Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes.

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome is unclear, but studies suggest that genetic factors are involved in its pathogenesis. Considering possible involvement of the serotonergic system in neuroleptic malignant syndrome, the authors examined the association between neuroleptic malignant syndrome and polymorphisms of the 5-HT1A and 5-HT2A receptor genes. METHOD: The authors examined the frequencies of gene polymorphisms in the 5-HT1A (Arg219Leu) and 5-HT2A (Thr25Asn and His452Tyr) receptor genes in 29 patients previously diagnosed with neuroleptic malignant syndrome, 94 neuroleptic-treated patients with schizophrenia who had no history of neuroleptic malignant syndrome, and 94 healthy comparison subjects. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to screen gene mutations. RESULTS: No polymorphic allele was detected in the patients who had experienced the neuroleptic malignant syndrome. CONCLUSIONS: The authors cannot conclude that polymorphisms in the 5-HT1A and 5HT2A receptor genes are factors determining susceptibility to the neuroleptic malignant syndrome.

Cognitive loss in dementia with Lewy bodies and Alzheimer disease.

BACKGROUND: Dementia with Lewy bodies (DLB) is emerging as a common cause of degenerative dementia. Some preliminary evidence exists that the pattern of cognitive impairment in DLB is different from that in Alzheimer disease (AD). OBJECTIVE: To delineate features of cognitive impairment of DLB on standardized neuropsychological tests. METHODS: We performed neuropsychological assessments of 26 patients with probable DLB (based on criteria of the consortium on DLB international workshop) and of 52 patients with probable AD (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke [now the National Institute of Neurological Disorders and Stroke])-Alzheimer's Disease and Related Disorders Association) who were matched to the patients with DLB 2:1 by age, sex, education, and Mini-Mental State Examination score. RESULTS: Compared with the group with probable AD, the group with probable DLB scored significantly lower on the picture arrangement, block design, object assembly, and digit symbol substitution subtests of the Wechsler Adult Intelligence Scale-Revised and on the Raven Colored Progressive Matrices test and significantly higher on the Mini-Mental State Examination locational orientation subtest and the Alzheimer's Disease Assessment Scale word recall subtest. A discriminant analysis revealed that the word recall score on the Alzheimer's Disease Assessment Scale and the block design score on the Wechsler Adult Intelligence Scale-Revised were the best discriminant factors. CONCLUSIONS: The disproportionately severe visuoperceptual, visuoconstructive, and visuospatial dysfunction and the disproportionately mild memory impairment in DLB compared with AD, which likely reflect the distribution of the pathologic changes in DLB, can help to differentiate DLB from AD.

Visuoperceptual impairment in dementia with Lewy bodies.

BACKGROUND: In dementia with Lewy bodies (DLB), vision-related cognitive and behavioral symptoms are common, and involvement of the occipital visual cortices has been demonstrated in functional neuroimaging studies. OBJECTIVES: To delineate visuoperceptual disturbance in patients with DLB in comparison with that in patients with Alzheimer disease and to explore the relationship between visuoperceptual disturbance and the vision-related cognitive and behavioral symptoms. DESIGN: Case-control study. SETTING: Research-oriented hospital. PATIENTS: Twenty-four patients with probable DLB (based on criteria of the Consortium on DLB International Workshop) and 48 patients with probable Alzheimer disease (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) who were matched to those with DLB 2:1 by age, sex, education, and Mini-Mental State Examination score. MAIN OUTCOME MEASURES: Four test items to examine visuoperceptual functions, including the object size discrimination, form discrimination, overlapping figure identification, and visual counting tasks. RESULTS: Compared with patients with probable Alzheimer disease, patients with probable DLB scored significantly lower on all the visuoperceptive tasks (P<.04 to P<.001). In the DLB group, patients with visual hallucinations (n = 18) scored significantly lower on the overlapping figure identification (P = .01) than those without them (n = 6), and patients with television misidentifications (n = 5) scored significantly lower on the size discrimination (P<.001), form discrimination (P = .01), and visual counting (P = .007) than those without them (n = 19). CONCLUSIONS: Visual perception is defective in probable DLB. The defective visual perception plays a role in development of visual hallucinations, delusional misidentifications, visual agnosias, and visuoconstructive disability charcteristic of DLB.

