P-Tau and Subunit c Mitochondrial ATP Synthase Accumulation in the Central Nervous System of a Woman with Hurler-Scheie Syndrome Treated with Enzyme Replacement Therapy for 12 Years.

We report an autopsy case of a woman with mucopolysaccharidosis type I (MPS I) Hurler-Scheie syndrome who was treated with enzyme replacement therapy (ERT) for 12 years. This was the first case of MPS I treated with ERT in Japan. Pathological analysis showed no glycosaminoglycan accumulation in the liver and spleen as a result of long-term ERT, although severe aortic stenosis, diffuse intimal hyperplasia of the coronary artery, and fibrous hypertrophy of the endocardium were observed. Additionally, we detected subunit c mitochondrial ATP synthase (SCMAS) accumulation and mild tauopathy (hyperphosphorylated tau or p-tau, both 3-repeat and 4-repeat tau accumulation) in the same area of the cerebral limbic system and central gray matter of the mid brain and pons. Tauopathy is an important pathological finding in Alzheimer's disease and other neurodegenerative disorders; however, in MPS I, it is unclear whether tauopathy is a primary or secondary phenomenon. Thus, in this report, we describe pathological accumulation of p-tau and SCMAS in the context of MPS I and discuss the mechanisms and importance of these findings in the pathogenesis of MPS I.

Three novel mutations of the MCT8 (SLC16A2) gene: individual and temporal variations of endocrinological and radiological features.

We performed genetic analysis and clinical investigations for three patients with suspected monocarboxylate transporter 8 (MCT8) deficiency. On genetic analysis of the MCT8(SLC16A2) gene, novel mutations (c.1333C>A; p.R445S, c.587G>A; p.G196E and c.1063_1064insCTACC; p.R355PfsX64) were identified in each of three patients. Although thyroid function tests (TFTs) showed the typical pattern of MCT8 deficiency at the time of genetic diagnosis in all patients, two patients occasionally were euthyroid. A TRH test revealed low response, exaggerated response and normal response of TSH, respectively. Endocrinological studies showed gonadotropin (Gn) deficiency in two adult patients. On ultrasonography, goiter was detected in one patient. Interestingly, pituitary magnetic resonance imaging (MRI) demonstrated atrophy and thinness of the pituitary gland in two patients. Our findings suggest that thyroid status in patients with MCT8 deficiency varies with time of examination, and repeated TFTs are necessary for patients suspected of MCT8 deficiency before genetic analysis. In addition, it is noteworthy that some variations were observed on the TRH test and ultrasonography of the thyroid gland in the present study. Morphological abnormality of the pituitary gland may be found in some patients, while Gn deficiency should be considered as one of the complications.

[Safety and efficacy of surgical closure of the larynx for recurrent aspiration pneumonia in persons with severe motor and intellectual disabilities: a comparative study with tracheoesophageal diversion].

OBJECTIVE: We retrospectively investigated the efficacy and complications of surgical closure of the larynx (SCL) for recurrent aspiration pneumonia in comparison with tracheoesophageal diversion. METHODS: The subjects were persons with severe motor and intellectual disabilities (SMID) who had undergone surgery for recurrent aspiration pneumonia between 1994 and 2011: A 8 SCL patients group and a 16 tracheoesophageal diversion patients group. We investigated two groups the lower respiratory infection incidence, length of hospital stay for the surgery, postoperative complications, and rate of cannula withdrawal, by reviewing medical records. RESULTS: Both the SCL and the tracheoesophageal diversion group showed a reduction in the incidence of infection after surgery, indicating that the efficacy of SCL was equivalent to that of tracheoesophageal diversion in preventing aspiration pneumonea. The SCL group showed a reduction in the length of hospital stay and an increased rate of cannula withdrawal as compared with the tracheoesophageal diversion group. CONCLUSION: The efficacy of SCL was equivalent to that of tracheoesophageal diversion in preventing aspiration for SMID. We consider SLC to have potential for reducing the burden on patients.

Pathology of the first autopsy case diagnosed as mucolipidosis type III α/ß suggesting autophagic dysfunction.

