C. Sugiura1, 2 M. Shiota1 Y. Maegaki2 Original Article 286 K. Yoshida3 T. Koeda4 T. Kitahara3 K. Ohno2 Abstract Introduction We herein report a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC) who developed late-onset neuropsychological symptoms. He demonstrated characteristic clinical features of MLC during childhood, such as slowly progressive megalencepaly, motor impairment with ataxia and spasticity, mild mental retardation, and well-controlled epilepsy. Thereafter, he showed specific neuropsychological symptoms, such as motor and vocal tics, compulsive behavior, perseveration, acquired stuttering, and dystonia since the age of 12. His performance abilities had been unchanged but his verbal abilities had degraded during the past 14 years. Higher cortical dysfunction tests revealed a frontal lobe dysfunction. On repeated brain MRI, a leukoencephalopathy with subcortical cysts remained stationary from infancy. On single photon emission computed tomography (SPECT), a hypoperfusion in the frontal lobe was detected at the age of 3.5 and 17, but the severity of hypoperfusion was also unchanged, respectively. Our results indicate that the frontal lobe dysfunction may be relevant to the late-onset neuropsychological symptoms with MLC. Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a newly defined neurologic disorder characterized by megalencephaly, a slowly progressive deterioration of motor function with ataxia and spasticity [10]. Magnetic resonance imaging (MRI) shows diffuse white matter abnormalities and subcortical cysts, particularly in the anterior temporal region since early infancy. Mutations of the MLC1, a gene that has been mapped to chromosome 22 qtel, are responsive for the cause of MLC [6,14]. It is known that the clinical symptoms were closely related to age irrespective of the imaging findings in early childhood [16]. Although CT or MRI show diffuse white matter abnormalities, the clinical symptoms are usually mild in early childhood. Most reported patients with MLC are children under the age of 10 [15,16], while, the later clinical course of MLC is still not well known. A few reports represented the clinical course in patients from adolescence to young adulthood and described that the neurological symptoms in later childhood tended to differ from those in early childhood [2,11,13]. We herein report a patient with MLC, who has been followed from the age of 7 months to 18 years. His early clinical and imaging findings have been previously described [5]. We herein focused on his late-onset specific neuropsychological symptoms, such as tic disorders, compulsions, acquired stuttering, and motor perseveration. Key words Tic · compulsive behavior · dystonia · frontal lobe dysfunction · megalencephalic leukoencephalopathy with subcortical cysts Affiliation 1 Department of Pediatrics, Tottori Prefectural Rehabilitation Center, Yonago, Tottori, Japan 2 Division of Child Neurology, Institute of Neurological Science, Faculty of Medicine, Tottori University, Japan 3 Department of Rehabilitation, Tottori Prefectural Rehabilitation Center, Yonago, Tottori, Japan 4 Department of Education, Faculty of Regional Science, Tottori University, Tottori, Japan Correspondence Dr. Chitose Sugiura · Division of Child Neurology · Institute of Neurological Science · Faculty of Medicine · Tottori University · 36 – 1 Nshimachi · Yonago 683 – 8504 Tottori · Japan · E-mail: sugiurac@grape.med.tottori-u.ac.jp Received: June 15, 2006 · Accepted after Revision: November 15, 2006 Bibliography Neuropediatrics 2006; 37: 286 – 290 © Georg Thieme Verlag KG Stuttgart · New York · DOI 10.1055/s-2006-955930 · ISSN 0174-304X Downloaded by: NYU. Copyrighted material. Late-Onset Neuropsychological Symptoms in a Japanese Patient with Megalencephalic Leukoencephalopathy with Subcortical Cysts Fig. 1 a to c Magnetic resonance imaging features at 17 years of age. Axial Flair images (a,c) and Coronal T1-weighted image (b) show diffuse high intensity of cerebral white matter (a,c), cystic lesions in the bilateral temporal lobes (a) and the frontal lobe (b). Clinical presentation The patient, an 18-year-old male, has been diagnosed for MLC since early infancy on the basis of his characteristic brain imaging findings and clinical features, such as slowly progressive megalencephaly, motor impairment with ataxia and spasticity, mild mental retardation, and well-controlled epilepsy (previously published) [5]. At the age of 15, the MLC1 gene mutation was identified in his blood sample; homozygous for a mutation of the serine residue at position 280 to a leucine residue. The patient was admitted to our hospital for the purpose of rehabilitation at the age of 12. He was also left-handed. He was able to walk with a short leg brace. A neurological examination revealed moderate mental retardation, ataxic gate, mild dysarthria, and right hemiplegia. The cranial nerve palsy and extrapyramidal signs were unremarkable. A few months after admission, he developed compulsive behaviors, such as repeatedly washing his hands, clearing