The first genetically confirmed Japanese patient with mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is a rare neurodegenerative disorder characterized by severe psychomotor delay and visual impairment. We report the brain pathology in the first Japanese patient of MLIV with a novel homozygous missense mutation in MCOLN1. We detected the localized increase in p62-reactive astrocytes in the basal ganglia.

Ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities.

Nasogastric tube feeding is a common method of parenteral nutrition. We observed ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities (SMID) during examination with a laryngeal fiberscope while swallowing. These ulcers were healed by changing the method of inserting the nasogastric tube. The patients were three men aged 25, 39, and 55 years. The muscle tone of the whole body was increased in all of the patients. Two patients had severe scoliosis, and the other patient had lordosis in the thoracic vertebrae and had received laryngo-tracheal diversion. All of the patients received intermittent or continuous respiratory care. The pharynx of the patients with severe scoliosis became thinner and the feeding tubes ran obliquely. The feeding tube in the patient who received laryngo-tracheal diversion entered the cut and closed trachea through the glottis. Ulcers were observed on the laryngeal side of the epiglottis in all of the patients. The ulcers were healed by preventing feeding tubes from running obliquely or by using the naso-gastric tube made of different materials in the patients with severe scoliosis. In the patient who received laryngo-tracheal diversion, we succeeded in avoiding the glottis by keeping his face forward while inserting the feeding tube. Then feeding tubes were changed with guidewires, and the ulcers were healed. When using nasogastric tube feeding for persons with SMID with a large increase in muscle tone and/or with severe scoliosis, adopting a method of inserting feeding tubes that avoids damaging the epiglottis with a laryngeal fiberscope is required.

[A case of melioidosis occurring after a long-term stay in Vietnam that developed pulmonary cavitation and relapsed with multiple pulmonary nodules].

A 69-year-old man complained of fever in September 2009, after returning from Vietnam where he has been working for 20 years. He had diabetes mellitus and was on diabetic oral medication. He was examined at a nearby hospital, and found out to have pneumonia with cavity formation in the right upper lobe which was found out to be not due to tuberculosis. Although the patient once recovered with antibacterial medicine, after a few months, in January 2010, he was admitted to our hospital because of recurrent fever. Computed tomography revealed multiple pulmonary nodules which were thought to be pulmonary emboli, as well as subcutaneous abscess, spleen abscess, and kidney abscess. Blood test showed that he also had DIC. As Burkholderia pseudomallei was cultured from the subcutaneous abscess and blood, was diagnosed as melioidosis. The patient was treated with meropenem for 8 weeks, and then a maintenance oral antibacterial medicine was continued for the next 6 months. The patient fully recovered after those treatments and has not relapsed since then. This is the ninth case report of melioidosis in Japan which is an imported infectious disease.

[Clinical features of reversed halo sign in cryptogenic organizing pneumonia].

Reversed halo sign (RHS) is often seen in computed tomography (CT) scans of cryptogenic organizing pneumonia (COP). To investigate its clinical features, we retrospectively reviewed 30 cases of COP in 13 men and 17 women, whose age range 28 to 73, with a mean of 58.4 years. All diagnoses were made with transbronchial lung biopsy (TBLB), but it took an average of 24.8 days from the first visit until the diagnosis of COP. RHS was seen in 7 cases (23%) and multiple RHSs were seen in 3 cases. We treated 5 cases (71%) with steroids. Their CT images showed parenchymal abnormalities which started as nodular lesions, then enlarged, and then the central lesion changed into ground-glass opacities, until finally, RHS was formed. The presence of RHS does not necessarily indicate a marked difference in the clinical course of COP. In conclusion, in the present series RHS was a phase of the clinical course of COP, and was useful to diagnose COP.

[Usefulness of serum procalcitonin measurement in the diagnosis of respiratory infectious diseases].

The serum concentration of procalcitonin (PCT) is specifically elevated in severe bacterial infections. In Japan, PCT has been used as a serum marker for bacterial sepsis since February, 2006. However, the evidence of it in respiratory infectious diseases is limited. In the present study, we analyzed 57 episodes of systemic inflammatory response syndrome in 53 inpatients to investigate the usefulness of serum PCT measurement in respiratory infectious diseases. Although the sensitivity and a negative predictive value in common bacterial infections were low, the specificity and positive predictive value were 95% and 93%, respectively. This suggests that the significance of serum PCT measurement relies on confirming the diagnosis of common bacterial infections. Analysis using a receiver operating characteristic (ROC) curve demonstrated that serum PCT was a more reliable measure of bacterial sepsis than leukocyte counts in the peripheral blood or serum C-reactive protein. In cases of community-acquired pneumonia, except atypical pneumonia, the hospital mortality rate was significantly higher in PCT-positive patients than in PCT-negative patients (38% vs. 0%), indicating that serum PCT could be a factor predicting in-hospital death.

