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1.
Clin Neurol Neurosurg ; 144: 36-8, 2016 May.
Article in English | MEDLINE | ID: mdl-26967522

ABSTRACT

Exome sequencing revealed a novel missense mutation (c.2152G>A, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world. We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8.


Subject(s)
Asian People/genetics , Exome/genetics , Mutation, Missense/genetics , Paraplegia/diagnosis , Paraplegia/genetics , Proteins/genetics , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/genetics , Humans , Male , Middle Aged , Pedigree
2.
Clin Auton Res ; 26(1): 1-5, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26607591

ABSTRACT

PURPOSE: To determine whether frontotemporal lobar degeneration (FTLD) is associated with similar cardiovascular autonomic dysfunction to that seen in amyotrophic lateral sclerosis (ALS), we compared cardiovascular parameters between ALS patients and patients with FTLD. METHODS: In ten patients with FTLD (mean age ± SD: 71.6 ± 4.6 years) and 12 patients with ALS (mean age ± SD: 71.4 ± 4.6 years), MSNA (using microneurography), heart rate (HR), and blood pressure (BP) were recorded simultaneously. RESULTS: MSNA was significantly higher in both groups of patients compared with the controls (p < 0.01), while there were no significant differences in MSNA between the patients with FTLD and those with ALS. During head-up tilt, changes in HR, BP, and the frequency of MSNA bursts were smaller in the patients than in controls (p < 0.05 or p < 0.01). CONCLUSIONS: Patients with FTLD and ALS showed similar dysfunction of HR, BP, and sympathetic outflow to muscles.


Subject(s)
Amyotrophic Lateral Sclerosis/physiopathology , Frontotemporal Lobar Degeneration/physiopathology , Muscle, Skeletal/innervation , Sympathetic Nervous System/physiopathology , Aged , Blood Pressure/physiology , Cross-Sectional Studies , Female , Heart Rate/physiology , Humans , Male
3.
Rinsho Shinkeigaku ; 55(6): 424-7, 2015.
Article in Japanese | MEDLINE | ID: mdl-26103817

ABSTRACT

Creutzfeldt-Jakob disease (CJD) presents with rapidly progressive dementia associated with several symptoms including pyramidal, extrapyramidal, and cerebellar signs. In Japan, patients with PRNP gene mutations comprise 18.3% of CJD cases. In the present study, we report a 74-year-old man with a double mutation in the PRNP gene. He showed dysarthria, gait disturbance, and cognitive impairment. High signal intensity was observed in the bilateral cortex on brain MRI in diffusion-weighted images. There were high total Tau protein and 14-3-3 protein levels in the cerebrospinal fluid. We diagnosed him as having CJD clinically, and analyzed the PRNP gene, which revealed a V180I mutation and a M232R one, i.e., a compound heterozygous status. In our patient, the disease has very slowly progressive (total disease course, 37 months). The V180I and M232R mutations are specific mutations to Japanese CJD patients. For patients with a double PRNP gene mutation, only V180I and M232R have been known. Patients with a double mutation (V180I /M232R) in the PRNP gene might show an atypical disease course with a slow progression.


Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , Mutation , Prions/genetics , Aged , Humans , Male , Prion Proteins
4.
Rinsho Shinkeigaku ; 55(2): 81-6, 2015.
Article in Japanese | MEDLINE | ID: mdl-25746069

ABSTRACT

A 54-year-old man was admitted due to progressive gait disturbance and cognitive impairment. On MRI, a hyperintense region was observed in the periventricular white matter on FLAIR imaging, with Gd-enhancement in the choroid plexus and periventricular wall. Cerebrospinal fluid (CSF) examination showed marked abnormalities including a high white blood cell count (WBC, 360 cells/mm(3). 83% lymphocytes), an elevated protein level (1,416 mg/dl), a low glucose level (12 mg/dl), and elevated cryptococcal antigen with positive Indian ink staining. Cryptococcal ventriculitis was diagnosed. The patient was initially treated with liposomal amphotericin B, fluconazole, voriconazole, and flucytosine for 38 weeks, followed by administration of itraconazole and fluconazole with some improvement. The brain MRI after one month showed septum formation in the posterior horn, which was suggestive of ventriculitis. Although ventriculitis is rare, we should pay attention to the presence of ventriculitis due to cryptococcal infection in the central nervous system.