his throat, and wiping objects that have been touched by others, etc. He thereafter developed a complex motor and vocal tic: e.g., eye blinking, head jerk, shoulder shrugging, arm or leg jerks, and dystonic movements. These tics were enhanced in intensity by emotional stress, thus resulting in difficulties in daily and social lives and school performance. At 13 years of age, his speech became more inarticulate due to the repetition of sounds and syllables. In addition, he had motor perseveration; repeating the same motions, such as, squatting down in the same place, picking up chopsticks and then putting them down again, chewing and holding foods in his mouth, and so on. His peculiar behaviors were further aggravated in spite of our administration of mental therapies and medication with fluvoxamine maleate. A hearing impairment on the right side, which was incidentally found on a school health examination at the age of 14, also remained unchanged. Other neurological symptoms such as gate ataxia, spasticity, and mental retardation were nonprogressive and his epileptic seizure was well controlled with antiepileptic drugs. 287 Imaging and Neurophysiological Investigation On MRI performed at the age of 17, leukoencephalopathy with subcortical cysts was unchanged and cerebral cortex and basal ganglia were relatively preserved (Fig. 1). On single photon emission CT (SPECT) performed at age of 17, a remarkable reduction in the cerebral blood flow was symmetrically observed in the superior frontal and temporal lobes, but was preserved in the occipital lobes, basal ganglia, thalamus, and cerebellum (Fig. 2). The brain auditory-evoked potential (BAEP) revealed mild sensorineural hearing impairment with thresholds above 65 dB at the age of 15. On EEG, normal background activity without epileptic discharge was recorded at 18 years of age, although sporadic focal paroxysmal discharges had been detected in the bilateral frontal region until 16 years of age. Neuropsychological Investigation A neuropsychological investigation was performed at the age of 18. The results of neuropsychological tests are summarized on Table 1a to 1c. Wechsler Intelligence Scale for Children-III (WISC-III) revealed the full-scale, verbal, and performance IQs to be 48, 47, and 60, respectively. Kohs Block-Design test, to assess of viscospatial disorganization, showed an IQ of 80. To assess for frontal lobe cognitive function, we used the Keio Wisconsin card sorting test (KWCST) and the modified Stroop Color-Word test (Stroop test) [3]. On KWCST, Nelson-type perseverative errors were highly present in comparison to the predictive score for his intelligence quotient [4]. In the Stroop test, the color-word Sugiura C et al. Late-Onset Neuropsychological Symptoms … Neuropediatrics 2006; 37: 286 – 290 Downloaded by: NYU. Copyrighted material. Case Report Original Article Fig. 2 Single photon emission CT involving 99 m Tc-ECD 600MBq at 17 years of age. The blood flow ratios in (e – f), compared to averaged blood flow in the cerebellar hemispheres (a,b), were 0.78, 0.75, 0.72, and 0.65, respectively. These ratios in (e – f) at 3.5 years of age were 0.77, 0.75, 0.91, 0.95, respectively (data not shown). Table 1a Summary of neuropsychological tests: general intelligence test Table 1b Summary of neuropsychological tests: frontal function test Test Test Score # Reference Reference 47 WCST-Keio version 1st task/2nd task 1st task/2nd task [3] 60 Categories completed 2/3 2.18/4.02 Perseverative errors 17/9 5.84/2.45 7 years 12 years WISC-R VIQ 71 PIQ 68 FIQ 66 Kohs Block Design test ND 18 years WISC-III ND 48 66 80 Modified Stroop test (Japanese version) 30.01 seconds Color-word 36.99 seconds Interference – 6.98 seconds [4] Table 1c Summary of neuropsychological tests: high cognitive function test (Hamamatsu scale) Cognitive domain Tasks Score Reference (score, range) Temporal orientation orientation NP Immediate memory digit learning perseverative errors Word fluency animal naming 8 16.7 ± 4.01 – attention Kana-pick out: story 16 38.2 ± 10.6 7.21 ± 2.63 non-meaning 19 40.0 ± 9.69 Immediate memory immediate memory (5 words) 3 4.49 ± 0.58 Short-term memory 5-min memory (5 words) 4 3.98 ± 1.04 Unilateral spatial neglect figure copy NP Recency-recognition figure re-call (5 min) NP NP : normal, # average at 8 – 10 years in normal control 288 interference time was prolonged. Moreover, to evaluate a higher cognitive function, we used the “Hamamatsu” higher brain function scale (Hamamatsu scale), which has been used to assess the higher cognitive function in Japan [17]. The results of the Hamamatsu scale such as high perseverative errors on serial digit learning (immediate memory) and a low score on animal naming (word fluency), and the Kana pick-up test (attention) suggested a frontal lobe dysfunction. The Hamamatsu scale also showed normal scores for verbal (intermediate memory), nonverbal memory (recency-recognition test), and figure copy (unilateral spatial neglect), thus indicating that his memory functions were not disturbed. Discussion In