[A case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung].

We report a rare case of extranodal NK/T-cell lymphoma, nasal type, with skin ulceration and multiple nodules in the lung, and will compare this case with others in the literature. A 54-year-old man was troubled with flare and swelling of his right arm for one month. He was referred to our hospital because of subcutaneous nodules with ulceration on the right arm, fever, and general fatigue. Chest radiograph revealed multiple nodular shadows in both lungs. The patient was admitted for further evaluation. Chest computed tomography revealed multiple nodules in both lungs with ground-glass opacities around some of them. Some nodules seemed to be clustered in the right lower lobe. Biopsy specimens of subcutaneous nodules and transbronchial biopsy specimens of pulmonary tissue demonstrated only extensive necrosis. A VATS lung biopsy from the right S9 was then taken. Pathological and immunohistological findings suggested a diagnosis of extranodal NK/T-cell lymphoma, nasal type (WHO classification), stage IVB. The patient was transferred to the department of hematology in another hospital for systemic chemotherapy, but died 2 months later.

[A case of pulmonary aspergillosis subacutely forming a cavity during the course of microscopic polyangiitis].

A 77-year-old woman was referred to our department with hemoptysis. Microscopic polyangiitis (MPA) with resultant alveolar hemorrhage was diagnosed because of diffuse infiltrate of the right lung, proteinurea, renal dysfunction and the presence of MPO-ANCA. The disease responded well to corticosteroid therapy. She was discharged, but as corticosteroid was gradually tapered, an irregularly-shaped nodule appeared in the right upper lung field within 2 weeks. She was re-admitted because the nodule increased in size with cavity formation in spite of the administration of antibacterial agent. Pulmonary aspergillosis was diagnosed, since bronchial washing and transbronchial lung biopsy revealed the presence of Aspergillus fumigatus. Serum beta-D-glucan was decreased and the cavity was reduced in size, responding to the treatment with micafungin. However, she died later of systemic infection by a herpesvirus. We report this case because of the interesting course of pulmonary aspergillosis that subacutely formed a cavity.

Oxidative stress as a biomarker of respiratory disturbance in patients with severe motor and intellectual disabilities.

Oxidative stress plays an important role in aging and various diseases such as cancer, cardiovascular diseases, diabetes mellitus and bronchial asthma. However, little is known about a potential role of oxidative stress in the pathogenesis of severe motor and intellectual disabilities (SMID) in terms of respiratory disturbance, which is the most common complication. In the present study, we examined the urinary levels of oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG), hexanoyl-lysine adduct (HEL) and acrolein-lysine adduct (ACR) in patients with SMID. The mean level of urinary 8-OHdG in SMID patients was significantly higher than that in normal controls (18.8 +/- 9.0 ng/mg Cre and 10.5 +/- 2.9 ng/mg Cre, respectively) (p < 0.01). There was no significant difference of the mean level of urinary HEL between patients with SMID and normal controls (81.9 +/- 40.3 pmol/mg Cre and 69.2 + /-37.7 pmol/mg Cre, respectively), while the mean level of ACR in patients with SMID was higher than that of normal controls (220.5 +/- 118.6 nmol/mg Cre and 144.9 +/- 62.0 nmol/mg Cre, respectively) (p < 0.05). In addition, the level of 8-OHdG was strongly correlated with the severity of respiratory disturbance evaluated as the respiratory disturbance score (RDS) (Spearman r = 0.73, n = 14, p < 0.01). In contrast, there was no correlation between the levels of these oxidative stress markers and age or medication of antiepileptic drugs. These results suggest that urinary 8-OHdG is a potentially useful biomarker for evaluating the severity of respiratory failure in patients with SMID.

Protracted juvenile neuronal ceroid lipofuscinosis--an autopsy report and immunohistochemical analysis.