Subject(s)
Cerebral Ventriculitis/diagnosis , Cerebral Ventriculitis/microbiology , Cryptococcosis , Cryptococcus neoformans , Gait Disorders, Neurologic/etiology , Memory Disorders/etiology , Antifungal Agents/administration & dosage , Antigens, Fungal/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cerebral Ventriculitis/complications , Cerebral Ventriculitis/drug therapy , Cryptococcus neoformans/immunology , Disease Progression , Drug Therapy, Combination , Humans , Magnetic Resonance Imaging , Male , Middle Aged
5.
J Hum Genet ; 60(4): 217-20, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25631098

ABSTRACT

On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.


Subject(s)
Hypogonadism/genetics , Mutation , Phospholipases/genetics , Retinal Dystrophies/genetics , Spinocerebellar Ataxias/genetics , Base Sequence , Exome , Female , Genetic Association Studies , Heterozygote , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Hypogonadism/diagnosis , Male , Neutrophils/pathology , Retinal Dystrophies/diagnosis , Spinocerebellar Ataxias/diagnosis
6.
J Hum Genet ; 59(10): 569-73, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25142508

ABSTRACT

To date, four families with spinocerebellar ataxia type 5 (SCA5) with four distinct mutations in the spectrin, beta, nonerythrocytic 2 gene (SPTBN2) have been reported worldwide. In the present study, we identified the first Japanese family with SCA5, and analyzed this family clinically and genetically. The clinical features of the five patients in this family revealed late-onset autosomal-dominant pure cerebellar ataxia. We collected DNA samples from the majority of the family members across two generations, and exome sequencing combined with Sanger sequencing revealed a novel heterozygous three-nucleotide in-frame deletion mutation (c.2608_2610delGAG) in exon 14 of the SPTBN2 gene. This mutation cosegregated with the disease in the family and resulted in a glutamic acid deletion (p.E870del) in the sixth spectrin repeat, which is highly conserved in the SPTBN2 gene. This is the first three-nucleotide in-frame deletion mutation in this region of the beta-3 spectrin protein highly likely to be pathogenic based on exome and bioinformatic data.


Subject(s)
Sequence Deletion , Spectrin/genetics , Spinocerebellar Ataxias/genetics , Aged, 80 and over , Base Sequence , DNA/chemistry , DNA Mutational Analysis , Exons , Female , Humans , Japan , Male , Middle Aged , Molecular Sequence Data , Pedigree
7.
Neurol Clin Pract ; 4(2): 175-177, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24790802

ABSTRACT

A 31-year-old woman presented with severe dystonia-parkinsonism. She had nonprogressive psychomotor retardation and cognitive dysfunction from childhood without evidence of dystonia or parkinsonism. At age 30, she then developed severe dystonia and gait disturbance. There was neither dystonia nor parkinsonism before age 30. MRI revealed cerebral atrophy and iron accumulation in the globus pallidus and substantia nigra (figure 1, A-D). The characteristic MRI findings were hyperintensity of the substantia nigra with a central band of hypointensity in T1-weighted axial slices (figure 1, B). Beta-propeller protein-associated neurodegeneration (BPAN) was diagnosed based on MRI findings and identification of a novel heterozygous mutation in the WDR45 gene (NM_007075.3: c.519+1_519+3del) (figure 2). This is a neurodegeneration involving brain iron accumulation (NBIA) characterized by psychomotor retardation from childhood and dystonia-parkinsonism in midadulthood.1,2 Although we could not analyze the father's gene since he had died, the mother had no mutation in the WDR45 gene (figure 2). Thus, it might be a de novo mutation in the WDR45 gene, as reported previously.1,2.

8.
Neuroreport ; 25(5): 303-6, 2014 Mar 26.
Article in English | MEDLINE | ID: mdl-24335782

ABSTRACT

Despite considerable interest, a pure vasodilator response by skin sympathetic nerve activity (SSNA) bursts in human limbs has not been observed in previous studies. In a patient with progressive nonfluent aphasia, SSNA, sympathetic skin response, and skin blood flow were simultaneously recorded at rest and during electrical stimulation. There was a very low frequency of SSNA bursts at rest, and when electrical stimulation was delivered, reflex bursts of SSNA were always observed followed by a sympathetic skin response and an increase in skin blood flow. The reflex latency of SSNA was slightly prolonged and the mean amplitude of reflex SSNA bursts was lower after electrical stimulation, compared with the responses in healthy controls. We report for the first time that the active vasodilator component of cutaneous sympathetic activity in limbs was recorded without any vasoconstrictor component in a patient with progressive aphasia.


