Toshiyuki Seto

Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation.

A longitudinal study of cranial magnetic resonance imaging (MRI) was carried out in 23 patients with mucopolysaccharidoses (MPS); 1 each of types IH, VI, and VII; 2 of type IS; 10 of type II; and 4 each of types IIIB and IVA. Six types of distinct abnormalities were 1) cribriform changes or spotty changes in the corpus callosum, basal ganglia, and white matter; 2) high‐intensity signal in the white matter on T2‐weighted image; 3) ventriculomegaly; 4) diffuse cerebral cortical atrophy; 5) spinal cord compression; and 6) megacisterna magna. The cribriform changes that corresponded to dilated perivascular spaces were found in the patients with MPS IS, II, and VI. The patchy and diffuse intensity changes were found in the patient with MPS II and IIIB, respectively. MPS IH and the severe type of MPS II showed marked ventriculomegaly. Marked cerebral atrophy was observed in all MPS IIIB patients and in the severe type of MPS II patients. Spinal cord compression was a feature usually observed in MPS IH, IVA, VI, and VII. Megacisterna magna was frequent in the patients with MPS II (6/10). In 2 of 5 patients, the therapeutic effect of bone marrow transplantation (BMT) was remarkable. Both the cribriform changes and the intensity change of the white matter in a MPS VI patient disappeared 8 years after the BMT. Slight improvement of cribriform change was noted in 1 patient with MPS II 3 years after the BMT. MRS was not sufficient to estimate the accumulation of glycosaminoglycans but was useful for evaluating neuronal damages.

Nucleotide sequences of the matrix protein gene of subacute sclerosing panencephalitis viruses compared with local contemporary isolates from patients with acute measles

Measles viruses isolated from brain cells of patients with subacute sclerosing panencephalitis (SSPE) have numerous mutations, especially in the matrix protein (M) gene. To find whether the M genes of these SSPE viruses were mutated randomly or in a pattern, we sequenced this gene from three strains of defective measles virus isolated in Osaka, Japan. We could deduce the sequence of the possible progenitor measles virus for each patient by comparison of the isolate with measles viruses prevailing at roughly the same time and place as the primary infection. Biased hypermutation affected the M genes of all three SSPE viruses, although the molecular mechanisms for the mutations might be various. Replacements of U with C in the plus strand accounted for 76% of all mutations in two of the strains, but in the other strain, replacements of A with G accounted for 52% of the mutations, and the U residues were unchanged.

Efficient isolation of subacute sclerosing panencephalitis virus from patient brains by reference to magnetic resonance and computed tomographic images

Subacute sclerosing panencephalitis virus has been isolated with difficulty from brains of infected patients. More strains are needed for the study of the pathogenesis of this virus. To make the isolation more efficient, we selected portions to be examined from the brains of three patients with reference to findings of repeated magnetic resonance and computed tomographic imaging. Three cell lines susceptible to measles virus field strains were used. In all three cases viruses were isolated most effectively from recent lesions and with Vero cells. Our results suggested that these imaging methods and Vero cells could be used for improvement in the efficiency of isolation of this virus from patient brains.

The matrix gene expression of subacute sclerosing panencephalitis (SSPE) virus (Osaka-1 strain): a comparison of two sibling viruses isolated from different lobes of an SSPE brain.

The Fr/V and Oc/V sibling viruses of the Osaka‐1 strain of the subacute sclerosing panencephalitis (SSPE) virus were defective in cell‐free virus production. By radioimmunoprecipitation assay, the matrix (M) protein was not detected in cells persistently infected with the Osaka‐1 strain. This undetectable expression was consistent with the selective reduction of antibody response to the M protein in the patient from whom the Osaka‐1 strain was isolated. The sequence of the M gene, however, predicted that the protein could be synthesized because the translational start and stop codons for the protein were not altered. Northern blot hybridization demonstrated the selective defect of the monocistronic mRNAs for the M protein and the phosphoprotein (P) together with the dominant presence of the P‐M bicistronic mRNA. This absence of the M mRNA was further confirmed by primer extension analysis. Therefore, the undetectable expression of the M protein in the infected cells was proved to be caused by a transcriptional defect. The two sibling viruses, isolated from remote portions of an SSPE brain, were indistinguishable in their viral characters, including the M gene sequences, which indicates the possibility of clonal expansion of the strain in the brain.

A case of TUBA1A mutation presenting with lissencephaly and Hirschsprung disease

Gene mutation of tubulin alpha-1A (TUBA1A), a critical component of microtubules of the cytoskeleton, impairs neural migration and causes lissencephaly (LIS). The approximately 45 cases of disease-associated TUBA1A mutations reported to date demonstrate a wide spectrum of phenotypes. Here we describe an 8-year-old girl with lissencephaly, microcephaly, and early-onset epileptic seizures associated with a novel mutation in the TUBA1A gene. The patient developed Hirschsprung disease and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which had not previously been described in TUBA1A mutation-associated disease. Our case provides new insight into the wide spectrum of disease phenotypes associated with TUBA1A mutation.

Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition.

