Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Changes of immunomodulatory cytokines associated with omalizumab therapy for severe persistent asthma.

Omalizumab is an anti-IgE monoclonal antibody that was proven effective for the treatment of severe asthma. IgE plays a central role in allergic asthma, and an anti-allergic effect of omalizumab has been confirmed in terms of its impact on Th2 cytokines. The objective of the present study is to determine the influence of omalizumab on clinical parameters and circulating immuoregulatory cytokines. Patients with severe allergic asthma were enrolled and given four months of omalizumab therapy. Changes of symptoms and other parameters were assessed, including the asthma control test (ACT) score, morning peak expiratory flow (PEF), peripheral eosinophil count, total serum IgE, and pulmonary function tests. The use of corticosteroids and short-acting bronchodilators, as well as the number of unscheduled hospital visits, were monitored. Circulating levels of cytokines were analyzed with a multiplex cytokine immunoassay in patients with or without omalizumab therapy. Asthma symptoms (evaluated by the ACT score and morning PEF) improved with omalizumab treatment, while total IgE was elevated. Use of corticosteroids and short-acting bronchodilators and the number of unscheduled hospital visits for exacerbation of asthma were all reduced by omalizumab treatment. The level of macrophage inflammatory protein 1-δ (MIP1-δ) was significantly reduced after omalizumab therapy and was high in patients without omalizumab. IL-16 also tended to decrease with omalizumab therapy. Both MIP1-δ and IL-16 decreased as asthma improved over the 4-month period of omalizumab therapy. These findings suggest that omalizumab may act via IgE-mediated immunoregulation of MIP1-δ and IL-16.

Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma.

Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma.

Positron emission tomography demonstrated localized luxury perfusion in subacute sclerosing panencephalitis.

Positron emission tomography (PET) was performed on two patients in different stages of subacute sclerosing panencephalitis (SSPE) and compared with the concurrent computed tomography (CT) findings and clinical status. Case 1, which was in stage II, showed luxury perfusion in the anterior half of the cerebrum and decreases of cerebral blood flow and oxygen metabolism in the right frontal watershed zone, where CT showed low density. Case 2, which was in stage III, showed marked decreases of cerebral blood flow and cerebral metabolic rate of oxygen in all regions except the occipital region. The present PET study demonstrated that SSPE showed inflammatory-destructive progression and rostral-caudal progression. Further, it was suspected that low density on CT scan, especially in the watershed zone, resulted partly from disturbances in cerebral circulation.

Cerebral blood flow and oxygen metabolism in rett syndrome.

Positron emission tomography was performed on six patients with Rett syndrome to investigate cerebral blood flow and oxygen metabolism, and the results were compared with the concurrent clinical status of the patients. The cerebral metabolic rate of oxygen (CMRO2) was low in five patients, and oxygen extraction fraction was low in four patients; both had a tendency to decline with advancing age. Although the cause is unknown, it is suggested that impaired oxidative metabolism exists in Rett syndrome. An analysis of the distribution among brain regions showed that the ratios of values for the frontal cortex to those for the temporal cortex for both cerebral blood flow and CMRO2 were lower than those for the controls, which may indicate the loss of hyperfrontality in Rett syndrome.

Reduced regional cerebral metabolic rate for glucose at the terminal stage in a case of late infantile neuronal ceroid lipofuscinosis.

Regional cerebral metabolic rate for glucose was determined for six different areas of the gray matter in an 8-year-old girl with late infantile neuronal ceroid lipofuscinosis. In all regions, the rates were almost half of the control values. The regional cerebral metabolic rate for glucose was relatively preserved in the striatal region and severely reduced in the frontal cortex.

A phase II study of carboplatin-cisplatin-etoposide combination chemotherapy in advanced non-small-cell lung cancer.