Subject(s)
Aphasia/physiopathology , Leg , Regional Blood Flow/physiology , Skin/blood supply , Skin/physiopathology , Vasodilation/physiology , Adult , Aged , Electric Stimulation , Female , Humans , Peroneal Nerve/physiopathology , Time Factors
9.
J Neural Transm (Vienna) ; 120(3): 445-51, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22886108

ABSTRACT

To unravel the pathogenesis of cold limbs in Parkinson's disease, we evaluated cutaneous vasomotor neural function in 25 Parkinson's disease patients with or without cold limbs and 20 healthy controls. We measured resting skin sympathetic nerve activity, as well as reflex changes of skin blood flow and skin sympathetic nerve activity after electrical stimulation, with the parameters including skin sympathetic nerve activity frequency at rest, the amplitude of reflex bursts, the absolute decrease and percent reduction of blood flow, and the recovery time which was calculated as the interval from the start of blood flow reduction until the return to baseline cutaneous blood flow. The resting frequency of skin sympathetic nerve activity was significantly lower in patients with Parkinson's disease than in controls (p < 0.01). There were no significant differences between the patients and controls with respect to the amplitude of skin sympathetic nerve activity and the absolute decrease or percent reduction of blood flow volume. In the controls, the recovery time (9.4 ± 1.2), which was similar to Parkinson's disease patients without cold limbs (9.0 ± 0.7), while the recovery time ranged (15.7 ± 3.2) in Parkinson's disease patients with cold limbs. Recovery was significantly slower in these patients compared with the other groups (p < 0.05). It is possible that cold limbs might arise due to impaired circulation based on prolonged vasoconstriction by peripheral autonomic impairments, in addition to central autonomic dysfunction in Parkinson's disease.


Subject(s)
Parkinson Disease/physiopathology , Regional Blood Flow/physiology , Sensation Disorders/physiopathology , Skin/blood supply , Adult , Aged , Cold Temperature , Electric Stimulation , Electrophysiology/methods , Female , Humans , Male , Microelectrodes , Middle Aged , Parkinson Disease/complications , Reflex , Sensation Disorders/etiology , Skin/innervation , Sympathetic Nervous System/physiopathology
10.
Rinsho Shinkeigaku ; 52(4): 234-8, 2012.
Article in Japanese | MEDLINE | ID: mdl-22531655

ABSTRACT

A 29-year-old man developed muscle weakness in the neck at age 27. An increasing serum creatine kinase (CK) activity was detected. The first examination at our hospital revealed severe muscular atrophy at the front of the neck. Subsequently, muscular atrophy and weakness developed in the shoulders and upper extremities with an increasing serum CK level, which reached 9,159 IU/l. Needle electromyography (EMG) was not able to reveal typical myopathic change represented low-amplitude motor unit potentials (MUPs) in the proximal parts of the upper and lower extremities at the first examination, but in the course of the disease, the MUPs amplitude decrease in the same muscles. Serum examination gave a positive result for anti-signal recognition particle (SRP) antibodies. A biopsy of the deltoid muscle revealed necrotizing myopathy including small angular fiber-like atrophy without inflammatory cell infiltration or fibrotic proliferation. He was treated with prednisolone and tacrolimus with the diagnosis of polymyositis. The characteristic feature in this patient is that muscular atrophy and weakness were mainly observed in the neck. Moreover, the neurogenic changes on EMG in the early stage are also observed on atypical. Polymyositis with anti-SRP antibodies has the distinctive feature of typical polymyositis with cellular infiltration clinically and pathologically. In this respect, this case has striking and suggestive features of polymyositis with anti-SRP antibodies.


Subject(s)
Autoantibodies/analysis , Muscular Atrophy/immunology , Muscular Atrophy/pathology , Polymyositis/pathology , Signal Recognition Particle/immunology , Adult , Humans , Male , Polymyositis/immunology
11.
Mov Disord ; 25(1): 111-6, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20077484

ABSTRACT

We report two Creutzfeldt-Jakob disease (CJD) patients with rhythmic pupillary and palpebral oscillation who had a mutation of prion protein codon 200 that resulted in the substitution of lysine for glutamate (Glu/Lys). Alternating dilation and constriction of the pupils combined with elevation and descent of the eyelids occurred in correspondence with periodic sharp wave complexes (PSWCs) on the electroencephalogram and with myoclonus of the head, face, and extremities. The onset of pupillary dilation and palpebral elevation coincided with the PSWCs. Initiation of these rhythmic pupillary and palpebral movements may depend on sympathetic activity, but the site of the generator is unclear. Such rhythmic pupillary and palpebral oscillation may be a feature of rapidly progressive CJD with predominant right hemispheric involvement.