Intracerebral cell transplantation therapy for murine GM1 gangliosidosis

We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid beta-galactosidase knock-out mice (BKO) from C57BL/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL/6 overexpressing the normal human beta-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells were prepared and injected into the ventricle of newborn BKO mouse brain. The mice were examined at 1, 2, 4, and 8 weeks and 6 months after injection. In each experiment, the injected cells migrated into the whole brain effectively and survived for at least 8 weeks. Decrease in ganglioside GM1 level was also observed. FBC could survive for 6 months in recipient brain. However, the number of transplanted FBC decreased. In the brains of MSC- or mixed cell-treated mice, no grafted cells could be found at 6 months. To achieve sufficient long-term effects on the brain, a method of steering the immune response away from cytotoxic responses or of inducing tolerance to the products of therapeutic genes must be developed.

Twelve-year-old girl with intracranial epidural abscess and sphenoiditis

We report the case of a 12-year-old girl with an intracranial epidural abscess and sphenoiditis. Although she had no history of sinusitis, she developed acute severe headache, fever, and vomiting. Emergent CT and MRI showed a spherical space-occupying lesion of diameter 3 cm in the right cranial fossa with rim enhancement. The lesion was thought to be an epidural abscess adjacent to the right sphenoiditis. On the basis of the MRI findings, we performed emergent surgery to drain the abscess and sinusitis because of severe and rapidly worsening headaches. The patient showed great improvement the day after the operation. Intravenous antibiotics were administered for 8 days. She has completely recovered, with neither sequelae nor recurrence at 7 months after the operation. We believe that this report will be a useful reference for cases of acute onset headache and may be helpful in diagnosis and treatment decisions for severe sinusitis-related intracranial abscess in childhood.

Dyschromatosis symmetrica hereditaria complicated by intracranial hemangiomas and Parry-Romberg syndrome

(375 mg/day) for prostate cancer, and also with ursodeoxycholic acid, ezetimibe, bisoprolol fumarate, clopidogrel sulfate, ethyl icosapentate and candesartan cilexetil for more than a year. Three months after ingestion of flutamide, he developed itchy, scaly, erythematous lesions on his sun-exposed areas including head, face, earlobes and neck. Four months later, hyperand hypopigmentation developed on the existing erythematous lesions on the sun-exposed areas during topical corticosteroid therapy (Fig. 1a). Presence of reports of flutamide-induced photosensitive dermatitis made us discontinue flutamide immediately. A skin biopsy specimen from the neck lesion with hyperpigmentation showed marked basal hyperpigmentation of the epidermis with increased number of dermal melanophages (Fig. 1c). In contrast, a specimen from a hypopigmented lesion revealed loss of the basal pigmentation (Fig. 1d). The minimal response dose to ultraviolet (UV)-A was within normal range (4 J/cm) at 4 months after cease of flutamide. Patch and photo patch tests with flutamide (crushed tablet, 1% and 10% in white petrolatum) were also negative. Druginduced lymphocyte stimulation test (DLST) with flutamide was positive (SI, 280%; <180%). He was treated with hydrocortisone butyrate and maxacalcitol shading with sunscreen. His lesions responded well, and the depigmented areas decreased to more than 50% after 13 months therapy (Fig. 1b). Photoleukomelanoderma/photoleukomelanodermatitis is a slow-developing and rare form of drug eruption. The known causative drugs are limited, including thiazide, tetracycline, afloqualone, fenofibrate and flutamide. The patch and photo patch tests with flutamide were negative in the present case, which probably resulted from unavailability of a patch for the involved sun-exposed area. The absorption wavelength of flutamide is 292 nm, and flutamide is a potent UV-A photosensitivity inducer. The absorbance wavelength of flutamide did not change upon photo-irradiation, and flutamide showed no photo-coupling with bovine serum albumin. Recently, the requirement of intracellular drug processing before covalent binding to albumin was reported. Because flutamide presents in the plasma as an active metabolite, hydroxyl-flutamide, the metabolite is a potent photo-hapten after effective irradiation. DLST is generally negative in photosensitivity dermatitis, but was positive in the present case. This suggests presence of allergic reactions to flutamide or its active metabolite. The skin manifestation of PLMD is a bizarre mosaic like mixture of hyperand hypopigmented lesions, and compromise patients’ quality of life. The combination therapy with topical corticosteroid and vitamin D3 is effective for PLMD. Vitamin D3 influences melanocyte maturation and differentiation and also upregulates melanogenesis. Unfortunately, it takes a long time for recovery from depigmentation. Immediate discontinuation of the suspicious drug in photosensitive dermatitis is indispensable. An increase of flutamide therapy because of the aging of the population is suspected; therefore, we should be aware of PLMD caused by flutamide.

Mutations in NSD1 and NFIX in Three Patients with Clinical Features of Sotos Syndrome and Malan Syndrome

Mutations in nuclear receptor SET domain-containing protein 1 gene ( NSD1 ) are related to Sotos syndrome, which is characterized by overgrowth, macrocephaly, distinctive features, and neurodevelopmental disabilities. On the other hand, mutations in the nuclear factor I/X gene ( NFIX ) can lead to Malan syndrome, also known as Sotos-like syndrome, or to the Marshall-Smith syndrome. In this study, using next generation sequencing (NGS), we identified de novo mutations in NSD1 and NFIX in three patients with developmental disabilities associated with overgrowth or macrocephaly. Overall, we confirmed that clinical entities of congenital malformation syndromes can be expanded by molecular diagnoses via NGS.