The juvenile form of neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene, and is characterized by progressive loss of vision and development of motor deficits. A few patients exhibit a more protracted clinical course and are diagnosed with protracted JNCL (PJNCL). Here, we report the autopsy in a case of PJNCL in a 55-year-old male and immunohistochemical examination of the involvement of oxidative stress and glutamate excitotoxicity in neurodegeneration. The patient was born to consanguineous parents (I assume this means that the parents were related. If not, then the sentence will need to be changed again.) and had brothers with similar neurological disease. He showed mental retardation and visual impairment in the first decade which gradually developed along with motor dysfunction for over 40 years. At autopsy, the cerebral pyramidal neurons revealed deposition of lipopigments, which demonstrated 'finger print' and curvilinear profiles on electron microscopy. He also exhibited cerebellar cortical atrophy, fibrillary gliosis in the white matter, and rarefication in the globus pallidus. Immunohistochemically, the number of neurons immunoreactive for advanced glycation end product was elevated in the cerebellar cortex and midbrain. Immunoreactivity for excitatory amino acid transporter 1 was reduced in the cerebellar dentate and inferior olivary nuclei. These findings suggest that oxidative damage to proteins and disturbed glutamate transport can be involved in PJNCL.

Mechanisms of neurodegeneration in neuronal ceroid-lipofuscinoses.

Neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative diseases and autosomal recessive lysosomal storage disorders. We examined the involvement of cell death, oxidative stress, and glutamate excitotoxicity using immunohistochemistry against Bcl-2, Bcl-x, oxidative products to proteins, lipids and DNA, calcium-binding proteins (calbindin-D28K, parvalbumin, calretinin), and glial glutamate transporters (excitatory amino acid transporters 1 and 2), in addition to terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) in the brains from three cases of late infantile form of NCL (LINCL) and one case of juvenile form of NCL (JNCL) to investigate the neurodegenerative mechanisms. In the cerebral and cerebellar cortex, all of three LINCL cases demonstrated neurons with TUNEL-immunoreactive nuclei, whereas the JNCL case did not show TUNEL-immunoreactive nuclei. The coexistence of the nuclear TUNEL-immunoreactivity nuclei and cytoplasmic deposition of 4-hydroxy-2-nonenal-modified protein in the frontal cortex and hypoglossal nucleus may suggest a possible interrelationship between DNA fragmentation and lipid oxidation in LINCL. Additionally, glycoxidation of protein and oxidative stress to DNA seemed to be involved in the cerebellar and cerebral degeneration, respectively. Interneurons immunoreactive for calbindin-D28K and parvalbumin were severely reduced in the cerebral cortex, whereas those for calretinin were comparatively well preserved in LINCL, indicating the possibility of altered GABAergic system. The disturbance of expression of glial glutamate transporters seemed to be heterogeneous and mild. These findings suggest the possibility of new treatments for neurodegeneration in LINCL using antioxidative agents and/or GABAergic medications.

An autopsy case of caudate nucleus lobulation accompanied with diaphragmatic eventration.

We describe an autopsy female case of multiple anomalies with lobulation of caudate nucleus tail, diaphragmatic eventration, skeletal anomalies, pyramidal tract anomaly, and meningothelial meningioma. Her psychomotor development was delayed, and she developed bilateral eventration of the diaphragms on X-ray film in her third decades. Right hemi-colonectomy was performed for volvulus at the age of 44 years, and meningioma was incidentally identified. She died at the age of 47 years. Autopsy demonstrated the partial deficiency of the muscular tissue in the circular thinned membranous area predominantly on left side including the central tendon of the diaphragm. The tails of the bilateral caudate nucleus demonstrated excessive lobulations, and the brainstem pyramidal tract showed hypoplasia. Immunoreactivity for tyrosine hydroxylase was deficient in the lobulated tail of caudate. We believe that this case is characterized by a rare combination of eventration, skeletal and nervous anomalies.

Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival.

In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R-R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified.

Pathological study of bronchospasms/tracheomalasia in patients with severe motor and intellectual disabilities.

This report concerns two autopsy cases of severe motor and intellectual disabilities (SMID) who died of bronchospasms or tracheomalasia. One case had no anatomical change in the tracheal wall except for an endotracheal granuloma, while the other showed softening of the tracheal wall. Since patients with SMID have risk factors for bronchospasms and tracheomalasia, such as gastro-esophageal reflux, aspiration, and thoracic deformities, it is important that we suspect the possibility of these conditions, when we see the respiratory distress in cases of SMID.

Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes.

Clinicopathological features of the renal disease in Arima syndrome were studied in five autopsy cases. All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure. Decreased urinary concentrating ability and excessive sodium loss were the characteristic laboratory findings. Gross examination showed that both kidneys were small and showed multiple cysts of various sizes. The histological examinations revealed chronic sclerosing tubulo-interstitial nephropathy with cystic tubuli predominantly located at cortico-medullary areas. These observations suggest that the renal disease in Arima syndrome is in accordance with nephronophthisis both clinically and pathologically. Contrary to the previous literature which described that Arima syndrome can be distinguished from other Joubert-related cerebello-oculo-renal syndromes by its unique renal disease, i.e., cystic dysplastic kidney (CDK), our study indicates that the phenotype of the renal disease is common among these syndromes as well as abnormalities in other organs, suggesting the underlying similar molecular mechanisms.

