Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy. CASE PRESENTATION: The proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20). CONCLUSIONS: Our cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

[What is the Core Symptom and Neural Mechanism of Asperger Syndrome? From Our Ten Years of Clinical Observation of Adults with Autism Spectrum Disorder].

In 2008, we launched a new outpatient clinic and day care service designed exclusively for adults with autism spectrum disorder (ASD). Since then, more than 6000 people visited our facility. We have also launched the Medical Institute for Developmental Disabilities Research (MIDDR) at Showa University, where neuroimaging studies with a 3.0 Tesla MRI scanner and rehabilitation studies intended to support people with ASD for job seeking were conducted for the past five years. As our subjects were found to have normal or high intelligence, we present here our research studies on Asperger syndrome patients with the focus on their resting-state functional connectivity network. We also review hypotheses of brain functioning in Asperger syndrome.

Functional significance of the electrocorticographic auditory responses in the premotor cortex.

Other than well-known motor activities in the precentral gyrus, functional magnetic resonance imaging (fMRI) studies have found that the ventral part of the precentral gyrus is activated in response to linguistic auditory stimuli. It has been proposed that the premotor cortex in the precentral gyrus is responsible for the comprehension of speech, but the precise function of this area is still debated because patients with frontal lesions that include the precentral gyrus do not exhibit disturbances in speech comprehension. We report on a patient who underwent resection of the tumor in the precentral gyrus with electrocorticographic recordings while she performed the verb generation task during awake brain craniotomy. Consistent with previous fMRI studies, high-gamma band auditory activity was observed in the precentral gyrus. Due to the location of the tumor, the patient underwent resection of the auditory responsive precentral area which resulted in the post-operative expression of a characteristic articulatory disturbance known as apraxia of speech (AOS). The language function of the patient was otherwise preserved and she exhibited intact comprehension of both spoken and written language. The present findings demonstrated that a lesion restricted to the ventral precentral gyrus is sufficient for the expression of AOS and suggest that the auditory-responsive area plays an important role in the execution of fluent speech rather than the comprehension of speech. These findings also confirm that the function of the premotor area is predominantly motor in nature and its sensory responses is more consistent with the "sensory theory of speech production," in which it was proposed that sensory representations are used to guide motor-articulatory processes.

[Communication disorder in chronic stage stroke patients].

Although aphasia is a common neurological condition, and its diagnostic procedure is mostly established, it is not easy to fully evaluate the communicative ability of each patient, as there are huge interindividual differences among patients, and their abilities may vary depending on their circumstances. Even with the advancement of neuroimaging technique, the relationship between lesion localizations and symptoms remains elusive. To evaluate their residual abilities which helps daily communication, it is valuable to observe their abilities in a setting which reflects real social contexts. In this presentation a patient with total aphasia who showed rich communicative abilities in a group therapy setting is presented, which was discrepant from his results of standardized language evaluation. We found that his residual communicative abilities have things much in common with linguistic abilities shown to reside in the right hemisphere. The observation also revealed that the group treatment of patients with chronic aphasia provides a unique occasion to participate in social activities which helps to fulfill their psychosocial needs.

Steroid-responsive thalamic lesions accompanying microbleeds in a case of Hashimoto's encephalopathy with autoantibodies against α-enolase.

A 67-year-old man receiving antithrombotic therapy developed rapidly progressive amnesia. T2-weighted images of brain MRI revealed hyperintense lesions in the bilateral thalami accompanied by microbleeds. Antithyroglobulin antibodies and autoantibodies against the N-terminal of α-enolase (NAE) were identified in the patient's serum; therefore, Hashimoto's encephalopathy (HE) was suspected. Although the patient's radiological findings improved following steroid therapy, his symptoms did not improve, possibly due to increased thalamic microbleeds. Because anti-NAE antibodies are possibly associated with vasculitis, HE accompanied by anti-NAE antibodies may be exacerbated by microbleeds in patients receiving antithrombotic therapy.

Face specific broadband electrocorticographic spectral power change in the rhinal cortex.

Recent studies have revealed additional face areas in the anterior temporal lobe in addition to the 'core' face areas (fusiform face area, occipital face area, and face area in the superior temporal sulcus). The electrocorticogram of a patient who underwent implantation of subdural grid electrodes in the right anterior ventral temporal lobe revealed a strong face-specific response both in event-related potentials (ERP) and in the induced broadband spectral power change at an electrode located on the anterior collateral sulcus, straddling the border between the perirhinal and entorhinal cortices. The ERP and induced broadband power changes were highly specific to facial stimuli, which was obvious even in a single trial analysis. The face-specific response was recorded in an area with perfect overlap of the 'anterior temporal face patch' in the anterior collateral sulcus, proposed based on human functional magnetic resonance imaging (fMRI) results. A recent fMRI study in monkeys reported a face-specific visual response in the rhinal cortex, suggesting that the basic structural configuration of face responsive areas are preserved across species. Although the rhinal cortex has long been regarded as part of the memory system, recent data suggest that it also plays a role in perception. The face-specific response in the present study might reflect visual processing based on complex conjunctions of visual features required for facial processing.

Effect of sound intensity on tonotopic fMRI maps in the unanesthetized monkey.

