preliminary communication: neuroanatomical variations of the posterior fossa in men with the fragile...

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American Journal of Medical Genetics 31:407-414 (1988) Preliminary Communication: NeuroanatomicalVariations of the Posterior Fossa in Men With the Fragile X (Martin-Bell) Syndrome Allan L. Reiss, Shilpesh Patel, Ashok J. Kumar, and Lisa Freund The Johns Hopkins University School of Medicine Departments of Psychiatry (A. L. R., S. P., L.F.) and Radiology (A. J. K.) and The Kennedy institute (A. L. R.), Baltimore, Maryland Four men with fragile X (fra (X)), or Martin-Bell, syndrome were studied by magnetic resonance imaging (MRI) to determine whether detectable abnormalities of the cerebellum were present. The cerebellum was chosen because of the apparently increased tendency for fra (X) patients to demonstrate autistic behavior and accumulating evidence implicating cerebellar abnormalities in autism. Com- pared with a control group of four normal men, fra (X) patients had a significantly decreased area of the cerebellar vermis, particularly the posterior portion, on planimetric analysis in the midsagittal plane. The pons and fourth ventricular areas also were decreased and increased, respectively, in the fra (X) men. Neuroanatom- ical and animal research increasingly implicates the cerebellar vermis as an important component in functional brain systems subserving sensory and motor integration, learning, and modulation of affect, motivation, and social behavior. Thus, vermis dysfunction could account for many of the behavioral and cognitive abnormalities observed in fra (X) males, particularly those which overlap with the behavioral syndrome of autism. Key words: fragile X syndrome, neuroanatomy, vermis, cerebellum, pons, autism, mental retardation INTRODUCTION The estimated incidence of nearly 1 per 1,OOO live born males for the fragile X (fra (X)) syndrome in the general population has served to stimulate research to Received for publication February 22, 1988; revision received April 18, 1988. Address reprint requests to Dr. Allan L. Reiss, Department of Developmental Neuropsychiatry, The Kennedy Institute, Room 106, 707 North Broadway Street, Baltimore, MD 21205. 0 1988 Alan R. Liss, Inc.

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American Journal of Medical Genetics 31:407-414 (1988)

Preliminary Communication: Neuroanatomical Variations of the Posterior Fossa in Men With the Fragile X (Martin-Bell) Syndrome

Allan L. Reiss, Shilpesh Patel, Ashok J. Kumar, and Lisa Freund

The Johns Hopkins University School of Medicine Departments of Psychiatry (A. L. R., S. P., L.F.) and Radiology (A. J. K.) and The Kennedy institute (A. L. R.), Baltimore, Maryland

Four men with fragile X (fra (X)), or Martin-Bell, syndrome were studied by magnetic resonance imaging (MRI) to determine whether detectable abnormalities of the cerebellum were present. The cerebellum was chosen because of the apparently increased tendency for fra (X) patients to demonstrate autistic behavior and accumulating evidence implicating cerebellar abnormalities in autism. Com- pared with a control group of four normal men, fra (X) patients had a significantly decreased area of the cerebellar vermis, particularly the posterior portion, on planimetric analysis in the midsagittal plane. The pons and fourth ventricular areas also were decreased and increased, respectively, in the fra (X) men. Neuroanatom- ical and animal research increasingly implicates the cerebellar vermis as an important component in functional brain systems subserving sensory and motor integration, learning, and modulation of affect, motivation, and social behavior. Thus, vermis dysfunction could account for many of the behavioral and cognitive abnormalities observed in fra (X) males, particularly those which overlap with the behavioral syndrome of autism.

Key words: fragile X syndrome, neuroanatomy, vermis, cerebellum, pons, autism, mental retardation

INTRODUCTION

The estimated incidence of nearly 1 per 1,OOO live born males for the fragile X (fra (X)) syndrome in the general population has served to stimulate research to

Received for publication February 22, 1988; revision received April 18, 1988.

Address reprint requests to Dr. Allan L. Reiss, Department of Developmental Neuropsychiatry, The Kennedy Institute, Room 106, 707 North Broadway Street, Baltimore, MD 21205.

0 1988 Alan R. Liss, Inc.

