Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1.

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.

[Clinical findings of a patient with hemiballism after superficial temporal artery-middle cerebral artery anastomosis for idiopathic middle cerebral artery stenosis].

A 32-year-old woman experienced several episodes of transient numbness on the left side of her face and body. MR angiography revealed severe stenosis in the right middle cerebral artery (MCA). Abnormal collateral vessel networks were not observed, and idiopathic MCA stenosis was diagnosed. She underwent superficial temporal artery (STA)-MCA anastomosis of the right hemisphere. The surgery eliminated the transient ischemic attacks; however, she developed hemiballism in the left side of her face and left upper limb 2 weeks after the surgery. The ballism disappeared 1.5 years after onset without any treatments. A few patients with development of chorea after STA-MCA anastomosis has been reported in moyamoya disease, but not in those with MCA stenoses. It has been previsouly reported that the development of an involuntary movement might be associated with hypermetabolism in the contra lateral striatum after STA-MCA anastomosis. We considered that a similar mechanism may have caused hemiallism in our patient. We need to recognize that STA-MCA anastomosis could cause hemichorea or hemiballism.

Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells.

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.

Novel PHOX2B mutations in congenital central hypoventilation syndrome.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is caused by mutation of paird-like homeobox 2B (PHOX2B). Approximately 90% of patients were found to carry polyalanine repeat expansion mutation (PARM), and the remaining 10% had non-PARM (NPARM). In PARM, the length of the polyalanine expansion correlates with clinical disease severity. Most patients with NPARM have hypoventilation symptoms in the neonatal period and complications of Hirschsprung disease, dysregulation of autonomic nervous system, and tumors of neural crest origin. Data on the genotype-phenotype association may contribute to the clinical management of the disease. METHODS: We studied the genetic background of Japanese CCHS patients according to PHOX2B sequencing. RESULTS: Of 133 Japanese CCHS patients we identified 12 patients carrying 11 different NPARM (approx. 9% of the patients) and described the clinical manifestations in seven of them with the following novel mutations: c.941-945del5, c.678_693dup16, c.609_616del8, c.620_633del14, c.663_711del 49, c.448C>G and c.944G>C. All patients had hypoventilation in the neonatal period and also had Hirschsprung disease, with the exception of two patients carrying c.620_633del14 and c.663_711del49 mutations. The patient carrying the c.609_616del8 mutation also had a benign mediastinal tumor. CONCLUSION: Most patients carrying NPARM had severe symptoms with frequent complications, as in previous reports, and should be carefully monitored for various complications, including neural crest-derived tumor.

Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1).

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1.

Clinical findings of a probable case of MM2-cortical-type sporadic Creutzfeldt-Jakob disease with antibodies to anti-N-terminus of α-enolase.

We report the case of a 76-year-old woman presenting with 47-month history of progressive dementia and cortical blindness with no family history. Antibodies against thyroid glands and the N-terminus of α-enolase (NAE) were detected in her serum. Neurological examination revealed progressive dementia, frontal signs, visual disturbance, and exaggerated bilateral tendon reflexes in both legs. Diffusion MRI showed cortical hyper-intensities in the bilateral occipital and parietal, and the left frontal and temporal cortices. 99mTc-ethyl cysteinate dimer-single photon emission computed tomography indicated decreased regional cerebral blood flow throughout the bilateral parietal lobes and partially in the left frontal and temporal lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129 in peripheral blood. Cerebrospinal fluid examination, including 14-3-3 and total tau protein detection, revealed normal levels; however, prion proteins were amplified by the real-time quaking-induced conversion method. Hashimoto's encephalopathy was excluded on the basis of unresponsiveness to corticosteroids. The symptoms progressed slowly. Periodic sharp-wave complexes were observed on electroencephalogram 36 months after the onset of symptoms; the patient reached a state of akinetic mutism at 47 months. This was a probable case of MM2-cortical-type sCJD with anti-NAE antibodies based on the World Health Organization (WHO) diagnostic criteria for sCJD, genetic information, and the slowly progressive course. However, this case did not meet with the probable WHO diagnostic criteria until 3 years after symptom onset, highlighting the difficulty of diagnosing a living case of the MM2-type of sCJD. Therefore, establishment of clinical diagnostic criteria for MM2-type of sCJD is required.

Reduction in the numbers of drugs administered to elderly in-patients with polypharmacy by a multidisciplinary review of medication using electronic medical records.

AIM: Polypharmacy is a major problem for elderly patients in developed countries. We investigated whether a multidisciplinary medication review using electronic medical records could reduce the number of drugs administered to elderly patients receiving polypharmacy. METHODS: The present study included 432 elderly patients (188 women, 244 men; 267 patients aged 65-74 years and 165 patients aged ≥75 years) who were admitted to and discharged from the Department of Neurology and Geriatrics, Gifu University Hospital, between 2004 and 2011; those who died at the hospital were excluded. The names, categories, and numbers of orally administered drugs at admission and discharge were examined retrospectively using electronic medical records. The histories of continuous oral immunotherapy use at the hospital, falls during the 2 years before hospital admission and the presence of fall risk factors were also evaluated. P-values <0.05 were considered statistically significant. RESULTS: On average 1.14 ± 3.07 fewer types of drugs were given to patients at discharge than at admission in patients receiving polypharmacy (P < 0.001). However, the number of drugs given to patients undergoing continuous oral immunotherapy increased by 1.67 ± 3.47 (P < 0.001). The number of drugs was reduced in 33.1% of fallers, and 36.3% of non-fallers. In both fallers and non-fallers, there was a reduction in drug categories associated with falls. CONCLUSIONS: Multidisciplinary medication review using electronic medical records could significantly reduce the numbers of drugs taken by elderly inpatients receiving polypharmacy, including drugs associated with falls, in both fallers and non-fallers Geriatr Gerontol Int 2017; 17: 653-658.

Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan.

OBJECTIVE: To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan. METHODS: We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed. RESULTS: Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family. CONCLUSION: SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.

[A case of nonsystemic vasculitic neuropathy with spondylosis deformans in an 84-year-old woman].

We report an 84-year-old woman with left lower limb muscle weakness and numbness who also had weakness in her right lower limb, which showed spontaneous partial improvement. Neurological examination revealed lower extremity weakness and sensory disturbance in all modalities, predominantly distally on the left side. Laboratory studies yielded normal results, except for a slightly high erythrocyte sedimentation rate. Nerve conduction studies showed axonal neuropathy in the right tibial nerve, and loss of action potentials in other lower limb nerves. Histological study of the left sural nerve revealed mainly loss of axons and differences in the density of fascicules in the axons. In addition, inflammatory cells infiltrated around small blood vessels. Therefore, we diagnosed nonsystemic vasculitic neuropathy. Magnetic resonance imaging revealed that she also had spondylosis deformans and radiculopathy, which was more difficult to differentiate. Neural biopsy was important for diagnosis.

High frequency of calcification in basal ganglia on brain computed tomography images in Japanese older adults.

AIM: To investigate the frequency of calcification in the basal ganglia and the dentate nuclei in the cerebellum, and compare the difference in age and area, we examined the brain computed tomography (CT) images of all patients in two representative university hospitals in Japan. METHODS: We examined the brain CT images of 2526 patients in Gifu University Hospital (UH) and 2573 patients in Niigata UH. These patients were examined in these hospitals from October 2009 to September 2010. RESULTS: Punctate calcification of the basal ganglia was observed in 435 of 2526 patients (17.2%) in Gifu UH and 530 of 2573 patients (20.6%) in Niigata UH. The frequency of calcification increased with age. Patchy calcification of the basal ganglia was observed in 32 (1.3%) and 50 patients (1.9%) in Gifu UH and Niigata UH, respectively. Among patients aged over 65 years, 24 (2.1%) and 34 (3.1%) patients showed patchy calcification in Gifu UH and Niigata UH, respectively. Calcification of the cerebellar dentate nuclei was detected in just seven and four patients in Gifu UH and Niigata UH, respectively. CONCLUSION: Compared with previous reports, the frequency of calcification of the basal ganglia in this study markedly increased. This might be because of the increased number of older adults and the increased sensitivity of CT.

Diffuse skeletal muscles uptake of [18F] fluorodeoxyglucose on positron emission tomography in primary muscle peripheral T-cell lymphoma.

A 40-year-old man presented with weakness of neck extensor muscles. Cervical magnetic resonance imaging showed high-intensity areas in muscles of the left lateral cervical region on T2-weighted images. Fluorodeoxyglucose-positron emission tomography scan demonstrated striking fluorodeoxyglucose uptake by multiple skeletal muscles of the neck, chest, and abdominal region. Muscle biopsy demonstrated peripheral T-cell lymphoma, unspecified. The diagnosis was primary skeletal muscle peripheral T-cell lymphoma. Primary skeletal muscle non-Hodgkin's lymphoma of T-cell immunophenotype is extremely rare and fluorodeoxyglucose-positron emission tomography demonstrated striking fluorodeoxyglucose uptake in multiple skeletal muscles and served as a quite useful modality for the diagnosis of this patient.

High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr's Disease.

Patients with marked calcification of the basal ganglia and cerebellum have traditionally been referred to as having Fahr's disease, but the nomenclature has been criticized for including heterogeneous etiology. We describe 3 patients with idiopathic bilateral striatopallidodentate calcinosis (IBSPDC). The patients were a 24-year-old man with mental deterioration, a 57-year-old man with parkinsonism and dementia, and a 76-year-old woman with dementia and mild parkinsonism. The former 2 patients showed severe calcification of the basal ganglia and cerebellum, and the latter patient showed severe calcification of the cerebellum. We found significantly increased levels of copper (Cu), zinc (Zn), iron (Fe) and magnesium (Mg), using inductively coupled plasma mass spectrometry in the CSF of all these 3 patients. The increased levels of Cu, Zn, Fe and Mg reflect the involvement of metabolism of several metals and/or metal-binding proteins during the progression of IBSPDC. More numerous patients with IBSPDC should be examined in other races to clarify the common mechanism of the disease and to investigate the specific treatment.

[Rapidly progressive parkinsonism that developed one year after ventriculoperitoneal shunting for idiopathic aqueductal stenosis: a case report].

A 46-year-old woman was diagnosed with having idiopathic aqueductal stenosis for which she underwent ventriculoperitoneal (V-P) shunting. One year after the surgery, she developed acute parkinsonism and sylvian aqueduct syndrome. Brain magnetic resonance imaging (MRI) did not reveal any signs of hydrocephalus and fluorodopa positron emission tomography (PET) did not reveal any decrease in accumulation of fluorodopa at the striatum. On admission, the Unified Parkinson Disease Rating Scale (UPDRS) (Part III) score was 30 points. The preliminary diagnosis was parkinsonism associated with V-P shunting: therefore, the levodopa dosage was increased from 200 mg/day to 600 mg/day. Thereafter, the symptoms of parkinsonism and the sylvian aqueduct syndrome markedly improved, and the UPDRS (Part III) score decreased. If such a patient presents without signs of hydrocephalus or shunt malfunction, dopaminergic medication should be used as the initial treatment.