulo, Bauru, Brazil
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  • Lucilene Arilho Ribeiro,

    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
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  • Silvio Garcia Meira Jr,

    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
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  • Antonio Richieri-Costa

    Corresponding author
    1. Division of Clinical Genetics, Hospital de Reabilitação de Anomalias Craniofaciais, University of São Paulo, Bauru, Brazil
    • HRAC-USP, PO Box 620, Rua Silvio Marchione 320, CEP 17012-900, Bauru, SP, Brasil.
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  • How to cite this article: Santiago G, Abramides DVM, De-Vitto LPM, Ribeiro LA, Meira SG Jr, Richieri-Costa A. 2006. Language skills and neuropsychological performance in patients with SHH mutations and a holoprosencephaly-like phenotype. Am J Med Genet Part A 140A:2085–2090.

Abstract

Here, we evaluate linguistic skills and neuropsychological performance in a sample of patients with SHH mutations and a holoprosencephaly (HPE)-like phenotype, a minor form of classic HPE. Our findings suggest that patients with SHH mutations and a HPE-like phenotype have normal cognitive ratios and significant language impairment. Imaging evaluation by magnetic resonance imaging (MRI) was normal in three patients and in one there was hypoplasia of the anterior commissure and the presence of a temporal cyst, apparently not related to the clinical findings. © 2006 Wiley-Liss, Inc.

INTRODUCTION

Central nervous system embryogenesis requires a highly integrated process in the specification of type, timing, and location of molecules that regulate different stages of development from neuronal induction to synapse formation, resulting in a normal structural and functional brain [Wilkie and Morriss-Kay, 2001; Lacbawan and Muenke, 2002].

During the last decade, the increasing amount in electrophysiological, neuropsychological, neuroimaging, and molecular genetics studies have stressed the importance of the frontal cortex in speech/language areas. During the evolution of mammalian species, the neocortex, and speech and hearing areas became larger and more complex, especially in humans. The prefrontal cortex is particularly critical for specific cognitive capabilities that require working memory, planning, and selective attention [Hashimoto and Sakai, 2002; Sakai et al., 2003; Winterer and Goldman, 2003; Poeppel and Hickok, 2004]. The role of genetics in human prefrontal function is complex and a large number of genes might be involved [Winterer and Goldman, 2003].

Our main purpose is to investigate language skills and neuropsychological performance in patients with SHH mutations and a holoprosencephaly (HPE)-like phenotype, a minor form of classic HPE. Here, we report on four patients.

MATERIALS AND METHODS

Subjects

This study was approved by the Ethics Committee of the Hospital de Reabilitação de Anomalias Craniofaciais (HRAC) after obtaining informed consent for four unrelated Brazilian patients (two boys and two girls), ranging in age from 4 to 18 years old. They were evaluated at the Clinic of Speech/Hearing Genetics of the HRAC in a prescreened sample of patients [Ribeiro et al., 2004; Richieri-Costa and Ribeiro, 2006], and were selected for having SHH mutations and facial signs of the HPE-like phenotype, consisting of a hypoplastic premaxilla, hypoplastic nose with flattened alae and nasal tip, poorly developed philtrum, single maxillary central incisor, cleft lip/palate, and malocclusion. Imaging evaluation by magnetic resonance imaging (MRI), formal audiological evaluation (auditory brainstem response, tympanometry, and tonal audiometry), and language and cognitive skills were studied. Characteristics of the population are summarized in Table I.

Table I. Data of Patients With SHH Mutations
SubjectsAge (years)GenderScholarshipSHH mutation
119F2nd gradeH140Q
214MElementary school 8th yearS280X
3 8MElementary school 2nd yearC363Y
4 4FPre-schoolL218P

PROCEDURES

Intelligence Assessment

Intelligence was assessed by the Wechsler Pre School and Primary Intelligence Scale (WPPSI) [Wechsler, 1967] for those less than 6 years, Wechsler Intelligence Scale for Children (WISC-III) [Wechsler, 1991] for those between 6 and 16 years 11 months, and Wechsler Adult Intelligence Scale (WAIS) [Wechsler, 1981] for those above 17 years. Results are given in Verbal Intelligence Quotient (VIQ), Performance Intelligence Quotient (PIQ), and Full Intelligence Quotient (FIQ). Normal values according to WHO ranges ≥70 [World Health Organization the ICD–10, 1992].

Audiometric Tests

Pure tone audiometry, tympanometry, otoacoustic emissions, and auditory brain evoked responses were performed in all patients.

