Journal of Child Neurology

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Fragile X Syndrome and Cerebral Perfusion Abnormalities: Single-Photon Emission Computed Tomographic Study Nimet Kabakus, Mustafa Aydin, Haluk Akin, Tansel Ansal Balci, Abdullah Kurt and Ersoy Kekilli J Child Neurol 2006; 21; 1040 DOI: 10.1177/7010.2006.00230 The online version of this article can be found at: http://jcn.sagepub.com/cgi/content/abstract/21/12/1040

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Journal of Child Neurology / Volume 21, Number 12, December 2006

Original Article

Fragile X Syndrome and Cerebral Perfusion Abnormalities: Single-Photon Emission Computed Tomographic Study Nimet Kabakus, MD; Mustafa Aydin, MD; Haluk Akin, MD; Tansel Ansal Balci, MD; Abdullah Kurt, MD; Ersoy Kekilli, MD Received July 27, 2005. Received revised Nov 12, 2005. Accepted for publication Dec 11, 2005. From the Departments of Pediatric Neurology (Drs Kabakus, Aydin, and Kurt), Genetic Medicine (Dr Akin), and Nuclear Medicine (Dr Balci), Firat University Faculty of Medicine, Elazig, Turkey, and Department of

Nuclear Medicine (Dr Kekilli), Inonu University Faculty of Medicine, Malatya, Turkey. Address correspondence to Dr Nimet Kabakus, Department of Pediatric Neurology, Firat University Faculty of Medicine, 23119 Elazig, Turkey. Tel: +90 424 241 62 30; fax: +90 424 238 80 96; e-mail: nimetkabakus@ yahoo.com.

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Fragile X Syndrome and Cerebral Perfusion / Kabakus et al

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ABSTRACT Fragile X syndrome is an inherited disorder caused by a defective gene on the X chromosome. It is associated with developmental or behavioral symptoms and various degrees of mental retardation. Morphologic abnormalities and altered perfusion of various brain areas can underlie these functional disturbances. The aim of this study was to investigate the cerebral perfusion state in patients with fragile X syndrome using single-photon emission computed tomography (SPECT). Structural and functional assessment was also performed by magnetic resonance imaging (MRI) and electroencephalography (EEG). Eight boys with cytogenetically confirmed fragile X syndrome (mean age 8.8 6 4.4 years, range 5–18 years), were included. All patients had mental retardation, with a mean IQ of 58.9 6 8.8 (range 40–68), and additional neurobehavioral symptoms. SPECT revealed cerebral perfusion abnormalities in six patients (75%), most commonly in the frontoparietotemporal area and prominent in the right hemisphere. The SPECT and EEG findings were concordant: hypoperfused areas in SPECT corresponded to regions of persistent slow-wave paroxysms on EEG. On the other hand, cranial MRI was abnormal qualitatively only in two patients (25%) showing cerebellar and vermal hypoplasia and cerebral hemispheric asymmetry. Our results indicate that cerebral perfusion abnormalities, which are correlated with electrophysiologic findings but not necessarily with anatomic abnormalities, can underlie the pathogenesis of the clinical findings observed in fragile X syndrome. (J Child Neurol 2006;21:1040–1046; DOI 10.2310/7010.2006.00230).

Fragile X syndrome is a genetic disorder caused by a mutation in the fragile X mental retardation 1 (FMR1) gene showing a semidominant inheritance. Behavior, learning, language, and memory problems are expected.1 The multisystemic changes of the disease are due to inhibition of the expression of the FMR1 gene and a deficiency or an absence of the fragile X mental retardation protein.2 The fragile X mental retardation protein is a selective ribonucleic acid (RNA) binding protein implicated in regulating translation of its messenger RNA ligands. Fragile X mental retardation protein plays critical roles in controlling cytoskeleton organization and might underlie the pathogenesis of fragile X mental retardation.3 A relationship might exist between the neurobehavioral findings and the structural and functional abnormalities of the different areas of the central nervous system in fragile X syndrome.4–10 We investigated the possible cerebral perfusion abnormalities by single-photon emission computed tomography (SPECT) in combination with clinical, electroencephalographic (EEG), and magnetic resonance imaging (MRI) data.

neous sleep whenever possible or during sleep induced with chloral hydrate. MRI was performed on a 1.5-Tesla open scanner (High Speed Model, General Electric Signa) with 3 mm slice thickness.

