Intronic variant in IQGAP3 associated with hereditary neuropathy with proximal lower dominancy, urinary disturbance, and paroxysmal dry cough.

In 2008, we reported a clinically and genetically new type of autosomal dominant disorder of motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. To identify the nucleotide variant causative of this disease, we reanalyzed the linkage of the original Japanese pedigree including seven newly ascertained subjects with updated information. We assigned the locus of the disease to 1p13.3-q23 (maximum logarithm-of-odds score = 2.71). Exome sequencing for five patients and one healthy relative from the pedigree revealed 2526 patient-specific single-nucleotide variants (SNVs). By rigorous filtering processes using public databases, our linkage results, and functional prediction, followed by Sanger sequencing of the pedigree and 520 healthy Japanese individuals, we identified an intronic SNV in IQGAP3, a gene known to be associated with neurite outgrowth. Upon pathological examination of the sural nerve, moderate, chronic, mainly axonal neuropathy was observed. By histochemical analyses, we observed a patient-specific increase of IQGAP3 expression in the sural nerve. We concluded that the variant of IQGAP3 is associated with the disease in our pedigree.

Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene.

Spastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a "likely pathogenic" variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

Combined treatment with prednisolone and tacrolimus for myasthenia gravis with invasive thymoma.

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Symmetrical brainstem encephalitis caused by herpes simplex virus.

We describe a 53-year-old man with herpes simplex virus (HSV) brainstem encephalitis diagnosed based by positive HSV immunoglobulin M antibodies from cerebrospinal fluid. The MRI findings of this case had three unique features. First, the lesions were symmetrical. Second, the lesions may have been associated with reactivation of HSV infection in the region of the trigeminal nerve. Third, diffusion-weighted and apparent diffusion coefficient (ADC) imaging, conducted for the first time on an HSV brainstem encephalitis case, suggested that the lesions were associated with vasogenic edema.

Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama study.

To explore the validity of the criteria for dementia with Lewy bodies (DLB) revised in 2005, we examined community based consecutive autopsy cases. 10.3% of the non-demented subjects and 31.2% of the demented subjects showed the Lewy body pathology. Applying the revised pathological criteria to the 205 demented subjects, the types of LB pathology of 11 cases (5.4%) were brainstem-predominant, 24 cases (11.7%) were limbic type and 24 cases (11.7%) were diffuse neocortical type, although there were many subjects not to fit the criteria exactly. The prevalence of Lewy bodies (LBs) was almost same regardless of gender; however, the extent of the LB pathology among females was more severe than that in males. The likelihood of DLB being modified by concomitant Alzheimer's pathology was as follows: 27 cases (13.2%) showed low likelihood, 16 cases (7.8%) showed intermediate likelihood and 16 cases (7.8%) showed high likelihood. Since the numbers of clinical features of DLB were significantly higher in the pathological intermediate and high likelihood DLB groups than in the low likelihood DLB group or no LB group, both the intermediate and high likelihood groups of DLB should be considered as pathological DLB.

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough.

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Bell-shaped sensory impairments of all modalities in a neurosarcoidosis patient.

We describe a 45-year-old man with neurosarcoidosis complaining of bell-shaped tightening and pain with sensory disturbance of superficial and deep sensations. The patient showed subacute progressive sensory impairment in bilateral C7-Th12 dermatomes. Triceps and patellar tendon reflexes were decreased. Chest X-ray revealed bilateral hilar lymphadenopathy without pleural effusion. There was abnormal accumulation of gallium in the bilateral hilar lymph nodes, parotid glands, and lacrimal glands on scintigraphy. Examination of bronchoalveolar lavage fluid showed an elevated CD4/CD8 ratio. Transbronchial lung biopsy showed non-caseating granulomas with many epitheloid cells and occasional Langhans giant cells without any necrotic lesion. The tuberculin reaction was negative, and elevation of serum lysozyme and IgG level were seen. These findings fulfilled the clinical criteria for sarcoidosis. Spine MRI demonstrated no abnormality. Studies of short-latency somatosensory evoked potentials showed delayed N13 latency and absent N19 and N28 potentials bilaterally. A nerve conduction study revealed no abnormality. The patient's muscle strength was normal through the entire clinical course. Therefore, we consider that his sensory impairment was caused by peripheral neuropathy, especially in the dorsal root region. Neurosarcoidosis is important for differentiating bell-shaped sensory impairments of all modalities.

[Pathological study on abducent paralysis of the vocal cord in a patient having multiple system atrophy with nasogastric intubation].

A 74-year-old man developed instability of gait from age 64, difficulty in writing from age 66 and dysarthria-hypohidrosis from around age 67. These symptoms progressed slowly accompanied with orthostatic hypotension and dysarthria, which decline his ADL. At age 71, he was admitted to our hospital and underwent nasogastric intubation. After admission, he also showed the decrease in his voluntary activities, accidental ingestion and loud snoring during sleep. He died of accidental aspiration pneumonia at age 74. Postmortem examination revealed severe pathological changes as multiple system atrophy (MSA) in the central nervous system. There was a small ulcer in the hypopharyngeal region, and acute inflammation of the ulcer came down to the posterior cricoarytenoid muscle. Combined with severe neurogenic atropy due to MSA, local inflammation of the ulcer associated with nasogastric intubation appeared to have resulted in severe damage of the posterior cricoarytenoid muscle.

A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy.

Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.

A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia.

Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CK-emia (IHCK). We examined a four-generation Japanese pedigree of familial IHCK. The multipoint linkage analysis of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing followed by multiple filtering processes, we identified one novel heterozygous nonsynonymous single nucleotide variant (SNV), c.7034G>C, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree. Mutation Taster predicted this substitution as "disease causing" (p=0.999). The PolyPhen-2 and PANTHER subPSEC scores for the substitution are 0.911 (possibly damaging) and -3.56 (probably damaging), respectively. We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal variant with a very low frequency. Immunohistochemistry and Western blotting of biopsy samples consistently showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of RYR1 was also significantly reduced in the patient (p=0.009). These results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect. We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK.

[A case of hemophagocytic syndrome associated with miliary tuberculosis].

We reported a case of a 76-year-female with hemophagocytic syndrome caused by military tuberculosis. The patients had complained high fever over 38.0 degrees C and anorexia. Her chest X-ray and computed tomography revealed disseminated miliary shadows in both lung fields. Laboratory examinations revealed anemia, thrombocytopenia and liver dysfunction. Bonemarrow aspirate revealed tuberculous granulomas and tubercle bacilli by acid-fast stains, and hemophagocytosis by macrophages. We diagnosed as miliary tuberculosis and tuberculosis-associated hemophagocytic syndrome, and started antituberculous and steroid therapy. After these therapy, fever, laboratory examinations dramatically improved. In this case, serum IL-18, sICAM-1, sVCAM-1 were elevated. These cytokines and adhesion molecules were reported to elevate in both hemophagocytic syndrome and tuberculosis correlating with disease activity. We conclude that IL-18, sICAM-1, sVCAM-1 may play important roles in pathogenesis of tuberculosis associated hemophagocytic syndrome.

Anhedonia in Japanese patients with Parkinson's disease: analysis using the Snaith-Hamilton Pleasure Scale.

BACKGROUND: Anhedonia, a lowered ability to experience physical or social pleasure, has recently been recognized as a non-motor symptom of Parkinson's disease. OBJECTIVE: To identify the frequency of anhedonia and the factors influencing hedonic tone in Japanese patients with Parkinson's disease. PATIENTS AND METHODS: We recruited 86 consecutive outpatients with a clinical diagnosis of PD attending two Japanese hospitals (one university hospital and one community hospital) in February 2010. We used the self-rating Snaith-Hamilton Pleasure Scale (SHAPS) translated into Japanese language from the original English version to assess and quantify hedonic tone as a subjectively experienced phenomenon. We studied the association of anhedonia with the variables age, age at onset, gender, disease duration, disease severity and antiparkinsonian drugs. RESULTS: Thirty-nine patients (45%) were male and 47 (55%) were female. Mean age was 72.01±9.07 (49-89) years, with mean age at onset of 64.93±11.42 (31-88) years. Mean disease duration was 7.20±5.54 (1-23) years. The mean Hoehn and Yahr scale was 2.76±0.78. The mean SHAPS score of the total sample was 1.19±1.86. The SHAPS score of 14 patients (16.3%) was 3 or more, indicating anhedonia. The mean SHAPS score was lower in patients taking pramipexole (0.58±0.97) than in patients not taking pramipexole (1.57±2.16). Multiple linear regression analysis identified pramipexole as a significant negative influencing factor on the SHAPS score, while disease severity and entacapone treatment were identified as positive influencing factors. The age, onset age, gender, disease duration, and use of pergolide, amantadine, zonisamide, selegiline, anticholinergic agents and droxidopa did not significantly affect the SHAPS score. CONCLUSION: Anhedonia is not rare non-motor symptom in Japanese patients with Parkinson's disease. This study suggests an anti-anhedonic property of pramipexole.

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient.

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.

Expansion of the phenotypic spectrum of SCA14 caused by the Gly128Asp mutation in PRKCG.

Two cases of spinocerebellar ataxia type 14 (SCA14) with a G128D mutation in the protein kinase C gamma gene (PRKCG) without a definite family history have been reported previously. Here, we describe the first familial cases of SCA14 with a G128D mutation in PRKCG. Among three family members, the chief complaints varied and included ataxic gait, cervical dystonia, and positional vertigo. Moreover, retinal degeneration and facial muscle weakness were observed, although these are not expected to be present in SCA14. Cerebral blood flow evaluation using single photon emission computed tomography (SPECT) also differed among family members. It is possible that patients with the G128D mutation suffering from SCA14 may sometimes be classified as unaffected due to the varying clinical signs among family members.

Altered expression of COX-2 in subdivisions of the hippocampus during aging and in Alzheimer's disease: the Hisayama Study.

BACKGROUND: It has been reported that nonsteroidal anti-inflammatory drugs may delay the onset of Alzheimer's disease (AD). Since nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX), COX-2, an inducible form of COX, may be involved in the pathology of AD in association with the arachidonic acid cascade. In addition, it has been suggested that alterations in the balance of polyunsaturated fatty acids are associated with brain dysfunctions such as neurodegerative pathologies of the aging brain. METHOD: To explore COX-2 expression in the hippocampus, we analyzed 45 consecutive autopsy subjects without dementia and 25 AD patients derived from the town of Hisayama, Japan. RESULTS: The neuronal expression of COX-2 in the CA3 subdivision of the hippocampus, subiculum, entorhinal cortex and transentorhinal cortex were consistently observed in both nondemented and AD brains, and COX-2 immunoreactivity correlated with age in nondemented brains. In AD patients, neurons of CA1 exhibited increased COX-2 immunoreactivity which correlated with the severity of AD pathology. This correlation was not apparent in nondemented subjects. CONCLUSION: These results suggest that COX-2 expression may be differentially regulated among subdivisions of the hippocampus and that elevated COX-2 expression in the CA1 of AD brains may be associated with AD pathology and thus cognitive dysfunction.