Language Assessment

Three standardized language tests were used, according to the patient's age and specific criteria of each test: Illinois Test of Psycholinguistic Abilities (ITPA), Token Test Receptive Language, and Academic Performance Test (APT) for writing language. Communicative abilities and oral language skills (phonological, semantic, syntactic, and pragmatic aspects) were priorities for evaluation [Kirk et al., 1968, 1978; Carroll, 1972].

Each patient's behavior during communicative activities was analyzed by simple tasks for comprehension and joining/keeping/starting a conversation.

Oral language evaluation was evaluated by directed activities and automatic speech (counting from 1 to 20, saying the days of the week or the months of the year) at all language levels: phonologic, semantic, syntactic, and pragmatic. Verbal understanding evaluation also involved all language levels. Reception and emission, and phonological awareness were required for the use of syntactic rules and lexical identification.

Standardized language tests performed after clinical evaluation and analysis of the obtained data. The following procedures were used:

  • (1)Illinois Test of Psycholinguistic Abilities: used to evaluate communicative process-related abilities. It was divided into 12 subtests that allow assessment of visual and auditory reception; visual and auditory sequencing memory; visual and auditory association; visual, auditory, and grammatical closure; verbal and manual expression and sound combinations. By interpreting ITPA results, we were able to quantify and compare the performance and skills of the patients in relation to language and communicative process.
  • (2)Token Test for receptive language: used to measure understanding abilities by presenting 20 symbols, differing in form (square or circle), size (large or small), and color (black, white, yellow, green, and red).
  • (3)Academic Performance Test: used to evaluate required skills for scholarship accomplishment, more specifically writing, reading, and arithmetic. Results were recorded in specific protocols. Required tasks included dictation, mathematic operations, and solving complex situations presented verbally by the therapist or by a text.

Magnetic Resonance Imaging Evaluation

All subjects had undergone brain MRI in a 1.0-tesla unit (Philips Gyroscan) in axial (T1, T2, and Flair), sagittal (T1), and coronal sequences (T2).

RESULTS

Intelligence Assessment

Table II shows the values obtained in the evaluation of the IQs in the four patients with SHH mutations. All patients were found to have IQ scores in the normal range according to the OMS values. Patients 2 and 3 had marked impairment in the digit span subtest, showing deficits in working memory. Patient 3 had significant discrepancy between VIQ and PIQ.

Table II. Psychological and Language Evaluation Results
SubjectsVIQPIQFIQLanguage evaluation
011059499Normal
02108104105Normal
03988289Learning disability
04948688Language disorder

Audiometric Tests

Standard baseline audiometric tests were within normal ranges in the four patients.

Language Evaluation

Language evaluation showed impairment in different language skills at different levels. All patients had been referred as having delayed speech development.

Results of testing are provided in Tables II–VI. Subjects 1 and 2 showed normal performance by clinical evaluation with a full range of sounds, proper grammar, and proper semantics in spontaneous speech. Conversational interaction during testing showed normal speech, language, and communicative performance. Normal performance was observed in the ITPA, Revised Token Test, and APT. Cognitive evaluation by WISC-III (subject 1) and WAIS (subject 2) were within the normal range.

Table III. Characterization of Language Deficits
SubjectsAge (years)Oral languageWritten languageReasoning
SyntacticSemanticPhonologicPragmaticReadingWritingDisgraphyLogicMathematic
  1. −, normal; +, impaired; /, no evaluation.

0118
0214
03 8+++++++++
04 4++++/////
Table IV. Scalar Scores (SS) Values and Psycholinguistic Age (PLA) in Each Skill and Composed Psycholinguistic Age (CPA) Obtained in ITPA of Patients
SubjectsITPARepresentational levelAutomatic level
ReceptionAssociationExpressionClosureSequential memorySupplementary subtests
AuditoryVisualAuditoryVisualVerbalManualGrammaticalVisualAuditoryVisualAuditory closureSound combination
3SS3138303524322634291934 28
 PLA 6 8 6 7 2 6 4 7 4 6 7 3
4SS3233283032283632313226 29
 PLA 2 3 3 3 2↓2 3 3 2 2 2↓2y
Table V. Representation Token Test
SubjectsScoreClassification
135Medium
236Medium
329Medium
4 2Grave
Table VI. Representation of Normal (N) Scores Comparing to Obtained (O) Scores in Subjects 1, 2, and 3 (S)
SWritingArithmeticReadingTotalClassification
NONONONO
1≥3034≥2333≥6870≥119137Medium-superior
2≥3034≥2325≥6870≥119129Medium
3≤190≤90≤570≤860Inferior

Clinical evaluation in subjects 3 and 4 showed impairment in all levels: syntactic, semantic, phonological, and pragmatic. Evaluation of subject 3 also showed learning impairment in oral and written language, and in perpetual procedures. Subject 4 showed marked oral language impairment.