this report, we described the long-term clinical course of the patient with MLC, especially in later childhood to adolescence. The clinical symptoms in patients with MLC were reported to be closely related to age [16]. Megalencephaly is usually the only initial symptom with or without mild neurological signs of less than 2 years of age, and thereafter neurological dysfunction and deterioration develop. However, the neurological symptoms have so far been described mainly in early childhood, namely in individuals under 10 years of age. We summarized the age-related clinical symptoms based on the present patient and the literatures [2, 5,10,11,13,15,17] (Table 2), and noticed that the clinical symptoms in the advanced stage differed from those in the early stage. In the advanced stage, extrapyramidal symptoms such as dystonia [2] and athetoses [2,13] and neuropsychological symptoms such as depression, aggression and dementia [10], appeared. In a severe case, choreoathetosis also occurred since early childhood [7]. Our patient also developed complex motor tics and compulsions since 12 years of age. His motor tic included dystonic movement and the clinical characteristics of his tics and compulsion were similar to Tourette’s syndrome (TS). We examined the cognitive functions with some neuropsychological batteries in the present case. In term of Evaluation of intellectual abilities using the Wechsler tests and Kohs Block Design test, his performance abilities, particularly visuoperceptive or visuospatial processes, had been unchanged but his verbal abilities had degraded since the age of 7. The discrepancy between the performance and the verbal abilities may be related with the lesional brain dysfunctions and characteristic SPECT findings; hypoperfusion in the superior frontal and temporal lobes relative to parieto-occipital lobes. Berg et al. [1] reported lowered VIQ was related to left frontal brain damages. Therefore, this deteriorated verbal IQ and the results of WCST, the modified Sugiura C et al. Late-Onset Neuropsychological Symptoms … Neuropediatrics 2006; 37: 286 – 290 Downloaded by: NYU. Copyrighted material. Original Article Color Table 2 The change in the clinical course and suspected foci Clinical symptoms Neuroimaging Suspected foci Reference early infantile onset and nonprogressive leukoencephalopathy with subcortical cysts – none [5, 15, 16] neuropsychological symptoms other findings Under 2 years – none – none – macrocephaly 2 – 10 years – ataxia – mild MR – epilepsy – cerebellum – spasticity – learning disorder – dysarthria – pyramidal tract – hearing loss – cerebral cortex (collaterally) After 10 years – involuntary movement – depression – dystonia – dementia – athetosis – compulsion – tic – cognitive dysfunction above findings with/without slowly progressive cerebral cortical atrophy – basal ganglia [2, 10, 13] – cerebral cortex (dominantly) Original Article motor symptoms MR: mental retardation, oblique letter: clinical symptoms of our original case stroop test, and Hamamatsu’ scale would suggest the frontal lobe dysfunction. Compulsions, AS, and perseveration could be, at least in part, related to a frontal lobe dysfunction. In the long-term follow-up studies in patients of MLC with mild clinical course, the increase in white matter cystic changes [9] and slowly progressive cerebral atrophy [2,10] have all been described in the late stage. In addition, a neuropathological study revealed the cerebral cortex and basal ganglia to be affected in a severe case [12]. Therefore, a dysfunction of cerebral cortex and basal ganglia might have been responsible for the symptoms observed in the advanced stage. In the present patient, however, the MRI and SPECT findings were unchanged over the past 15 years, while additional symptoms developed in late childhood. From the course of our patient, the neuropsychological prognosis with advanced stage of MLC should be guarded, since severity of the neuroimaging findings were not always reflected by the clinical symptoms until terminal stage of MLC. In our patients, it was interesting to note that neuropsychological symptoms developed and verval ability slightly degraded, while the performance ability was unchanged and MRI did not progress. The MLC1 gene has been reported to be involved in the etiopathogenesis of schizophrenia with periodic catatonia [8]. The neuropsychological symptoms observed in the advanced stages of MLC may also be MLC1 gene-related symptoms. We herein reported a patient with MLC and described the longterm follow-up findings of clinical symptoms, neuroimaging findings, and neuropsychological tests. The accumulation of long-term clinical and imaging studies is thus necessary to understand the entire clinical course of MLC. References 1 Berg RA. Tests of intellectual abilities. In: Golden CJ and Vincente PJ (eds) Foundations of clinical neuropsychology. New York: plenum, 1983, pp 76-78. 2 Blattner R, von Moers A, Leegwater PAJ, Hanefeld FA, van der Knaap MS, Kohler W. 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