408 Reiss et al.

clarify the molecular-genetic, cytogenetic, cognitive, and behavioral aspects of this condition. Despite the fact that central nervous system (CNS) dysfunction leading to cognitive deficits and behavioral abnormalities is the primary cause of disability in the individual with fra (X) syndrome, little information is currently available about the neurobiology of this condition, particularly with respect to possible neuroanatom- ical abnormalities. To date, computerized tomographic analysis and neuropathological examination in a small number of individuals with fra (X) syndrome have demon- strated nonspecific findings such as ventricular enlargement and subtle abnormalities of cellular morphology and cytoarchitecture of the cortex [Rudelli et al., 1985; Veenema et al., 19871.

The question of whether a larger than expected percentage of males with the fra (X) syndrome meet stringent diagnostic criteria for autistic disorder has not been definitively answered. However, most behavioral studies do indicate that fra (X) males have a greater frequency of autistic behaviors compared with patients with a similar level of cognitive disability. The association of fra (X) with the behavioral syndrome of autism raises the possibility that data obtained from neurobiological investigations of autistic children may also be relevant to the fra (X) syndrome. Recently, neuroimaging and neuropathologic studies of autistic children have indi- cated that abnormalities of the cerebellum, particularly the cerebellar vermis, may be present in a subgroup of autistic individuals [Courchesne et al. , 1987; Jaeken and van der Berghe, 1984; Ritvo et al., 1986; Bauman and Kemper, 19851. Therefore, we initiated a pilot study to investigate cerebellar structure of men with the fra (X) syndrome.

PATIENTS AND METHODS

We studied four men with fra (X) syndrome, ranging in age from 19 to 31 years. The diagnosis of fra (X) syndrome was confirmed in each patient after chromosome analysis showed the presence of 20% or more of fra (X) cells in cultured lymphocytes. Composite IQ scores for the fra (X) men ranged from 36 to 68 on the Stanford-Binet Intelligence Scale, 4th Edition. Two of the four fra (X) men had a history of at least a moderate degree of autistic symptoms beginning in childhood, including extreme resistance to change, preoccupation with unusual sensory stimuli, motor stereotypies and deficits in social interaction. Only one of the four met DSM-111-R diagnostic criteria for “pervasive developmental disorder.” None of the fra (X) men had been exposed to cerebellar toxic events or agents, including perinatal anoxia, lead toxicity, malnutrition, hypothyroidism, or chronic treatment with phenytoin. There was no history of familial neurologic disease in the relatives of the fra (X) patients. Four normal men aged 21 to 32, with normal IQ and no evidence of developmental disability, served as the comparison group. All procedures followed were in accord with the ethical standards of the Joint Committee on Clinical lnvestigation of Johns Hopkins University.

MR images were obtained with a General Electric 1.5-T Signa System. TI weighted interleaved (consecutive) images, 5 mm thick, were generated in the sagittal and axial planes with a TR of 600-800 msec, TE of 20 msec, two excitations, 24-cm field of view, and a 256 X 256 matrix.

For planimetric analysis of area, a 12.7-cm X 17.3-cm print of the midsagittal slice was made at a standardized magnification and with all patient-identification

Neuroanatomy of Fragile X Syndrome 409

marks deleted. A high-resolution image of this photograph was then digitized onto an Apple Macintosh SE computer at a 1 : 1 magnification with the program Thunderscan. The areas of selected brain regions were then traced and automatically calculated in square millimeters with the program Macdraft. This procedure allowed for precise tracing of small detail of various structures through on-screen magnification of the image. Volumetric analysis of a brain structure was accomplished through similar computer procedures and calculated by multiplying the sum of the total area of sequential images in the axial plane by the slice thickness.

For certain brain structures, such as the cerebellar vermis, only planimetric analysis was possible because of the presence of indeterminate lateral borders in the axial plane. The vermis was divided into anterior 'and posterior portions by identifi- cation of the primary fissure. Thus, the anterior vermis contained lobules 1 through 5, and the posterior portion lobules 6 through 10. The paravermian space is defined here as the neuroanatomical area identified in the midsagittal plane that contains the vermis and surrounding CSF spaces (superior cerebellar cistern, fourth ventricle, and cerebellomedullary (rnagna) cistern).

All analyses were performed independently by two raters who were blinded as to whether the brain image being analyzed was from a fra (X) or control individual. Each rater made several tracings of the neuroanatomical areas of interest for each subject. For the neuroanatomical areas described here, intrarater reliability was 20.99, whereas interrater reliability was 2 0.96. As another means of examining the strong impression of important differences in the size of specific neuroanatomical areas between the fra (X) and control subjects obtained from descriptive and visual inspection of the data, statistical comparisons between the two groups were made with an independent t-test with a two-tailed significance level of P < .05. Despite the use of a rigorous statistical test, the small number of individuals participating in this study means that the statistical analysis be interpreted as supplementary rather than confirmatory.

