Polymorphism of NACP-Rep1 in Parkinson's disease: an etiologic link with essential tremor?

An allele (263bp) of the nonamyloid component of plaques (NACP)-Repl polymorphism has shown association with sporadic PD in a German population. The authors studied this polymorphism in 100 American PD patients and 100 healthy controls. The authors also studied 46 essential tremor (ET) and 55 Huntington's disease (HD) patients. Allele 263bp was significantly higher in PD patients (OR = 3.86) and ET patients (OR = 6.42) but not HD patients, compared with healthy controls. The association of allele 263bp with PD and ET suggests a possible etiologic link between these two conditions.

A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene.

OBJECTIVES: To identify the disease-causing mutation and its molecular consequence for a clinically distinct type of myotonic myopathy. BACKGROUND: The authors encountered a unique myotonic disorder of early onset in a 37-year-old man and his 47-year-old sister. METHODS: After examining known loci of inherited myotonic disorders, the authors looked for mutations within the CLCN1 gene using single strand conformation polymorphism and direct sequencing. To investigate the disease mechanism, reverse transcriptase PCR analyses of total RNA were performed. RESULTS: In the proband and his affected sister, two novel mutations comprising a compound heterozygous state in the CLCN1 gene were identified: 1) a base (G) insertion in exon 7 generating a premature termination codon (fs289X) in the D5 domain, and 2) a C-to-T substitution in exon 23 resulting in a missense mutation (P932L). These mutations accompanied a clinical phenotype that is distinguishable from recessive myotonia congenita by progressive generalized muscle weakness, severe distal muscle atrophy, joint contractures, high serum creatine kinase levels, and conspicuous myopathic changes on muscle histopathology. Reverse transcriptase PCR analyses detected only the P932L mutant mRNA in skeletal muscle, suggesting that the fs289X mRNA is degraded rapidly. CONCLUSIONS: These data suggest that fs289X is a null mutation, rendering the patients with the compound heterozygous genotype of fs289X/P932L to exclusively express P932L homomeric channels that may have caused the "dystrophic" phenotype.

Variability and validity of polymorphism association studies in Parkinson's disease.

BACKGROUND: In recent years, interest in gene-environment interactions has spurred a great number of association studies on polymorphism of different genes. OBJECTIVE: To review case-control studies of genetic polymorphisms in PD, and perform meta-analysis of individual gene polymorphism. METHODS: The authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD. The key words used were "PD" and "polymorphism." The authors supplemented the search with relevant references quoted in these published articles. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. RESULTS: The authors identified 84 studies on 14 genes, including dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), monoamine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acetyltransferase 2 (NAT2), APOE, glutathione transferase (GSTT1, GSTM1, GSTP1, and GSTZ1), and mitochondrial genes (tRNAGlu and ND2). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0). No significant differences were found for the other genes. CONCLUSION: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu. Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.

Alcohol dehydrogenase polymorphism and Parkinson's disease.

A particular alcohol dehydrogenase (ADH) polymorphism (allele A1) in the promoter region of the gene has been recently demonstrated to be associated with increased risk of Parkinson's disease (PD). In a case control study, we examine frequencies of ADH A1 allele in 100 PD patients (i.e. 200 alleles), 100 diseased controls (i.e. 200 alleles), and 194 healthy controls (i.e. 388 alleles). In addition, we study possible association of a combined non-amyloid component of plaque (NACP-Rep 1) allele and ADH A1 allele with risk of PD. There was no statistical significance of the frequencies of ADH A1 allele between PD patients 12/200 (6%), diseased controls 13/200 (6.5%), and healthy controls 20/388 (5.2%). No strong evidence of an association was found between ADH A1 allele and PD susceptibility in our study patients. There was also no suggestion of linkage disequilibrium between NACP-Rep 1 and ADH A1 alleles.

Serial magnetic resonance images in a patient with congenital sensory neuropathy with anhidrosis and complications resembling heat stroke.