SPECT Examination For brain SPECT perfusion imaging, 740 mBq

99m

Tc-HMPAO (Frederic

Joliot-Curie National Research Institute, Budapest, Hungary) was injected intravenously in a tranquil place with dimmed light, after about a 30-minute rest with the patients’ eyes closed and ears occluded and within 15 minutes after placement of an intravenous line. It was performed using a twoheaded gamma camera (Adac Vertexplus V-60) equipped with a highresolution, low-energy collimator that permits a spatial resolution of 9.5 mm full width at half-maximum. The projection data were acquired for 25 seconds per projection at 60 equal angles of a complete revolution (0– 360). Data were obtained from the keV photo peak (20% window) and a 64 3 64 matrix and zoom factor of 1.85. Reconstruction was performed by filtered back-projection using a gaussian filter (cutoff frequency 0.38 cycle/ cm, order 20) with attenuation correction by the Chang method. The slice thickness of SPECT samples was 6.3 mm. After reconstruction, orbitomeatal transaxial, coronal, sagittal, and parallel to the central gyrus 99mTc-

MATERIALS AND METHODS

HMPAO SPECT images were obtained. Visual SPECT analysis was done on the basal nuclei, thalamus, and all cortical areas in the coronal, sagittal, and

Subjects This study was performed on eight patients with fragile X syndrome

orbitomeatal transaxial images.

diagnosed cytogenetically by lymphocyte culture in the presence of a folic acid antagonist. Patients were evaluated in detail for developmental

Data Analysis

milestones, perinatal events, cause of referral, family structure and history,

The data were demonstrated as mean 6 standard deviation and analyzed

and the presence of comorbidities, such as seizures. After detailed physical

statistically using the SPSS program, version 11.0 (SPSS Inc, Chicago, IL).

and neurologic examinations and general laboratory investigations,

Spearman’s correlation analysis was used for evaluation of the relation-

psychometric tests, EEG, MRI, and SPECT were performed. Institutional

ship between some parameters.

ethics approval and permission from the parents were obtained. The Leiter International Performance Scales-Revised, Stanford-

RESULTS

Binet Intelligence Scale, Vineland Social Maturity Scale, and Diagnostic and Statistical Manual of Mental Disorders-IV criteria were used for cognitive and behavioral assessment.11–13 Thirty-minute EEG recordings were made with the International 10-20 electrode system and a 10channel Nikon-Kohden device in a silent, private room during sponta-

Physical and Neuropsychiatric Findings The average age of the patients was 8.8 6 4.4 years (5–18 years). The most common physical findings were large ears (100%), an elongated face (n 5 6, 75%), a protruding mandible (n 5 5,

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Journal of Child Neurology / Volume 21, Number 12, December 2006

62.5%), and macro-orchidism (n 5 2, 25%). In addition, hypospadias, strabismus, myopia, and macrocephaly were seen, in one patient each (12.5%). All patients had mental retardation (100%). Their average IQ was 58.9 6 8.8 (range 40–68). Three cases (37.5%) had attention-deficit hyperactivity disorder (ADHD). Autism, social phobia, temper tantrum, stereotyped behavior with repetitive speech, and social anxiety were diagnosed, in one patient each (12.5%) (Table 1).

EEG and MRI Findings The EEG was normal in two patients (25%) and abnormal in six (75%) patients. The majority of these abnormalities (n 5 5, 83.3%) consisted in persistent slow-wave paroxysms, whereas one (case 7) resulted from voltage suppression. Only one patient (case 8) had complex partial seizures (Table 3). Two patients (25%) had qualitative abnormalities detected on cranial MRI. These qualitative abnormalities were cerebellar vermal hypoplasia (case 5) and cerebral hemispheric asymmetria (case 6; right 699.2 . left 533.6 cm3) (Figure 4).