It is reported that the combination of cisplatin (CDDP) and carboplatin (CBDCA) is synergistic in vitro. The objective of this study was to evaluate the therapeutic effect and safety of the two platinum compounds in combination with etoposide in the treatment of non-small-cell lung cancer (NSLC). Forty patients were registered. Based on the results of a phase I study, patients were treated with CDDP (80 mg/m2 i.v. on day 1), CBDCA (280 mg/m2 i.v. on day 1), and etoposide (80 mg/m2 i.v. on days 1-3). Of the 40 patients, 30 were men and 10 women. Histology revealed adenocarcinoma(AC) (n = 20), squamous cell carcinoma(SCC) (n = 18), and large cell carcinoma(LCC) (n = 2). Staging: IIIA (n = 3); IIIB (n = 17); and IV (n = 20). A 32.5% overall response rate [13 of 40; 95% confidence interval (CI) 18-47%] was achieved. The response rates in patients with SCC and AC were 55.6 and 10.0% (p < 0.005), respectively. The median duration of response was 47.1 weeks and the overall median survival time was 57.1 weeks. Leukopenia and thrombocytopenia--World Health Organization (WHO) grade IV--occurred in nine and 11 patients, respectively. Nonhematological toxicities were mainly nausea, vomiting, and alopecia. In conclusion, further investigations of this regimen are warranted in the treatment of NSLC.

A phase II study of combined chemoradiotherapy for limited disease-small-cell lung cancer.

A study to evaluate the efficacy of cisplatin, doxorubicin, and etoposide chemotherapy with combined radiotherapy was undertaken in 26 patients with limited disease-small-cell lung cancer. Patients were treated with cisplatin (80 mg/m2) intravenously (i.v.) on day 1, doxorubicin (30 mg/m2) i.v. on day 1, and etoposide (80 mg/m2) i.v. on days 1, 3, and 5, every 4 weeks for four cycles. Thoracic irradiation of 40 Gy in 20 fractions was delivered during 4 weeks to the primary site starting on day 8 of the second cycle of chemotherapy. The objective response rate was 100%. A complete response was observed in 10 patients (38%). The median survival time was 23 months, and the 3-year survival rate was 42%. Seven patients (27%) continued to survive at least 8 years and remain free from disease. Grade III/IV leukopenia was observed in 25 patients (96%). Grade III/IV thrombocytopenia developed in 19 patients (73%). Grade III/IV esophagitis was not seen. Interstitial pneumonitis occurred in two patients. This regimen is effective and has acceptable toxicity for use in the treatment of limited disease-small-cell lung cancer.

Phase I study of a carboplatin-cisplatin-etoposide combination chemotherapy in advanced non-small-cell lung cancer.

Cisplatin (CDDP)-containing chemotherapy has become the mainstay of clinical trials in unresectable non-small-cell lung cancer (NSCLC), but the role of chemotherapy in the routine management of NSCLC remains controversial. We conducted a phase I study with the combination carboplatin (CBDCA), CDDP, and etoposide (Etop) in unresectable NSCLC. CBDCA, at a starting dose of 80 mg/m2, on day 1, was combined with a fixed dose of CDDP (80 mg/m2, day 1) and Etop (80 mg/m2, days 1-3). Escalation was performed after four patients entered at each dose level. If no World Health Organization (WHO) grade 4 toxicity developed after the first cycle in more than half of the patients or WHO grade 3/4 toxicity in more than two thirds, the dose was escalated. The maximum tolerated dose was established at 300 mg/m2 for CBDCA. Thrombocytopenia and leukopenia were the dose-limiting toxicities. No grade 3/4 nonhematologic toxicities were seen. The recommended dose of CBDCA to be combined with CDDP (80 mg/m2, day 1) and Etop (80 mg/m2, days 1-3) is 280 mg/m2. This trial suggests that our combination chemotherapy may be effective in patients with advanced NSCLC. A multicenter phase II study based on these findings is now under way.