RESULTS

Table I demonstrates the areas and volumes of specific CNS structures in the fra (X) and comparison men. The most striking difference was the decreased area of the vermis in fra (X) subjects, particularly the posterior portion, as determined by planimetric measurement in the midsagittal plane. The ratios of posterior vermis to anterior vermis and posterior verrnis to paravermian area shown in the table highlight the distortion of normal vermal anatomy occurring in the fra (X) men. Figure 1 shows the most prominent example of decreased size of the vermis in a fra (X) man with a comparative midsagittal scan of a control subject. Figure 2 demonstrates the distri- bution of individual values obtained from fra (X) and comparison subjects. There is no overiap between the two groups in the range of values obtained for posterior vermis or posterior to anterior vermis ratio. Within the fra (X) group of men, the one with the highest full-scale IQ (68) also had the largest posterior to anterior vermis ratio.

Planimetric measures of fourth ventricular and pontine areas were significantly larger and smaller, respectively, in fra (X) men. A decrease in the anterior-posterior (width) dimension of the pons (t = -2.84, P = .03) as opposed to the superior- inferior (length) dimension (t = - 1.32, P = . 23) appeared to account for most of

410 Reiss et al.

TABLE I. Measurements of Neuroanatomicat Areas and Volumes in Fragile X and Control Subjects

Fragile X men Control men (n = 4) (n = 4)

Mean S.D. Mean S.D. P

Planimetric Measures (cm’) Vermis total 8.16 1.02 11.56 2.20 .03 1 Anterior vermis 3.80 0.46 4.70 1.02 NS Posterior vermis 4.34 0.64 6.84 1.20 .011 Fourth ventricle 2.30 0.22 1.52 0.42 .034 Pons 5.52 0.50 6.42 0.30 ,020 Corpus callosum 7.06 0.96 7.76 1.10 NS Paravermian 23.52 2.38 23.52 4.04 NS Cortical 88.40 6.92 92.86 6.94 NS Intracranial 183.44 9.62 194.38 16.20 NS

Cerebellum 147.94 8.23 142.90 12.75 NS Pons 15.13 1.85 16.19 I .45 NS

Posterior vermis:anterior vermis 1.149 0.148 1.465 0.081 .009 Posterior vermis:paravermian 0.187 0.036 0.292 0.043 ,009 Posterior vermis:intracranial 0.024 0.004 0.035 0.005 ,013

Volumetric measures (cm3)

Ratios

the decrease in area in fra (X) men. Pontine volume was not significantly different between the two groups of men. As predicted, planimetric and volumetric analyses of other structures and areas did not show significant differences between the two groups of men.

DISCUSSION

Despite the small number of subjects in this study, the size of the cerebellar vermis, particularly the posterior portion was found to be significantly smaller in fra (X) subjects compared with normal control men. Decreased pontine size in fra (X) subjects was also detected on planimetric analysis in the midsagittal plane. Volumetric analysis of the pons taken from axial images through the brainstem did not show a statistically significant difference between the two groups of men. This finding may be accounted for by two factors: 1) the anterior-posterior and superior-inferior borders of the pons are readily apparent in the midsagittal plane, whereas the lateral borders of this structure can be difficult to define in certain axial images, 2) the thickness of the slices (5 mm) made it difficult to judge where the superior and inferior borders of the pons occurred in volumetric analysis. This was demonstrated by the significant correlation between pontine volume and pontine width (r = 0.76, P < .05) and the lack of association between pontine volume and length ( r = 0.12, NS). Thus, there was a greater probability of error in volumetric analysis, compared with planimetric computation. Other structures measured by planimetric or volumet- ric analyses showed no differences between the fra (X) and control men. The difference in vermis size is particularly highlighted by the fact that total cerebellar volume was essentially equivalent in the two groups. Although more subtle abnor-

Neuroanatomy of Fragile X Syndrome 411

Fig. I . Midsagittal MRI scans in (A) normal subject and (B) fragile X subject (V = cerebellar vermis; P = pons).

412 Reiss et al.

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Fig. 2. Range of values in fragile X and control groups for the vermis, posterior vermis, and posterior- to-anterior vermis ratio. Solid circle (0) represents fra (X) individual; open circle (0) represents control individual.

malities in synaptogenesis, cytoarchitecture, or myelinization undetectable by brain imaging techniques cannot be ruled out in this study, these data suggest that neuro- pathological processes occurring in males as a result of the fra (X) mutation particu- larly affect the cerebellar vermis rather than the entire cerebellum or whole brain.