Mucolipidosis type III (MLIII) is a mild form of Mucolipidosis type II (MLII, I-cell disease) of late onset, of which almost no pathological study has been reported, as it is a very rare disease. We encountered the case of a 23-year-old man of Japanese and Caucasian mixed parentage diagnosed with MLIII by enzyme assay and genotyping. He died suddenly due to severe dilated cardiomyopathy. On the day after his death, autopsy was performed, and accumulation of Luxol Fast Blue (LFB) positive material was found to be most severe in the neuronal cells of dorsal root ganglions (DRG). Electromicroscopic DRG revealed the neuronal cytoplasm was filled with a zebra-body-like membranous matrix. We tried immunohistochemistry to investigate the mechanism of such accumulation in the DRG that resulted in double positive anti-ubiquitin antibody (FK-2) and anti-LC3 antibody (as specific marker for autophagy) staining, and speculated activating of autophagosome pathway, and 'zebra-body' should be suspected as dysfunctional autophagosome. We also detected foamy cell proliferation in the dura mater, Auerbach's plexus (peripheral nervous system), podocytes of almost all glomeruli, cartilage tissue in lumbar discs, and in cardiac muscle. We tried FK-2 and anti-LC3 antibody staining also for the podocytes, the area with the most marked proliferation of foamy cells, but the result was negative. This led us to speculate that these pathological findings, namely, accumulation of LFB-positive material and foamy fibroblast proliferation, might be the forms of dysfunctional autophagosome at various stages of development. This pathological study of MLIII supports the theory that MLIII is a mild type of MLII because of the close similarity of their pathological findings.

Clinical and genetic study of Japanese patients with type 3 Gaucher disease.

Information on the phenotypic variations seen in patients with type 3 (chronic neuronopathic) Gaucher disease (GD) is still limited compared with type 1 GD. We retrospectively investigated the clinical features of 42 Japanese patients with type 3 GD. The 42 patients classified as type 3 fell into two groups: those diagnosed as having type 3 GD at diagnosis (group A; n = 24) and those thought to have type 1 at diagnosis but who later developed neurological symptoms (group B; n = 18). The genotype of group A patients varied widely; however, L444P/L444P and L444P/F213I genotypes accounted for 83% in group B. All the patients who did not receive enzyme replacement with alglucerase or imiglucerase (4 in group A, 2 in group B) died. Nineteen patients received enzyme replacement in group A; however, 7 of these died despite the therapy. On the other hand, 14 patients received enzyme replacement alone in group B and 13 of them survived. Among the ERT-treated patients who survived, only one of 12 in group A and 12 out of 13 in group B can walk unaided. In conclusion, some Japanese GD patients who are thought to have type 1 at diagnosis develop neurological symptoms during their clinical course, and careful observation is essential for patients with characteristic genotypes. Moreover, enzyme replacement alone might not have a sufficient effect on the early onset neurological symptoms in type 3 patients. A different treatment strategy is needed to improve the prognosis of these patients.

Differences in CTG triplet repeat expansion in leukemic cells and normal lymphocytes from a 14-year-old female with congenital myotonic dystrophy.

We describe a rare case of acute lymphoblastic leukemia in a 14-year-old female with congenital myotonic dystrophy manifested as mental retardation, extensive contractures of multiple joints of the lower extremities, and severe scoliosis. Because of the potential toxicity of chemotherapy and the patient's poor performance status, a modified chemotherapy regimen was administered. Analysis of the greatly expanded number of CTG repeats at the 3' untranslated region of DMPK gene showed that the number of repeats was 233 greater in leukemic cells than in normal lymphocytes; this elongation may have occurred during the cellular proliferation of leukemic clones.

Successful treatment of Diamond-Blackfan anemia with metoclopramide.

Diamond-Blackfan anemia (DBA) is a congenital anemia characterized by a low reticulocyte count, the absence or severe reduction of hemoglobin-containing cells in the bone marrow, and normal megakaryocytic and granulocytic differentiation. Although the anemia may initially respond to corticosteroid therapy, many patients require lifelong red blood cell (RBC) transfusion, leading to infectious complications and iron overload. Metoclopramide has recently been used to treat DBA. Treatment with metoclopramide induces the release of prolactin from the pituitary and stimulates erythropoiesis. For these reasons, we used metoclopramide to treat a 20-year-old man with DBA refractory to low and high doses of corticosteroids, cyclosporin A, and tacrolimus (FK506). The hemoglobin and hematocrit slowly increased, and he has remained asymptomatic and transfusion-independent for 8 months. Metoclopramide therapy should be considered in patients with refractory DBA before treatment-related complications develop.

Brainstem cranial-nerve lesions in an infant with hypoxic cerebral injury.

Recent studies have revealed that the brainstem is characteristically involved in hypoxic encephalopathy in infants. However, few reports have described clinical and cranial magnetic resonance findings in detail because most patients with brainstem lesions die during delivery or soon afterward. Reported here is a patient who manifested selective brainstem injury caused by perinatal hypoxic cerebral injury and exhibited palsy of the lower-brainstem cranial nerves. Magnetic resonance imaging was used to demonstrate lesions of brainstem cranial nerves, which were consistent with symptoms of brainstem dysfunction.