Laboratory Findings

Relationships Between EEG, MRI Findings, Neurobehavioral Symptoms, and IQ With SPECT Five of the patients with hypoperfused areas (83.3%) had persistent slow-wave paroxysms on EEG in the same area, and in one of them (case 7), diffuse voltage suppression was observed (see Table 3). One patient (case 6) who had left cerebral hypoperfusion on SPECT had left hemisphere hypoplasia, whereas one of the two patients with a normal SPECT result (case 5) had cerebellar and vermal hypoplasia on MRI. All patients had mental retardation and neurobehavioral problems. No significant relationship could be determined between SPECT findings and IQs. For instance, case 1, who had a normal SPECT result, had a lower IQ (40) than SPECTpositive cases (see Table 3). There was no relationship between IQ and age (r 5 .103).

SPECT Findings Areas with perfusion abnormality are listed in Table 2 and illustrated in Figures 1 to 3. Cerebral perfusion abnormalities were observed in six cases (n 5 6, 75%), whereas two patients’ (n 5 2, 25%) SPECT findings were normal. Of the 17 abnormal perfusion areas, 16 (94.1%) were hypoperfused and 1 (5.9%) was hyperperfused. Of the hypoperfused areas, nine (60%) belonged to the right hemisphere and six (40%) to the left hemisphere. The frontoparietotemporal area was the most frequently hypoperfused area (n 5 14, 82.4%). In only one case, hyperperfusion areas were found in the optic nerves and globes (n 5 1) and not in cerebral structures. The two patients with no perfusion abnormalities were the youngest of all of the patients. Table 1. Physical Findings and Neurobehavioral Symptoms of the Patients With Fragile X Syndrome

DISCUSSION

Physical Finding

n

%

Large ears Elongated face Protruding mandible Macro-orchidism Hypospadias Strabismus Myopia Macrocephaly

8 6 5 2 1 1 1 1

100.0 75.0 62.5 25.0 12.5 12.5 12.5 12.5

Neurobehavioral symptoms

n

%

Mental retardation ADHD Social phobia Temper tantrum Autism Stereotyped behavior and repetitive speech Social anxiety

8 3 1 1 1 1 1

100.0 37.5 12.5 12.5 12.5 12.5 12.5

Fragile X syndrome is a common form of mental retardation. More striking is the neurobehavioral phenotype: cognitive dysfunction, hyperactivity, distractibility, a lack of impulse control, perseveration, social deficits, communication abnormalities, and autistic behavior.4,6,14,15 Several studies showed that these neurobehavioral symptoms result from cerebral dysfunction in different areas of the brain.2,9,10,16 Neuropsychologic, functional, and structural imaging studies have suggested that large areas of the central nervous system, especially the cerebellum and frontal regions, are involved in fragile X syndrome.4,9,15–17 Also, selective changes in brain size have been shown, which include reductions in the posterior cerebellar vermis, age-dependent increases in hippocampal volume, and an enlarged caudate nucleus and thalamus.8 Neurobehavioral symptoms seen in these patients might result from morphologic or perfusion abnormalities of the different brain areas. Of those,

ADHD 5 attention-deficit hyperactivity disorder.

Table 2. Abnormal Cerebral Perfusion Regions According to Brain SPECT Findings in the Patients With Fragile X Syndrome Frontal Lobes Patient 2 3 5 6 7 8

L

R

+

+

Parietal Lobes L

+ +

R

+ + +

+

Frontoparietal Regions L

R

Temporal Lobes L

R

+

+ +

Occipital Lobes L

R

Other Brain Regions* + x

+ +

+ +

SPECT 5 single-photon emission computed tomography. *Basal ganglia, optic nerves, and globes. + 5 hypoperfused region. x 5 hyperperfused region.