Subject(s)
Glutamic Acid/genetics , Lysine/genetics , Mutation/genetics , Prions/genetics , Pupil Disorders/genetics , Aged , Creutzfeldt-Jakob Syndrome/complications , Female , Humans , Magnetic Resonance Imaging/methods , Male , Periodicity , Pupil Disorders/etiology , Pupil Disorders/pathology
12.
Rinsho Shinkeigaku ; 49(5): 254-61, 2009 May.
Article in Japanese | MEDLINE | ID: mdl-19594102

ABSTRACT

Neuroferritinopathy is an autosomal dominant basal ganglia disease with iron accumulation caused by a mutation of the gene encoding ferritin light polypeptide (FTL). Six pathogenic mutations in the FTL gene have so far been reported. One such mutation was found in a Japanese family, thus suggesting that a new mutation in the FTL gene can therefore occur anywhere in the world. The typical clinical features of neuroferritinopathy are dystonia (especially orofacial dystonia related to speech and leading to dysarthrophonia) and involuntary movement, but such features vary greatly among the affected individuals. The findings of excess iron storage and cystic changes involving the globus pallidus and the putamen on brain MRI. and low serum ferritin levels are characteristic in neuroferritinopathy. Brain histochemistry shows abnormal aggregates of ferritin and iron throughout the central nervous system. Iron atoms are stored in the central cavity of the ferritin polymer and the E-helices of ferritin play an important role in maintaining the central cavity. A mutation in exon 4 of the FTL gene is known to alter the structure of E-helices, thereby leading to the release of free iron and excessive oxidative stress. Iron depletion therapy by iron chelation in symptomatic patients has not been shown to be beneficial, however before the nset of clinical symptoms, such a treatment strategy may still have some benefit. Neuroferritinopathy should therefore be considered in all patients presenting with basal ganglia disorders of unknown origin. These characteristic MRI findings may help to differentiate neuroferritinopathy from other diseases showing similar clinical features.


Subject(s)
Basal Ganglia Diseases , Iron/metabolism , Apoferritins/genetics , Basal Ganglia Diseases/diagnosis , Basal Ganglia Diseases/etiology , Basal Ganglia Diseases/pathology , Basal Ganglia Diseases/physiopathology , Dystonia/etiology , Genes, Dominant , Globus Pallidus/metabolism , Humans , Magnetic Resonance Imaging , Mutation , Putamen/metabolism
13.
J Neurol Sci ; 276(1-2): 88-94, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-18930252

ABSTRACT

The purpose of this study was to evaluate the clinical and pathological features in patients with progressive-type familial amyloidotic polyneuropathy (FAP) using autopsy and biopsy specimens. A proband is a 33-year-old man with FAP type I who developed motor, sensory and autonomic impairments with neuropathy, heart failure, and anorexia. Genetic findings of transthyretin (TTR) revealed G to A transition in codon 54 causing a rare mutation of TTR Lys54. He died of pneumonia and severe cardiac failure 4 years after onset. Autopsy showed heavy amyloid deposition in the heart, peripheral nerves, thyroid, skin, fat tissue, prostate and testis, moderate in the sympathetic nerve trunk, vagal nerve, celiac plexus, pelvic plexus, bladder, gastrointestinal tract, tongue, pancreas, lung, pituitary, blood vessel, gall bladder, adrenals and muscles, and free in the central nervous system, liver, kidney and spleen. Sural nerve biopsy in a sibling confirmed TTR amyloidosis immunohistochemically. Electronmicroscopic findings of amyloid fibrils were similar to that of FAP Met30. Immunoelectronmicroscopic findings indicated the relationship between amyloid fibrils or non-fibrillar structure and collagen fibers. The distribution of amyloid deposition, heavy in the heart and lacking in the kidney, is a characteristic feature and reflected severity of FAP with TTR Lys54.


Subject(s)
Amyloid Neuropathies, Familial , Lysine/genetics , Mutation/genetics , Prealbumin/genetics , 3-Iodobenzylguanidine/metabolism , Adult , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/pathology , Amyloid Neuropathies, Familial/physiopathology , Autopsy/methods , Disease Progression , Female , Glucose Tolerance Test , Humans , Male , Myocardial Perfusion Imaging/methods , Peripheral Nerves/metabolism , Peripheral Nerves/pathology , Sural Nerve/metabolism , Sural Nerve/pathology , Sural Nerve/ultrastructure
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