The co-occurrence of reductions in vermis and pontine areas can be explained by the fact that both structures have a common embryologic origin [Ghez and Fahn, 19851. Also, it is well known that the vermis makes extensive and reciprocal connec- tions with the pons [Ghez and Fahn, 19851. Thus, loss of cellular material in one area is likely to be associated with decreases in size of the other area. The relationship between vermis and pontine size was demonstrated by correlational analysis showing a positive association between pontine volume and vermis (r = 0.76, P < .05) and pontine area and vermis (r = 0.72, P < .05). Increased size of the fourth ventricle in the fra (X) patients is most likely due to hypoplasia or loss of brain matter in adjacent pontine and vermis structures. This was also shown by a negative association between pontine area and fourth ventricular size in the fra (X) group ( r = 0.97, P c .05).

Cognitive deficits in fra (X) males usually take the form of moderate to severe mental retardation, with particular weakness in sequencing skills and response to novel stimuli [Kemper et al., 19871. Autistic behaviors frequently observed in fra (X) males include motor abnormalities, such as stereotypies and hyperactivity, sensory- modulation disturbances , and qualitative abnormalities in communication, affect and social relating. The question that must be asked is whether abnormal development or function of the vermis is associated with all or some of these problems.

The vermis receives major afferents from vestibular nuclei, spinal and trigemi- nal sensory tracts, and multiple cortical sensory areas [Ghez and Fahn, 19851. Efferents from the vermis are primarily relayed through the fastigial nuclei of the cerebellum to the spinal cord, brainstem reticular formation, pontine vestibular nuclei, thalamus, cortex, and limbic structures such as the hippocampus, amygdala, and hypothalamus [Ghez and Fahn, 1985; Heath and Harper, 1974; Dietrichs, 19841. Laboratory animals in which vermis or fastigial nuclei lesions were produced experi-

Neuroanatomy of Fragile X Syndrome 413

mentally demonstrate abnormalities in behavior, including abnormal species-specific fear reactions [Supple et al., 19871, a lack of appropriate decrease in locomotor activity when presented with novel stimuli [Supple et al., 19871, and reduced social interaction [Berntson and Schumacher, 19801. Both animal and human data also increasingly implicate the cerebellum in general and the vermis in particular as participating in tasks related to learning and memory [Leiner et al., 1986; Teyler and Fountain, 1987; Leaton and Supple, 19861. These data suggest that the vermis may function as an important component in CNS networks subserving 1) processing and modulation of sensory and motor information; 2) modulation of affect, motivation, and social interaction; and 3) learning. Thus, vermis dysfunction could potentialIy be associated with many of the behavioral and cognitive features found in fra (X) males.

Vermis abnormalities have been reported as occurring in conjunction with other genetic and congenital syndromes. Examples include conditions such as the Dandy- Walker malformation and the Joubert syndrome[Friede and Boltshauser, 1978; Joub- ert et al., 19691. However, the profile of neuroanatomical abnormalities occurring in the posterior fossa and other brain regions in these conditions appears to be more severe and diffuse than that observed in the fra (X) men.

Because of small sample size, the findings presented here should be considered preliminary. However, the results do point to a need for further brain-imaging studies in larger numbers of adults and children with the fra (X) syndrome. In particular, the use of age and IQ matched individuals with developmental disabilities not due to fra (X) syndrome would demonstrate whether a particular pattern of abnormalities is specific to this condition. Further neuropathologic studies are also indicated in fra (X) individuals, with concentration on careful histologic examination of the posterior fossa. Although multiple neurotransmitters have already been implicated as occurring in the vermis, further elaboration of the neurochemistry of this region and associated areas is indicated. Lastly, psychophysiologic research investigating such other corre- lates of vestibular and brainstem function as eye movements and cardiorespiratory patterns may reveal abnormalities in fra (X) individuals.

ACKNOWLEDGMENTS

The authors thank Joseph T. Coyle, M.D., Mary Lou Oster-Granite, Ph.D., Lynne C. Huffman, M.D., and Seneith Cofield, B.A. for their assistance in prepara- tion of this manuscript. This research was supported in part by a National Institute of Mental Health Physician Scientist Award and a Johns Hopkins Clinician Scientist Award to Dr. Reiss and by the Surdna Foundation.

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Edited by John M. Opitz and James F. Reynolds