We report the results of serial computerized tomography (CT) and magnetic resonance imaging (MRI) in a 9-month-old Japanese girl with the rare disorder, congenital sensory neuropathy with anhidrosis (CSNA). She developed a prolonged high fever, anorexia, and weight loss with laboratory findings of hemoconcentration and elevated levels of GOT, LDH and creatine phosphokinase (CK) in May 1995, and was hospitalized. The cerebrospinal fluid (CSF) was normal on admission. Elevation of CSF myelin basic protein on the 16th hospital day suggested a destruction of the myelin sheath. The first MRI performed on the 16th hospital day revealed no marked abnormalities when the patient exhibited a high fever, generalized tonic-clonic convulsions, and impaired consciousness. The patient had a persistent high fever, and developed a second generalized tonic clonic convulsion and became comatose. A second MRI on the 20th hospital day showed a bilateral symmetrical paracentral hypo-intensity of the white matter with occipital hypo-intensity on T2-weighted images. MRI findings were considered to represent the complications of the high fever with a loss of water from the cerebral cortices and deep white matter. MRI and CSF findings indicated the presence of brain damage due to the high fever.

Decreased cerebrospinal fluid levels of substance P in Machado-Joseph disease.

To clarify the mechanism of brain impairment in Machado-Joseph disease (MJD), we measured the cerebrospinal fluid (CSF) levels of substance P in 7 patients (mean age 45.7 +/- 12.09 years) with this disease. Four patients had type I and three had type II disease. Findings were compared with those obtained in 14 age-matched controls, 8 patients with Parkinson's disease, 7 patients with multiple system atrophy, and 6 patients with myopathy. The CSF level of substance P was significantly (p = 0.0000) lower in the patients with MJD, being 44.5% of the control value. However, the mean CSF levels of substance P in the patients with Parkinson's disease, multiple system atrophy, or myopathy did not differ significantly from that in the control subjects. The alteration in the CSF level of substance P may be related to the neurological impairment observed in MJD.

CSF beta-endorphin levels in patients with infantile autism.

We measured CSF levels of beta-endorphin, an opioid hormone, in 19 patients with infantile autism and in 3 patients with Rett syndrome, and compared them with control values. In infantile autism, CSF levels of beta-endorphin did not differ significantly from those of age-matched controls. There was no significant correlation between CSF levels and clinical symptoms, including self-injurious behavior, pain insensitivity, and stereotyped movement. However, CSF levels of beta-endorphin were significantly higher in the patients with Rett syndrome than in the control (p < .05). Data suggest that neurons containing beta-endorphin may not be involved in patients with infantile autism. Thus, there is no relationship between dysfunction of brain opioid and autism.

Baló's concentric sclerosis in a 4-year-old Japanese infant.

We report the youngest known case with Baló's concentric sclerosis (Baló's disease), a variant of multiple sclerosis. This 4-year-old Japanese boy was diagnosed by clinical manifestations and by characteristic findings on magnetic resonance imaging (MRI). Dexamethasone was given intravenously, 3 mg twice daily for 10 days. The clinical manifestations were resolved within 2 weeks, and the MRI findings were markedly improved after 3 weeks. Following the initiation of steroid therapy, he showed remarkable clinical and physical improvement. It cannot be excluded that the clinical improvement resulted from the steroid therapy.

Neuroimaging and neuropathologic findings in AIDS patient with cytomegalovirus infection.

This 21-year-old male with hemophilia A developed cytomegalovirus (CMV) retinitis associated with acquired immunodeficiency syndrome (AIDS). He had a history of numerous blood transfusions. Serum antibody titers became positive for human immunodeficiency virus (HIV), when the patient was 18 years of age. Three years later, he developed CMV retinitis due to his immunosuppression. Ganciclovir (DENOSINE, TANABE SEIYAKU CO., LTD., Osaka, Japan) therapy given for 4 weeks produced a marked improvement in the ocular fundal findings, but the neurologic signs and symptoms, including headache, hypoesthesia, disorientation, and dementia became worse. T2-weighted magnetic resonance imaging (MRI) demonstrated a diffuse high intensity area in the periventricular white matter and small focal or patchy lesions in the hippocampus, basal ganglia, midbrain, medulla oblongata and the nucleus dentatus. The patient died of HIV encephalopathy and CMV infection. Characteristic CMV intranuclear inclusion bodies were observed histologically in most sites of the brain including the hippocampus, white matter, basal ganglia, midbrain, medulla oblongata, nucleus dentatus and the retina. Infiltration by monocyte-macrophage and multinucleated giant cells, which are characteristic of HIV encephalopathy, were observed in the periventricular white matter and the hippocampus. In this patient, the neuroimaging findings were compatible with the neuropathologic observations. MR imaging proved useful in detecting the central nervous system (CNS) lesions of AIDS and CMV infection.