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Fragile X Syndrome and Cerebral Perfusion / Kabakus et al

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Figure 1. Transaxial 99mTc-HMPAO single-photon emission computed tomographic image of patient 6 showing hypoperfusion in the left anterolateral region of the frontal cortex, right lateral region of the occipital cortex, and the left frontoparietal region. The arrows are showing the hypoperfused regions.

all of the hypoperfused regions belonged to cerebral tissues, whereas two hyperperfused regions belonged to optic nerves and globes. This might indicate an association between cerebral dysfunction and cerebral hypoperfusion in fragile X syndrome. Abnormalities in brain perfusion might be an effect or reflection of the underlying abnormalities in brain protein synthesis and other biochemical consequences of the genetic abnormalities. Abnormal cerebral perfusion was previously demonstrated in fragile X syndrome.9,10,15 In a SPECT study performed by Guerreiro et al on seven patients with fragile X syndrome aged between 8 and 19 years, all patients had hypoperfusion areas, most commonly in the frontal area, as well as in the cerebellum and parietal regions.9 Another study showed hypoperfusion in the frontal-subcortical structures.15 In this study, most of the hypoperfused areas seen in our patients were located in the frontoparietotemporal areas. These brain areas are responsible for formal intellectual ability; using initiative; making effort for an aim; concentration; critical capability; behaving harmoniously; imitating; optical, acoustic, and spacial perception; growth of symbolic thinking; reading, counting, and differentiating right from left; personalization; the accomplishment of past memory; and new impressions.9,14,15,17–19 Therefore, hypoperfusion of these areas might explain the cause of the neurobeha-

vioral symptoms seen dominantly in patients with fragile X syndrome. Poor concentration might result from frontal lobe dysfunction and cognitive defects from right hemisphere dysfunction in patients with fragile X syndrome.4 All of our patients had cognitive defects: the fact that the majority of the hypoperfused areas were in the right hemisphere supports this thesis. Two patients with normal SPECT findings were the youngest in our series. This condition might suggest that cerebral perfusion abnormalities seen in the patients with fragile X syndrome might become more noticeable as the patient gets older, and for that reason, symptoms and findings can intensify in time. It can be considered that the young patients did not show these abnormalities or these findings are secondary (to medication or a lack of stimulation or stereotypes) and therefore develop in time. When compared with the epilepsy incidence in the general population (5–6 in 10,000),20 patients with fragile X syndrome have an increased tendency to have epilepsy. Various studies have been performed concerning epilepsy and abnormal EEG findings in patients with fragile X syndrome.7,9,21–23 In one of these studies, Incorpora et al reported 20% convulsion frequency in fragile X syndrome, the most frequent seizure type being

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Journal of Child Neurology / Volume 21, Number 12, December 2006

Figure 2. Coronal 99mTc-HMPAO single-photon emission computed tomographic image of patient 7 displaying markedly decreased activity taken in widespread regions of both superior parietal cortices.

complex partial seizures, as well as EEG abnormalities (theta rhythm, diffuse spike wave, spike–and-wave discharges in the area of the left temporal and central regions, with multiple spikes and waves) without any convulsions.7 Berry-Kravis reported convulsions in 16 of 136 patients with fragile X syndrome (12%), the majority (n 5 12, 75%) of which were partial convulsions; in addition, 5 of the 22 patients without convulsions (23%) had EEG abnormalities.23 The percentage of epilepsy (n 5 1, 12.5%) and an abnormal EEG pattern (n 5 6, 75%) in our patients was also high. Moreover, SPECT and EEG findings overlapped, indicating cerebral dysfunction by two different neurophysiologic methods. Our findings might suggest that patients with fragile X syndrome who have pathologic findings in their EEGs, especially slowwave paroxysms, might also have a cerebral perfusion abnormality. Only one of the patients whose SPECT showed cerebral hypoperfusion had a qualitative abnormality on MRI. It can be said that brain malformations show various regional cerebral blood flow abnormalities, and these are spread over a larger area than detected by computed tomography (CT) or MRI. SPECT can be more sensitive in some instances than CT and MRI. A mean IQ of 30 to 55 and mental retardation from a mild to a more severe level are observed in fragile X syndrome.5 The average IQ of our patients (58.9 6 8.8) was higher than this