Medial temporal and whole-brain atrophy in dementia with Lewy bodies: a volumetric MRI study.

OBJECTIVE: Dementia with Lewy bodies (DLB) is emerging as a common cause of degenerative dementia. A recent pathologic study has indicated that the medial temporal lobe in patients with DLB was less atrophic than that in patients with AD. The purpose of this study was to examine whether medial temporal MRI volumetry was useful to differentiate DLB from AD clinically. METHODS: We compared the volumes of the hippocampal formation, amygdaloid complex, and whole brain in 27 patients with probable DLB (based on the criteria of the Consortium on DLB International Workshop), 27 patients with probable AD (based on criteria of the National Institute of Neurological Disease and Stroke/Alzheimer's Disease and Related Disorders Association), and 27 normal elderly subjects using an MRI-based volumetric technique. The three groups were matched for age and sex. Severity of cognitive disturbances represented by their Mini-Mental State Examination score was comparable between the DLB and AD groups. RESULTS: Hippocampal volume (normalized to intracranial volume) in the DLB group was significantly larger than that in the AD group, but significantly smaller than that in the normal control group. There were no significant differences in the amygdala and whole-brain volume between the DLB group and the AD group, but the atrophies of the amygdala and whole brain were more severe in the DLB group than those in the control group. CONCLUSIONS: These findings indicate the usefulness of MRI hippocampal volumetry in clinically discriminating patients with DLB from patients with AD.

Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia.

BACKGROUND: Polydipsia is a common disorder among chronic psychiatric patients. Impaired water excretion due to enhanced action and secretion of antidiuretic hormone has been reported in hyponatremic patients with polydipsia. Hypouricemia coexisting with hyponatremia is a hallmark of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The transitory coexistence of hyponatremia and hypouricemia in patients with polydipsia-hyponatremia syndrome is presented. METHOD: We examined the course of hypouricemia and hyponatremia in three schizophrenic patients with a long-standing history of polydipsia resulting in the presence of these conditions. In addition, we investigated the renal clearance of uric acid in five polydipsic patients without a previous history of water intoxication or hyponatremia (simple polydipsia). RESULTS: Both hyponatremia and hypouricemia were demonstrated in the presence of SIADH in one patient, during an episode of acute water intoxication in another, and in association with chronic hyponatremia in a patient who was following the target weight procedure. Elevated fractional excretion of uric acid percentage (FEUA%) was detected in two patients. These states appeared to be episodic or transitory. In the five patients with simple polydipsia, serum uric acid concentrations and FEUA% were maintained within the normal range. CONCLUSION: Altered uric acid regulation that resembles SIADH is present in patients with polydipsia-hyponatremia syndrome. Monitoring the uric acid concentration and FEUA% in polydipsic patients may be useful in identifying those patients with transiently impaired water excretion.

Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.

To examine a possible association between debrisoquine 4-hydroxylase gene mutations and neuroleptic malignant syndrome, we assessed frequencies of wild type and A and B mutant alleles of the CYP2D6 gene in 24 patients with a history of neuroleptic malignant syndrome, 50 patients with neuroleptic-treated schizophrenia but no history of neuroleptic malignant syndrome, and 50 healthy controls. Allele frequencies did not differ significantly between these groups. Homozygotes for CYP2D6A and for CYP2D6B, which indicate a poor-metabolizer phenotype for the CYP2D6 substrate, were not detected among the neuroleptic malignant syndrome cases. This result indicates no excess of poor CYP2D6 metabolizers in neuroleptic malignant syndrome. The aetiology of neuroleptic malignant syndrome is not explainable in terms of CYP2D6 gene mutations.