Uncoupling of blood flow and oxygen metabolism in the cerebellum in type 3 Gaucher disease.

Cerebral blood flow and oxygen metabolism were measured in a fourteen-year-old girl with type 3 Gaucher disease by using positron emission tomography (PET). Cranial CT and MRI showed only mild brain atrophy. PET demonstrated uncoupling of cerebral blood flow and oxygen metabolism, that is, a mild increase of cerebral blood flow and a reduction of oxygen extraction fraction and cerebral metabolic rate of oxygen only in the cerebellum. Although the mechanism is unknown, the above finding may reflect the underlying pathogenesis of the disorder. PET seems to be more sensitive than CT and MRI in detecting some functional abnormalities in the affected structures. However, further investigations must be done before concluding that this finding is unique to type 3 Gaucher disease.

Crossed cerebellar diaschisis in the Sturge-Weber syndrome.

Crossed cerebellar diaschisis (CCD) is known as a cerebellar hemispheric hypometabolism due to contralateral supratentorial infarction or tumor. We report a case with the Sturge-Weber syndrome (SWS), whose cerebral blood flow was reduced in the anatomically affected lesion of cerebrum and in the contralateral cerebellar hemisphere. Not only acquired diaschisis, but congenital ischemic disorders such as SWS also showed CCD.

Cerebral blood flow and oxygen metabolism in the Rett syndrome.

Positron emission tomography (PET) was performed on six patients with the Rett syndrome and the results were compared with the concurrent clinical status of the patients. The cerebral metabolic rate of oxygen (CMRO2) was low in five patients, and oxygen extraction fraction (OEF) was low in four patients; both had a tendency to decline with advancing age. Although the cause is unknown, it is suggested that impaired oxidative metabolism exists in the Rett syndrome. An analysis of the distribution among brain regions showed that the ratios of values for the frontal cortex to those for the temporal cortex for both the cerebral blood flow (CBF) and CMRO2 were lower than those for the controls, which may indicate the loss of hyperfrontality in the Rett syndrome. Distribution of brain metabolism may be immature in the Rett syndrome.

Decreased blood flow and oxygen metabolism in the cerebellum, brain stem and thalamus in a case with Menkes kinky hair disease.

Cerebral blood flow and oxygen metabolism were measured in a five-year-old boy with atypical Menkes kinky hair disease (MKHD) by using positron emission tomography (PET). The patient was diagnosed as having atypical MKHD because of low serum and urinary copper levels, and clinical symptoms. The CT revealed mild to moderate degrees of brain atrophy predominantly in the cerebellum. The PET demonstrated marked decreases of cerebral blood flow and oxygen metabolism in the cerebellum, brain stem and thalamus. These findings seem to reflect the neuropathological abnormalities observed in MKHD. PET seems to be more sensitive than CT in detecting abnormalities in the affected structures. However, because this case is atypical the question of whether typical cases show similar features on the PET remains.

Cerebral glucose metabolism in five patients with Lennox-Gastaut syndrome.

Regional cerebral glucose metabolic rates were estimated by positron emission tomography, in parallel with electroencephalography and cranial computed tomography in 5 patients with Lennox-Gastaut syndrome. The 5 patients, 3 boys and 2 girls, ranged in age from 10-15 years. Computed tomography revealed no gross abnormalities. Each patient received 2-5 mCi of 2-(18F)-fluoro-2-deoxy-D-glucose (18F-FDG) intravenously. Averaged cerebral glucose metabolic rates were reduced in each cerebral region as compared with controls. Unilateral hypometabolism was present in 4 patients: one in the inferior frontal gyrus as well as the posterior portion of the superior temporal gyrus; one in the inferior frontal gyrus; one in the posterior portion of the superior temporal gyrus; and one demonstrated diffuse hemispheric hypometabolism including the inferior frontal and posterior portion of the superior temporal gyrus. The side of hypometabolism was the same as the epileptogenic focus on the electroencephalogram. No focal changes were demonstrated on the electroencephalogram of a patient whose positron emission tomography revealed hemispheric hypometabolism. Hypometabolism of the inferior frontal and posterior portion of the superior temporal gyrus may relate to the possible pathogenesis of Lennox-Gastaut syndrome. Positron emission tomography has the potential to reveal a latent focal or lateralized abnormality in some patients with non-localized electroencephalographic changes.