Facioscapulohumeral muscular dystrophy: clinical diversity and genetic abnormalities in Japanese patients.

We studied 71 Japanese individuals, 42 patients (30 familial and 12 sporadic) suspected to have facioscapulohumeral muscular dystrophy (FSHD) and 29 family members, clinically and genetically using the chromosome 4qter DNA marker p13E-11. Early onset FSHD was detected in 7 patients, tortuosity of retinal arterioles and hearing impairment in 3 patients, progressive respiratory failure in 3 patients and limb-girdle type muscular weakness in 6 patients. Thirty-six (85.7%) FSHD patients, 3 asymptomatic family members and 1 of 35 healthy volunteers showed EcoRI digestion fragments shorter than 28kb. New mutations were detected in 25% of the patients with shorter EcoRI fragment. The age of disease onset appeared younger with successive generations in 6 parent-child pairs in FSHD families. We confirmed the existence of phenotypic and genetic diversities in Japanese patients with FSHD. It is still difficult to explain the phenotypic diversity merely by the size of the abnormal EcoRI fragment detected with the p13E-11 probe.

CSF beta-endorphin levels in pediatric neurologic disorders.

To investigate pediatric brain impairment, beta-endorphin levels, one of the opioid peptides that modulate human high cortical functions, were measured in cerebrospinal fluid (CSF). The study included 19 patients with infantile autism, 3 patients with Rett syndrome, 6 patients with infantile spasms, 16 patients with aseptic meningitis, and 23 age-matched controls. In the control group, the CSF beta-endorphin concentrations were negatively correlated with increasing age. There was no correlation between body temperature and the levels, and no significant difference in the levels according to sex. In infantile autism, the CSF level was not significantly different from that in controls. In Rett syndrome, it was significantly higher, while in infantile spasms it was lower than in controls. In aseptic meningitis, the CSF beta-endorphin level was significantly higher than in controls. The alterations in CSF beta-endorphin levels may play a role in these neurologic disorders and/or in central nervous system (CNS) infections.

Lithogenic bile.

So-called authors' lithogenic bile [Ch greater than 7.5 mg/ml, (TBS + PL)/Ch weight ratio less than 20] corresponds to the bile which falls well above the micellar zone boundary on triangular coordinates with high concentration of cholesterol. The authors supposed that, in man like hamsters and squirrel monkeys, in the process of alimentary formation of cholesterol gallstones gallbladder bile of which cholesterol concentration was high, and (TBS + PL)/Ch ratio was as low as that of gallbladder bile with cholestrol gallstones seemed to be lithogenic.

Postirradiation fibrosarcoma following radical mastectomy.

A case of fibrosarcoma arising in the scar of the radical mastectomy with postoperative irradiation of breast carcinoma is reported. The tumors arose five times in spite of the extirpations including surrounding tissue since 11 years after radical mastectomy and postoperative irradiation. All of arisen tumors were diagnosed fibrosarcoma histologically and with every recurrence the aggravation of malignancy of tumors was shown. In this case, the primary tumor of the breast was infiltrating carcinoma and no sign of fibrosarcoma was noted histologically. The mastectomy scar was indicated the irradiation therapy postoperatively and fibrosarcoma developed 11 years after postoperative irradiation. Namely, this case agreed to the strict criteria of the postirradiation sarcoma proposed by Cahan et al. In this paper, a case of postirradiation fibrosarcoma arising in the scar of radical mastectomy for carcinoma is presented.

Wraparound end-to-end hepaticojejunostomy (Roux-en-Y) for intrahepatic pigment calculi.

Intrahepatic pigment calculi are frequently found in East Asia and are associated with a considerable morbidity and mortality. The various methods of surgical treatment are unsatisfactory. A wraparound end-to-end hepaticojejunostomy presented may provide an effective and alternative method of treatment.