Visual hallucinations and regional cerebral metabolism in dementia with Lewy bodies (DLB).

To investigate the neurobiological bases of visual hallucinations in dementia with Lewy bodies (DLB), regional cerebral glucose metabolism was compared among three patient groups; DLB with visual hallucinations, DLB without visual hallucinations and Alzheimer's disease (AD) without visual hallucinations. The regional metabolism was significantly lower in both DLB groups than in the AD group in the primary visual area and the posterior temporal, parietal and lateral occipital association areas. The hypometabolism in the right posterior temporal and parietal areas was significantly milder in DLB with visual hallucinations than in DLB without hallucinations. The hypometabolism in the primary visual cortex and the relatively preserved metabolism in the right temporoparietal association cortices may be associated with the occurrence of visual hallucinations in DLB patients.

Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome.

Cytochrome P450IID6 (CYP2D6) plays an important role in the hepatic metabolism of various psychotropic drugs. We detected a mutation of the CYP2D6 gene in two patients who previously had episodes of neuroleptic malignant syndrome (NMS). They were homozygous for a mutated CYP2D6J allele conferring a poor-metabolizer phenotype. Possession of this trait may contribute to susceptibility to NMS.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and diabetes mellitus: molecular genetic analysis and family study.

Two MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) patients with diabetes mellitus (DM), and their family members are described clinically and genetically. The probands have the following features in common; normal early development, short stature, deterioration of intellectual ability, convulsions, cardiac conduction defect, sensorineural hearing loss, cortical blindness, and hemiparesis. Biochemical tests showed high levels of lactate and pyruvate in the blood and cerebrospinal fluid. Muscle biopsy showed ragged-red fibers. Molecular genetic analysis of both patients revealed that they had an A-to-G substitution at nucleotide position 3243 of the mitochondrial DNA in a heteroplasmic fashion. From these clinical and molecular genetic data they were diagnosed as having MELAS. In addition, fasting blood glucose levels were also high and they were diagnosed as having insulin-dependent DM. Some of the maternal family members in both cases also had insulin-dependent DM and several clinical symptoms of MELAS. DM and clinical features of MELAS were transmitted exclusively in the maternal line. In these cases, DM and MELAS might be a clinical manifestation of the same metabolic defect.

Corticobasal degeneration: widespread argentophilic threads and glia in addition to neurofibrillary tangles. Similarities of cytoskeletal abnormalities in corticobasal degeneration and progressive supranuclear palsy.

A 57-year-old man had exhibited cortical sensory disturbance, rigidity, spasticity, dementia, alien hand, grasp reflex, supranuclear ophthalmoplegia, pseudobulbar palsy, and neck dystonia for 4 years. Histological examination of autopsied specimens revealed neuronal loss in the cerebral cortex, with ballooned neurons, subthalamic nucleus, substantia nigra, basal ganglia, midbrain tegmentum, and the thalamus. There were neurofibrillary tangles in the subthalamic nucleus and the substantia nigra. Gallyas-Braak silver impregnation demonstrated numerous argentophilic tangles, threads, and a few argentophilic glia in the cerebral cortex, subcortical white matter, particularly in the precentral gyrus, subcortical nuclei, and the brainstem. These argentophilic structures were largely positive for tau, and negative for ubiquitin, paired helical filaments, and phosphorylated neurofilament. Ultrastructurally, 15-nm-wide straight tubules were observed in the neurons of the substantia nigra, globus pallidus, and the precentral cortex, coexisting with a few twisted tubules periodically constricted at 160- to 230-nm intervals. It was conclusively shown that Gallyas- and tau-positive cytoskeletal abnormalities occurred widely in brain of corticobasal degeneration. Both distribution and morphology of abnormal phosphorylated tau protein in corticobasal degeneration appear to resemble these features in progressive supranuclear palsy. These findings suggest a common cytoskeletal etiopathological significance in corticobasal degeneration and progressive supranuclear palsy.