Laryngeal dystonia in a case of severe motor and intellectual disabilities due to Japanese encephalitis sequelae.

Laryngeal dystonia is characterized by stridor due to vocal cord dystonia and is observed in extrapyramidal disorders. Recently, botulinum toxin injection has been used as a primary therapy. Generally, severe motor and intellectual disabilities (SMID) are frequently complicated by various types of respiratory disorders. We report a SMID case with Japanese encephalitis sequelae showing repeated vocal cord abductor disturbance due to laryngeal dystonia, in addition to generalized dystonia, in whom MRI revealed basal ganglia lesions. Tracheostomy was effective for the case, and we believe that botulinum toxin injection may be inappropriate in SMID, both ethically and technically. Also, laryngeal dystonia should be considered as a cause of respiratory disorders in SMID.

Thalamic lesions in a long-surviving child with spinal muscular atrophy type I: MRI and EEG findings.

Brain magnetic resonance imaging was conducted in a girl with genetically confirmed spinal muscular atrophy (SMA) type I. This patient has survived 6 years, to date, under mechanical ventilation. T2-weighted and fluid-attenuated inversion recovery images revealed high signal intensity lesions in the anterolateral portions of the bilateral thalami. Electroencephalography disclosed diffuse beta activity upon awakening and during light sleep. In addition, fast and prolonged spindles were observed. Although mild neuronal changes in the lateral nucleus of the thalamus have been described in several autopsied cases, this is the first study to demonstrate neuroradiologically and neurophysiologically the thalamic lesions in genetically confirmed SMA type I.

Peculiar form of cerebral microdysgenesis characterized by white matter neurons with perineuronal and perivascular glial satellitosis: A study using a variety of human autopsied brains.

Microdysgenesis (MD) is a neuropathological term that implies a variety of minor developmental abnormalities of the brain. Recently, MD has been used for pathological diagnosis of cerebral tissues surgically resected from epileptic patients. However, criteria or consensus on pathological diagnosis of MD is still vague and controversial because of the lack of control studies. Therefore, this study paid special attention to the presence of white matter neurons with perineuronal glial satellitosis (WMN-GS) and perivascular glial satellitosis (PVGS) in the white matter, which are occasionally observed in epileptic foci, in order to clarify whether they could be handled as definite findings of MD. The materials included 80 autopsied whole brains ranging from normal subjects to patients with cerebrovascular disorder, neurodegenerative diseases and malformations. In each case, the presence of WMN-GS and/or PVGS was searched in 10 gyri in all five lobes (rostral frontal lobe, caudal frontal lobe, parietal lobe, temporal lobe and oc-cipital lobe) and evaluated. Statistically significant, WMN-GS and/or PVGS preferentially appeared in a diseased group consisting of neuronal migration disorder and related conditions, such as polymicrogyria, nodular heterotopia or tuberous sclerosis, leading to a suggestive conclusion that the presence of WMN-GS and/or PVGS could be a peculiar form of MD possibly derived from neuronal migrational arrest or related events, even if they appear alone without any other gross abnormalities.

Autopsy case of multiple anomalies with hypoplastic cerebrum, eyes, and endocrine organs, mimicking Micro syndrome.

We report an autopsy case of multiple anomalies with severe micrencephaly, bilateral microphthalmos, and hypoplastic endocrine organs. We examined expressions of calcium-binding proteins and hypothalamic and pituitary hormones. A female proband presented with microcephaly, microphthalmia, and psychomotor development delay. At the age of 23 years, she died of cardiorespiratory failure. The endocrine organs demonstrated severe underdevelopment, and the hypoplastic eyeballs had remnant lens, vitreous hemorrhage, and retinal detachment. The brain weighed 260 g; the cerebrum, cerebellum, and brain stem were extremely small; and the tertiary sulci were absent in the cerebral surface. The cross-sectional area of cerebral cortex was reduced to about one third of those in the control, although six-layered lamination, density of pyramidal neurons, and expressions of calcium-binding proteins were comparatively preserved in the cerebral cortex. The third ventricle was hypoplastic, and the bilateral thalami appeared to be fused and the hippocampus was unrolled, whereas the corpus callosum was preserved. In the hypothalamus, the paraventricular nucleus was only identified, and the adenohypophysial somatotrophs were reduced. This may be the first autopsy report of Micro syndrome, which is characterized by microcephaly, brain malformations, optic atrophy, and hypogenitalism, although the case lacked agenesis of the corpus callosum.