[Cerebral blood flow and oxygen metabolism in Rett syndrome].

Positron emission tomography (PET) was performed in four patients with Rett syndrome (RS) to elucidate the cerebral blood flow and oxygen metabolism. Cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) were measured quantitatively with HEADTOME-IV using 15O2, C15O2 steady state inhalational technique. As to the correlation between CBF and CMRO2, these four patients were compared with nine cases with other neurological disorders. Case 1, the youngest girl among the patients, showed milder symptoms than others. In all patients, no abnormal findings except for mild brain atrophy were seen on CT. In case 1, values of CBF might be lower for her age than normal values by the report of Kety. OEF was markedly reduced in all regions of three patients with RS (cases 2, 3, 4). These decreased OEF might be caused by reduced oxygen metabolism. However, case 1 which was the youngest and had milder symptoms, showed almost normal values of OEF. The distribution of CBF and CMRO2 was thought not to be abnormal in all patients. On the other hand, there was no discrepancy between CBF and CMRO2 in nine neurological control subjects. Decreased value of OEF was known to be seen in mitochondrial encephalopathy as well as an early stage of cerebral infarction. In mitochondrial encephalopathy, OEF was thought to decrease by reduced oxygen metabolism due to disturbance of aerobic glycolysis. Although the cause of reduced oxygen metabolism in RS was obscure, these results suggested that in RS there was some disturbance of oxygen metabolism of the brain, and values of OEF might be related to clinical status of RS or age.

[Clinical features of cases whose cerebral blood flow was preserved only in the basal ganglia region].

In the series of our studies of positron emission tomography (PET), we had some cases whose cerebral blood flow was reduced in the cerebrum, cerebellum and brain stem, and was preserved only in the basal ganglia region. We studied their clinical features and electrophysiological findings of these cases. These 5 cases included neuronal ceroid lipofuscinosis, Krabbe disease, Tay-Sachs disease, progressive myoclonus epilepsy and subacute sclerosing panencephalitis. Clinically they showed symptoms associated with diffuse cerebral and brain stem involvements. Electrophysiological studies also revealed the involvements of cerebrum and brain stem. These 5 cases were classified to persistent vegetative state clinically. Vegetative state was considered to be heterogeneous concerning about cerebral metabolism. There may be one group presenting a peculiar cerebral metabolic condition described here in vegetative states. And this condition may be specific to some neurodegenerative or metabolic disorders that involve cerebellum and brain stem as well as cerebrum.

[Localized lesions on MRI in the globus pallidus, subthalamic nuclei and hippocampus in patients with severe intellectual and motor disabilities].

We examined the clinical picture of eight patients with severe intellectual and motor disabilities, who had experienced prolonged and severe neonatal jaundice, and showed localized lesions in the globus pallidus, subthalamic nuclei and hippocampus on MRI. All patients had athetoid tetraplegia, and five patients showed disturbed ocular movements and seven showed dysphagia. Five patients could communicate with others or utter words, and all showed mental retardation. Auditory brainstem responses were abnormal in seven, and the percentage of REM sleep on all-night polysomnography was reduced in three. Neither CT nor T1-weighted MR images could detect any changes in the pallidum or subthalamic nuclei, while T2-weighted MR images disclosed bilateral high signals in the pallidum, especially in the internal segment, in all patients. Five of the 7 patients, in whom coronal T2-weighted MR imagings were obtained, showed high signals in the subthalamic nuclei. The hippocampus showed atrophy and/or T2-prolongation in seven patients. In one autopsy case, these MRI changes were concordant with pathological lesions. In patients with athetoid cerebral palsy, brainstem dysfunctions, and abnormal ABR, localization of MRI lesions to the pallidum and subthalamic nuclei is evidence for neonatal bilirubin encephalopathy.