Place of the Hokkaido Ainu (northern Japan) among circumpolar and other peoples of the world. A comparison of the frequency variations of discrete cranial traits.

Fifteen discrete cranial variations were studied in Ainu and a number of populations from around the world. The major findings, extracted by B-squared distance analysis and Fisher's exact probability test, are as follows: A) The five key traits which distinguish Ainu from the predominant eastern Asians are (1) medial palatine canal, (2) hypoglossal canal bridging, (3) supraorbital foramen, (4) transverse zygomatic suture vestige, and (5) mylohyoid bridging. The frequency of the first trait is comparable to those of Africans, especially Subsaharan Africans, the second and fifth conform to those of the New World peoples, the third is similar to Australians and Subsaharan Africans, and the fourth is the only one aligning the Ainu to Northeast Asians. B) The frequencies of a few wormian bones in Ainu are significantly different from those of many Southeast Asians. The frequencies favour rough clinality from the south to as far north as the arctic area of Northeast Asia in the regions of western Oceania and eastern Asia. The present study confirms that Ainu and Jomon are certainly members of populations originated in Asia but possibly outliers of more predominant Asian populations.

[Siblings with spinocerebellar ataxia type 1 (SCA 1)--diagnosis by detecting the expansion of CAG repeat on chromosome 6p].

We reported siblings with spinocerebellar ataxia type 1 (SCA 1), diagnosed by detection of the expansion of CAG repeat in SCA 1 gene on chromosome 6. They were a 55-year-old woman (patient 1) and a 51-year-old woman (patient 2). There were eleven patients among the four generations in their family. They were from Obanazawa City in Yamagata Prefecture, located in the north-west region of Japan. The mode of inheritance was autosomal dominant. We confirmed the expansions of CAG repeat in SCA 1 gene in both patients. Clinically, they showed cerebellar ataxia and pyramidal signs especially in the lower extremities. The Patient 1 showed progressive external ophthalmoplegia without nystagmus, generalized amyotrophy and choreic movement of the fingers in advanced stage. On X-ray CT scan or MRI, the brainstem and cerebellum of the patient 1 were mildly atrophic, while those of the patient 2 showed normal appearances. Olivopontocerebellar atrophy is essential histopathological feature of SCA 1. However, some cases exhibit normal appearances of the brainstem on radiological imagings, because the brainstem involvement is often mild in SCA 1 patients.

[Siblings of early onset cerebellar ataxia with hypoalbuminemia].

Recently, a new syndrome of early onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) was reported in Japan. The clinical features of EOCA-HA overlap with those of Friedreich's ataxia (FA), and primary hypoalbuminemia is a characteristic laboratory finding of this syndrome. Genetic linkage analysis of EOCA-HA including this newly reported family revealed that the gene for EOCA-HA is located on the long arm of chromosome 9 as FA. However, several recombination events were observed between D9S15 in EOCA-HA, whereas no recombination events were seen in FA. We report on two siblings with EOCA-HA and discuss the clinical and laboratory features. The patients were a 25-year-old man (patient 1) and a 23-year-old man (patient 2). Their parents marriage was non-consanguineous. The mode of inheritance is compatible with autosomal recessive mode. Clinically, they showed cerebellar ataxia as the initial symptom in the late infantile period and subsequently showed choreoathetosis and ocular motor apraxia at the age of approximately fifteen years. Deep tendon reflexes were reduced in late infancy and finally disappeared. Amyotrophy and sensory impairment of the legs developed at approximately twenty. Abnormal electrocardiogram and diabetes mellitus were not observed. On X-ray CT scan or MRI, the cerebella of both patients were mildly atrophic. Clinical features in these siblings were indistinguishable from those of ataxia telangiectasia, but immunodeficiency syndrome was absent.(ABSTRACT TRUNCATED AT 250 WORDS)

[Three patients of complicated form of autosomal recessive hereditary spastic paraplegia associated with hypoplasia of the corpus callosum].