The monkey's auditory cortex includes a core region on the supratemporal plane (STP) made up of the tonotopically organized areas A1, R, and RT, together with a surrounding belt and a lateral parabelt region. The functional studies that yielded the tonotopic maps and corroborated the anatomical division into core, belt, and parabelt typically used low-amplitude pure tones that were often restricted to threshold-level intensities. Here we used functional magnetic resonance imaging in awake rhesus monkeys to determine whether, and if so how, the tonotopic maps and the pattern of activation in core, belt, and parabelt are affected by systematic changes in sound intensity. Blood oxygenation level-dependent (BOLD) responses to groups of low- and high-frequency pure tones 3-4 octaves apart were measured at multiple sound intensity levels. The results revealed tonotopic maps in the auditory core that reversed at the putative areal boundaries between A1 and R and between R and RT. Although these reversals of the tonotopic representations were present at all intensity levels, the lateral spread of activation depended on sound amplitude, with increasing recruitment of the adjacent belt areas as the intensities increased. Tonotopic organization along the STP was also evident in frequency-specific deactivation (i.e. "negative BOLD"), an effect that was intensity-specific as well. Regions of positive and negative BOLD were spatially interleaved, possibly reflecting lateral inhibition of high-frequency areas during activation of adjacent low-frequency areas, and vice versa. These results, which demonstrate the strong influence of tonal amplitude on activation levels, identify sound intensity as an important adjunct parameter for mapping the functional architecture of auditory cortex.

Anomic alexia of kanji in a patient with anomic aphasia.

The ability to read aloud kanji (logogram) words and to comprehend their meaning was systematically examined to clarify the underlying mechanism of kanji alexia in a patient with anomic aphasia. Confrontation naming, reading aloud and reading comprehension tasks were performed using 110 words from 11 semantic categories written in kanji or kana. Performance in oral reading of kanji words was significantly worse than oral reading of the same words transcribed into kana words. In addition, for kanji words reading aloud was much worse than reading comprehension. Oral reading of kanji words had a significant correlation with naming pictures corresponding to the words, but no correlation with comprehension of kanji words. Qualitative analyses demonstrated that errors in oral reading and naming tasks had many features in common. Our results indicated that some common mechanisms underlie both naming and oral reading of kanji words. We propose calling this type of alexia "anomic alexia of kanji", which should be distinguished from kanji alexia with difficulty in both reading aloud and comprehension. Lesions in our patient were located in the middle part of the left middle temporal gyrus and its subcortical area, which could be important for access to the phonological lexicon from semantics.

High-frequency gamma-band activity in the basal temporal cortex during picture-naming and lexical-decision tasks.

Gamma-band activity (GBA) in electroencephalograms (EEGs) has been shown to reflect various cognitive processes. GBA has typically been recorded in the 30-60 Hz range in scalp EEGs. Recently, task-related "high GBA" (HGBA) with frequencies up to 100 Hz has been observed in studies with invasive electrocorticograms (ECoGs). In the present study, we recorded ECoGs from the bilateral basal temporal cortices in a patient with epilepsy and evaluated the task-related HGBA (most prominently in the 80-120 Hz range) accompanying picture-naming and lexical-decision tasks. We examined picture naming using two categories (line drawings of animals and tools). The lexical-decision task was performed using words and pseudowords of two distinct Japanese writing forms, kanji (morphograms) and kana (syllabograms). Task-related HGBA was observed bilaterally during the naming task. Recordings from some electrodes revealed significant differences in HGBA between animal and tool pictures. In contrast to the naming task, there was apparent left dominance in the lexical-decision task. Furthermore, significant differences in HGBA were observed between the Japanese kanji and kana words and between the kanji words and kanji pseudowords. A number of differences in the HGBA observed in the recordings from the basal temporal area were consistent with previous findings from neuroimaging and patient studies and suggest that HGBA is a good correlate of visual cognitive functions.

Neural correlates of context memory with real-world events.

There has been little evidence for the difference in the retrieval processes of when and where something happened, one of the important factors in understanding episodic memory. We used positron emission tomography (PET) to identify the neural networks associated with temporal and spatial context memory of events experienced under experimental conditions similar to those of everyday life. Before PET, subjects experienced 36 events. The events were divided into four groups of nine each. The subjects experienced the first two groups of events before a 15-min recess and the other two after the recess; they experienced the first and last groups of events in one room, took a recess in another room, and experienced the second and third groups in a different room. During PET, the subjects were scanned under three different retrieval tasks: a time-retrieval task, a place-retrieval task, and a simple recognition task. The results showed that the retrieval of time and space, compared with the simple recognition, was associated with activity in substantially different regions as well as a common region: time retrieval with the posterior part of the right orbitofrontal cortex and left inferior parietal lobule, place retrieval with two regions in right parietal association cortex, right posterior cingulate gyrus, left precentral gyrus, and right cerebellum, and both with the right inferior frontal gyrus. These findings indicate that there are unique areas, in addition to a common area, for retrieving temporal and spatial context.

Thinking of the future and past: the roles of the frontal pole and the medial temporal lobes.

Human lesion data have indicated that the frontal polar area might be critically involved in having an insight into one's future. Retrospective memory mediated by medial temporal lobes and related structures, on the other hand, could be used to extract one's future prospects efficiently. In the present study, we investigated the roles of these two brain structures in thinking of the future and past by using positron emission tomography (PET) and a naturalistic task setting. We measured regional cerebral blood flow (rCBF) in healthy subjects while they were talking about their future prospects or past experiences, with regard to two different temporal windows (in years or days). Many areas in the frontal and the medial temporal lobes were activated during the future and past tasks compared with a control task requiring semantic retrieval. Among these, areas in anteromedial frontal pole showed greater activation during the future tasks than during the past tasks, showing significant effect of temporal distance from the present. Most areas in the medial temporal lobes showed greater or equivalent level of activations during the future tasks compared with the past tasks. The present results suggest that thinking of the future is closely related to retrospective memory, but that specific areas in the frontal pole and the medial temporal lobes are more involved with thinking of the future than that of the past.