[Long-term clinical course of sequelae in patients with neonatal anoxic encephalopathy resulting in profound mental retardation and motor disturbance].

A long-term observation has been made in 58 patients (30 males and 28 females) with severe sequelae of neonatal anoxic encephalopathy. They aged from 8 months to 65 years. All of them had motor disturbances and profound mental retardation. Motor function was improved in 4 patients with aging. In contrast, motor activity deteriorated in 11 cases, of which 4 showed a mental regression. Among them, patients who had originally better motor ability than sitting were likely to deteriorate by uncontrollable epilepsy and/or excessive administration of anticonvulsants. Regression of the patients with worse motor ability like bedridden appeared to attributable hypertonia of muscles and bodily deformation. Fifteen cases showed an exacerbation of general condition which originated predominantly to respiratory distress. Twelve patients died including 6 exacerbated cases. Exacerbation or death may have occurred frequently in specific periods of infancy, adolescence and youth with the patients who showed very low motor function such as bedridden and no locomotion.

[The cranial MRI in severe cerebral palsy: a comparative study with clinical data].

The magnetic resonance examination was performed in 38 patients with severe cerebral palsy (CP; 15 males and 23 females) who had both motor delay (unable to move anywhere) and mental retardation (I. Q or D. Q below 30). Neuroimaging findings were compared with the CP type, etiology, and grade of understanding of language. Cranial magnetic resonance imagings (MRI) in CP were divided into five types. Type 1 : nine predominantly showed cyst-liked ventricles and periventricular hyperintensity on T2-weighted imaging (PVH) and only scarred basal ganglia and thalamus were visible. All suffered from neonatal asphyxia and the clinical type was rigospastic tetraplegia (RST). Type 2: eleven predominantly showed PVH and hyperintensity on T2-weighted (HT2) in basal ganglia and thalamus. All suffered from neonatal asphyxia and the clinical type was RST or rigospastic diplegia. Type 3: five showed PVH and three had cortical atrophy. All suffered from neonatal asphyxia and the clinical type was spastic diplegia. Type 4: four predominantly showed HT 2 in putamen and thalamus. Three had cortical atrophy. All suffered from neonatal asphyxia. The clinical type was athetotic CP (ATH). Type 5: nine predominantly showed HT 2 in globus pallidus. Four had cortical atrophy and two had hippocampal atrophy. All suffered from neonatal jaundice and the clinical type was ATH. All patients who suffered from neonatal asphyxia and spastic CP had MRI in PVH. All patients who suffered from neonatal asphyxia and ATH showed HT 2 in putamen and thalamus. Almost patients who suffered neonatal jaundice and ATH showed HT 2 in globus pallidus. With athetotic CP, cases with atrophy of the cerebral cortex or/and hippocampus were lower grade of understanding of language than no atrophy of both. The result of studies of MRI are in agreement with neuropathological findings.

[Penetration of the esophageal and gastric ulcers to the cardioaortic system following hiatus hernia: a lethal complication in the severely-handicapped].

Among the severely-handicapped, hiatus hernia (HH) and/or gastroesophageal regurgitation (GER) are not uncommon. We report here three patients with HH and/or GER. Two of them died of massive hemorrhage in the alimentary tract from the heart or the thoracic aorta due to penetration of the gastric or esophageal ulcer. The third patient died of pneumonia, but autopsy proved multiple esophageal ulcers, one of which reached the wall of the brachiocephalic artery without penetration. We propose that proper treatment for HH and/or GER is required for the severely-handicapped, including surgical intervention, before their general conditions become worse and decompensatory.