value, and intellectual status did not show any correlation with age. It was determined that as the patients got older, neurobehavioral problems started.24 Attention deficit or ADHD, social anxiety, poor motor coordination, and autism can exist together with mental retardation in patients with fragile X syndrome at a high frequency.14,15 All of our patients had additional neurobehavioral problems, and cerebral perfusion abnormalities were determined in the majority of them. Also, their EEGs were abnormal; we speculate an association between neurobehavioral problems and cerebral hypoperfusion. Thus, it was reported that the findings in cases with fragile X syndrome can worsen with the age factor.24 In an experimental study made by Gruss and Braun, it was reported that in fragile X syndrome, the lack of fragile X mental retardation protein expression in female fmr1 knockout mice was accompanied by age-dependent, region-specific alterations in brain amino acids (aspartate, glutamate, taurine, and caminobutyric acid [GABA]), and monoamine turnover, which might be related to the reported synaptic and behavioral alterations in these animals.24 In conclusion, our study showed perfusion and electrophysiologic abnormalities in the patients with fragile X syndrome. These abnormalities can cause neurophysiologic dysfunction in various areas of the central nervous system. Larger series and a combination of sensitive laboratory

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Fragile X Syndrome and Cerebral Perfusion / Kabakus et al

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Figure 3. Transaxial 99mTc-HMPAO single-photon emission computed tomographic image of patient 8 showing relatively decreased activity taken markedly in a widespread area of the right temporal lobe anterior cortex, right inferior frontal cortex, and left frontoparietal region.

Table 3. Brain SPECT Findings, Neurobehavioral Symptoms, and IQ of the Patients With Fragile X Syndrome

Patient

Age (yr)

1 2

5 7

3

10

4 5

5 6

6

8

7

12

8*

18

Brain SPECT Findings Normal Hypoperfusion abnormality in the right basal ganglia and temporal lobe regions Relative decreased perfusion abnormality in frontal and temporal lobes, which marked for left side

EEG Findings Normal Delta activity in the bilateral temporal regions In the posterior (temporooccipital) regions, 3–4 Hz persistent slow-wave paroxysm more evident with HPV Normal Slow-wave paroxysm in the posterior regions

Normal Relative hypoperfusion in the lower and middle parts of the right parietal lobe, symmetric increased activity taken in optic nerves and globes Theta rhythm arising from Decreased activity taken in the left anterolateral centroparietal and region of frontal cortex, right lateral region of frontocentral regions occipital cortex, and left frontoparietal region; in a small area of the right superior parietal cortex Markedly decreased activity taken in widespread Diffuse voltage suppression regions of both superior parietal cortices Theta-delta rhythm in the Relative decreased activity taken markedly in a posterior regions widespread area of the right temporal lobe anterior cortex, right inferior frontal cortex, and left frontoparietal region

Neurobehavioral Symptoms

IQ

MR/social phobia MR/ADHD

40 66

MR/ADHD

68

MR/temper tantrum MR/ADHD

65 60

MR/autism

56

MR/stereotyped behavior and repetitive speech MR/social anxiety

60 56

ADHD 5 attention-deficit hyperactivity disorder; EEG 5 electroencephalography; HPV 5 hyperventilation; MR 5 mental retardation; SPECT 5 single-photon emission computed tomography. *The patient with seizures.