We report three patients with slowly progressive spastic paraplegia and dementia; MRI on these patients revealed hypoplasia of the corpus callosum. The mode of inheritance was supposed to be autosomal recessive. Patient 1 (26-year-old man) is an elder brother of patient 2 (21-year-old man). Their parents are first cousins. Patient 3 (woman), a sporadic case, died of pneumonia at the age of 44. Their motor development after the birth was normal, but patient 3 was mildly mentally retarded. Gait disturbance due to spastic paraplegia developed at the age of nine (patient 2), fifteen (patient 1) and nineteen (patient 3), respectively. They also showed slowly progressive mental deterioration. Patient 1 has also suffered from mild amyotrophy and sensory disturbance in the distal part of the extremities since the age of 25. Patient 3 was bed-ridden at the middle of her thirty's because of generalized amyotrophy and sensory disturbance in addition to spastic quadriplegia and profound dementia. Their MRI reveal the thinning of the corpus callosum. We think the thinning must be hypoplasia of the corpus callosum, because the cerebrum showed normal appearance on MRI in patient 1 and patient 2. These clinical findings and imaging studies are essentially similar to those of the cases reported by Iwabuchi et al (1991). We propose autosomal recessive HSP associated hypoplasia of the corpus callosum as a new type of HSP.

[Widespread argentophilic structures in progressive supranuclear palsy--an autopsy case report].

We report an autopsy case of progressive supranuclear palsy (PSP) with a five-year clinical course. A 67-year-old man was suffering from a gait disturbance and mental deterioration. Neurological examination at the age of 71 revealed pseudobulbar palsy, horizontal ophthalmoplegia, and truncal dystonia, and a diagnosis of PSP was made. Mental deterioration including forgetfulness and character change was also noted, and the patient sometimes exhibited intermittent stuporous states. Cranial computed tomography and magnetic resonance images revealed moderate brain atrophy, predominantly in the frontal lobes. The patient died of bronchopneumonia at the age of 71. Neuropathological examination confirmed typical pathological changes of PSP, such as neuronal loss, neurofibrillary tangles, and fibrillary gliosis in the subcortical nuclei. Gallyas-Braak silver impregnation revealed neurofibrillary tangles, silver-positive glia and thread-like structures in degenerating subcortical nuclei. In addition to these classical lesions, the argentophilic structures were detected in the cerebral cortex, cortical white matter and cerebellar white matter. In the cerebral cortex, they were abundant mostly in the precentral gyrus and subcortical white matter. Immunohistochemical studies revealed that most silver-positive structures were also tau 2 antibody-positive. Thus, these argentophilic structures seemed to be closely related to abnormal tau protein. Their distribution in this case implies that lesions related to abnormal tau protein may occur more extensively in the brains of PSP than expected.

[A family with Menzel's disease showing dementia and various extrapyramidal symptoms].

UNLABELLED: Recent progress in neurology has revealed that hereditary olivo-ponto-cerebellar atrophy (OPCA) is in fact three different diseases. These are Menzel's disease, in which degeneration in the olivopontocerebellar (OPC) system is quite severe and similar to that of the patient described by Menzel in 1891, spinocerebellar ataxia 1 (SCA 1), in which the gene locus exists in the short arm of chromosome 6, and hereditary OPCA with retinal degeneration. We present a family with Menzel's disease, some of whom showed dementia and various extrapyramidal symptoms including tremor, myoclonus, and choreoathetoid involuntary movement. MATERIALS: This dominant hereditary cerebellar ataxia family had five affected members in four generations. Neuropathological examination of one member (Case 3) revealed Menzel's disease. There was severe degeneration in the OPC system, the substantia nigra, Clarke's column, the posterior column, and the anterior horn of the spinal cord, and slight-to-moderate degeneration in the globus pallidus and subthalamic nucleus. However, the dentate nucleus, spinocerebellar tracts, and oculomotor nucleus including the medial longitudinal fasciculus were spared. The brain weight was 990 g. Case 1 (Case 3's grandmother) developed slowly progressive ataxia at the age of 55. She showed no involuntary movement or dementia. She died at 63 years of age. Case 2 (Case 3's mother) developed ataxia at 42 years of age, followed by tremor of the hands and head, and died at age 57. She did not show dementia. Case 3 (the autopsied case) developed progressive ataxia at 27 years of age, followed by mental deterioration, tremor, myoclonus, and generalized amyotrophy and sensory disturbance during her fifth decade.(ABSTRACT TRUNCATED AT 250 WORDS)

[MELAS associated with diabetes mellitus and point mutation in mitochondrial DNA].