Illinois Test of Psycholinguistic Abilities

Table IV shows the results obtained in the 12 subtests of ITPA by analyzing scalar scores (SS) and psycholinguistic age (PLA). Normal SS for comparative data among subjects is 36, with a variation of 2 [Bogossian and Santos, 1977].

For the analysis of abilities profile (Table IV), we used the difference between each subtest SS and the mean SS to determine whether the subjects had impairment of evaluated skills or not.

ITPA evaluation in subject 3 showed abnormal auditory reception, visual and auditory association, visual and auditory grammatical closure, verbal and manual expression, and visual and auditory sequential (sequencing) memory. The same findings were present in subject 4 with additional visual reception impairment.

Token Test

The results of subject 3 were within the normal range. Subject 4 had very low scores due to severe impairment of visual and auditory reception.

Academic Performance Test

This test was performed in subjects 1, 2, and 3. All evaluated abilities in subject 3 were abnormal. The APT was normal in subjects 1 and 2. Subject 4 was too young for this procedure. Subject 3 had lower scores than expected for his academic level. Correlation between normal cognition and poor academic performance can be attributed to impaired linguistic and perceptual abilities.

Image Evaluation

Imaging evaluation in subjects 1, 2, and 4 was within normal ranges. However, subject 3 had a hypoplastic anterior commissure and a left temporal cyst (Fig. 1). These findings in subject 3, who had the poorest performance in all the tests, might reflect a positive correlation between structural anomalies and clinical findings.

Figure 1.

MRI of patient 3 showing hypoplastic anterior commissure (a) and left temporal cyst (b).

DISCUSSION

The main finding in our study is that despite small sample size, patients with SHH mutations and an HPE-like phenotype, have normal cognitive ratios and significant language impairment. All patients had delayed language development compared to the normal population. These delays included syntactic, semantic, phonologic, and pragmatic problems. However, cognitive performance was normal in all subjects, whereas language evaluation was markedly impaired in subjects 3 and 4. Additional studies are necessary to understand the higher cortical functioning in patients with SHH mutations.

The clinical expression of HPE is quite variable, ranging from severe forms to minor forms in individuals who usually have normal cognition and normal brain imaging with the HPE-like phenotype. However, some obligate carriers may not have any phenotypic abnormalities [Cohen, 2001; Heussler et al., 2002; Roessler et al., 2003; Dubourg et al., 2004; Lazaro et al., 2004]. Variability in clinical expression has been attributed, in some instances, to temporal perturbations in sonic hedgehog signaling [Cordero et al., 2004]. However, other mechanisms may be involved [Heussler et al., 2002; Granata et al., 2005]. In recent years, increasingly interest has focused on genetic causes, mainly those related to CNS development [Cohen, 2001, 2003] and function [Charytoniuk et al., 2002; Hashimoto-Torii et al., 2003; Palma et al., 2005]. CNS higher functions involving hedgehog signaling have been reported infrequently [Hashimoto-Torii et al., 2003]. SHH and SIX3 contribute to proliferation, differentiation, and axon growth [Marti and Bovolenta, 2002; Li and Rosenfeld, 2004], but the functional significance in different regions of the CNS remains largely unknown.

Revolutionary studies in functional MRI have stressed the importance of the main cerebral areas in language acquisition and development [Etchepareborda and Lopez-Lazaro, 2005; Juch et al., 2005]. It has been suggested that a significant portion of the active frontal areas is recruited for extracting acoustic information and maintaining it in memory for decision, and that some regions at the border of the inferior/middle frontal gyrus may be unique to speech segmentation [LoCasto et al., 2004].

Few studies have been devoted to structural or morphogenetic genes related to CNS development and their relationship to specific brain functions. Recently, abnormal cognitive functioning and deficient auditory interhemispheric transfer were reported in patients with PAX6 mutations. PAX6 is a critical gene for development of the eye and brain and it is involved in cellular proliferation, neuronal migration, and axonal guidance [Bamiou et al., 2004; Ellison-Wright et al., 2004; Thompson et al., 2004]. The wide expression of SHH during CNS development [Dahmane and Ruiz-i-Altaba, 1999; Corrales et al., 2004; Sotelo, 2004] led us to consider the present group of patients as a model to study some basic aspects of higher CNS function, such as cognition and language.

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