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Journal of Child Neurology / Volume 21, Number 12, December 2006

8. Reiss AL, Patel S, Kumar AJ, Freund L: Preliminary communication: Neuroanatomical variations of the posterior fossa in men with the fragile X (Martin-Bell) syndrome. Am J Med Genet 1988; 31:407–414. 9. Guerreiro MM, Camargo EE, Kato M, et al: Fragile X syndrome. Clinical, electroencephalographic and neuroimaging characteristics. Arq Neuropsiquiatr 1998;56:18–23. 10. Schapiro MB, Murphy DG, Hagerman RJ, et al: Adult fragile X syndrome: Neuropsychology, brain anatomy, and metabolism. Am J Med Genet 1995;18:480–493. 11. Roid GH, Miller LJ: Leiter International Performance ScaleRevised, Wood Dale, IL: Stoelting Company, 1997. 12. American Psychiatric Association Task Force on DSM-IV: Diagnostic and Statistical Manual of Mental Disorders-IV, Washington D.C.: American Psychiatric Association, 2000. 13. Thorndike RL, Hagen EP, Sattler JM: The Stanford-Binet Intelligence Scale, Chicago, Riverside, 1986. Figure 4. Magnetic resonance image (MRI) of case 6 showing cerebral asymmetry.

techniques (positron emission tomography [PET], diffusionweighted imaging, and proton magnetic resonance spectroscopy; excitatory or inhibitory neurotransmitters; and performance tests), and multicentric studies are needed to investigate the possible relationships and their changes over time. References 1. Reiss AL, Lee J, Freund L: Neuroanatomy of fragile X syndrome: The temporal lobe. Neurology 1994;44:1317–1324. 2. Ferrando LMT, Banus GP, Lopez PG: Aspects of cognition and language in children with fragile X syndrome. Rev Neurol 2003;36: 137–142. 3. Lu R, Wang H, Liang Z, et al: The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci U S A 2004;101:15201–15206. 4. Munir F, Cornish KM, Wilding J: A neuropsychological profile of attention deficits in young males with fragile X syndrome. Neuropsychologia 2000;38:1261–1270. 5. Jones KL: Smith’s Recognizable Patterns of Human Malformation, 5th ed. Philadelphia, WB Saunders, 1997. 6. Hall JG: Chromosomal clinical abnormalities, in Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics, Philadelphia, WB Saunders, 2000, 325–333. 7. Incorpora G, Sorge G, Sorge A, Pavone L: Epilepsy in fragile X syndrome. Brain Dev 2002;24:766–769.

14. Eliez S, Reiss AL: Genetics of childhood disorders: XI. Fragile X syndrome. J Am Acad Child Adolesc Psychiatry 2000;39:264– 266. 15. Hjalgrim H, Jacobsen TB, Norgaard K, et al: Frontal-subcortical hypofunction in the fragile X syndrome. Am J Med Genet 1999;83: 140–141. 16. Kates WR, Folley BS, Lanham DC, et al: Cerebral growth in fragile X syndrome: Review and comparison with Down syndrome. Microscop Res Tech 2002;57:159–167. 17. Chang YC, Huang CC, Huang SC: Volumetric neuroimaging in children with neurodevelopmental disorders—Mapping the brain and behavior. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1998;39:285–292. 18. Sadock BJ, Sadock VA: Kaplan & Sadock’s Synopsis of Psychiatry, Philadelphia, Lippincott Williams & Wilkins, 2003. 19. Sparks BF, Friedman SD, Shaw DW, et al: Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002;59:184–192. 20. Cowan LD: The epidemiology of the epilepsies in children. Ment Retard Dev Disabil Res Rev 2002;8:171–181. 21. Sabaratnam M, Vroegop PG, Gangadharan SK: Epilepsy and EEG findings in 18 males with fragile X syndrome. Seizure 2001;10:60– 63. 22. Wisniewski KE, Segan SM, Miezejeski CM, et al: The Fra(X) syndrome: Neurological, electrophysiological, and neuropathological abnormalities. Am J Med Genet 1991;38:476–480. 23. Berry-Kravis E: Epilepsy in fragile X syndrome. Dev Med Child Neurol 2002;44:724–728. 24. Gruss M, Braun K: Age- and region-specific imbalances of basal amino acids and monoamine metabolism in limbic regions of female Fmr 1 knock-out mice. Neurochem Int 2004;45:81–88.

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