Point mutation of mitochondrial DNA has been described in the blood from a MELAS patient. The 39-year-old patient developed progressive dementia, stroke-like episodes, heart conduction defect (Lown-Ganong-Levin syndrome) and cortical blindness. CT scan revealed brain atrophy and low density areas in the bilateral occipital lobes. Laboratory tests showed hyperglycemia and lactic acidosis. Muscle biopsy showed ragged red fibers on Gomori trichrome staining. He was clinically diagnosed as having MELAS and insulin-dependent diabetes mellitus. Onset of diabetes mellitus and MELAS was almost same. Family history showed his mother's brother and sisters had also insulin-dependent diabetes mellitus. We amplified the leucine (UUR) tRNA gene from the patient's blood with polymerase chain reaction (PCR) and analysed it by restriction enzyme analysis and sequencing. Genetic analysis showed A-to-G substitution at the nucleotide position 3243 in the leucine (UUR) tRNA gene. This substitution made a new restriction site Apa I. Mutant DNA coexisted with wild type DNA (heteroplasmy). It is shown that in some types of mitochondrial encephalomyopathies, especially patients of Kearns-Sayre syndrome (KSS), diabetes mellitus is often complicated. And in KSS patients insulin receptor in normal, but insulin secretion from beta cells of pancreas is decreased. In MELAS patients, however, has diabetes mellitus been reported to be rarely complicated and relationship between MELAS and diabetes mellitus is not done. As far as we know, two cases, including ours, with genetically diagnosed MELAS have been reported to have diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Population prehistory of east Asia and the Pacific as viewed from craniofacial morphology: the basic populations in east Asia, VII.

Distance analyses were applied to 11 craniofacial measurements recorded in samples from East and Southeast Asia, Australia, Melanesia, Polynesia, and Micronesia for the purpose of assessing the biological affinities and possible origins of these populations. A clear separation between Australomelanesians and other populations from East and Southeast Asia and the Pacific is evident. The craniofacial variations suggest that the generalized Asian populations (Negritos, Dayaks, Lesser Sunda Islands, etc.) represent at least part of the morphological background of not only the majority of present Southeast Asians, but also the Neolithic Jomon people and their lineage in Japan, Polynesians, and western Micronesians. The original craniofacial features of Southeast Asians may have occurred as the result of convergent microevolution due to similar environmental conditions such as tropical rain forest. This supports the local-evolution hypothesis for modern Southeast Asian craniofacial features.

Comparison of craniofacial features of major human groups.

Distance analysis and factor analysis, based on Q-mode correlation coefficients, were applied to 23 craniofacial measurements in 1,802 recent and prehistoric crania from major geographical areas of the Old World. The major findings are as follows: 1) Australians show closer similarities to African populations than to Melanesians. 2) Recent Europeans align with East Asians, and early West Asians resemble Africans. 3) The Asian population complex with regional difference between northern and southern members is manifest. 4) Clinal variations of craniofacial features can be detected in the Afro-European region on the one hand, and Australasian and East Asian region on the other hand. 5) The craniofacial variations of major geographical groups are not necessarily consistent with their geographical distribution pattern. This may be a sign that the evolutionary divergence in craniofacial shape among recent populations of different geographical areas is of a highly limited degree. Taking all of these into account, a single origin for anatomically modern humans is the most parsimonious interpretation of the craniofacial variations presented in this study.