Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-ß therapy in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4(+) T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-ß treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.

[A case of autoimmune glial fibrillary acidic protein astrocytopathy with various symptoms such as optic disc edema and cerebellar ataxia].

A 59-year-old man had developed visual abnormality, nausea, headache, and weight loss since three months before. The ophthalmologist found severe optic disc edema in both eyes, and referred him to our hospital. The patient had mild cerebellar ataxia. Increased cerebrospinal fluid pressure, increased protein and cell counts, positive oligoclonal band, and contrast-enhanced head MRI showed multiple linear perivascular radial gadolinium enhancement around bilateral lateral ventricles. His subjective and objective findings significantly improved with steroid treatment. The cerebrospinal fluid was found to be positive for glial fibrillary acidic protein (GFAP) antibodies, and a diagnosis of GFAP astrocytopathy was obtained. When optic edema or radial contrast effects was observed on contrast-enhanced MRI, GFAP astrocytopathy should be considerd. Prompt immunotherapy is required to circumvent the development of permanent visual impairment.

[Long-term prognosis of analgesics abuse headache].

OBJECTIVE: To evaluate the long-term prognosis of analgesics abuse headache. METHODS: Ninety-five consecutive patients with analgesics abuse headache were treated in Toyonaka Municipal Hospital. Seventy-three patients (76.8%) had migraine, eighteen (19.0%) had tension-type headache and four (4.2%) new daily persistent headache. Seventy-seven (81.1%) were females and eighteen (18.9%) males. All patients were treated for six years from November 1997 to October 2003 and a total of sixty-nine patients were available for interview as of October 2004 at a mean time interval of 41.5 months after drug withdrawal therapy. Twenty-two patients were admitted to our inpatient withdrawal unit, twenty-five patients were treated by outpatient withdrawal therapy. Tapering analgesics gradually in conjunction with instituting preventive therapy treated twenty-two patients. RESULTS: Inpatient-Nine cases (41%) reported intake of analgesics on < or = 8 days/month, five cases (23%) on 9-15 days/month and eight cases (36%) > 15 days/month. Three cases (14%) developed recurrent analgesic abuse. Outpatient (abrupt discontinuation)--Twelve cases (48%) reported intake of analgesics on < or = 8 days/month, five cases (20%) on 9-15 days/month and eight cases (32%) >15 days/month. One case (4%) reported on recurrent analgesic abuse. Outpatient (tapering analgesics gradually)--One case (5%) reported intake of analgesics on < or = 8 days/month and twenty-one cases (95%) reported daily intake. Fifteen cases (68%) reported continuous analgesic abuse. Comparison between migraine and tension-type headache suggested that patients with migraine showed a tendency towards a better prognosis than patients with tension-type headache. CONCLUSIONS: These results demonstrate the efficacy of withdrawal treatment in difficult cases suffering from analgesics abuse headache. If patients cannot be safely or adequately treated as outpatients, inpatient treatment may be needed.

[A case of cholesterol embolization syndrome with cognitive impairment and pulmonary hemorrhage].

A seventy-year-old man developed color change in his left toes and was treated for frostbite. Eight months later, he developed cognitive impairment and was admitted to our hospital. A remarkable increase of eosinophils was observed in peripheral blood. Brain MRI revealed abnormal lesions in the fornix, corpus callosum, basal ganglia and frontal lobe. Steroid therapy ameliorated his symptom temporarily, but he suddenly developed cardiopulmonary arrest. His autopsy revealed severe pulmonary hemorrhage with alveolar vasculitis and cholesterol crystals in the brain, kidneys, liver, and the other organs. It was possible that cholesterol embolization to multiple organs including the brain induced systemic vasculitis that caused pulmonary hemorrhage and his critical prognosis. Cholesterol embolization should be considered when we see a patient with brain lesions accompanied with eosinophilia.

[A case of bilateral perisylvian polymicrogyria with epileptic attacks of focal inhibitory seizure followed by complex partial seizure].

A 20 year-old woman began to have epileptic attacks of focal inhibitory seizure with paralysis and hypesthesia of her left or right upper limb followed by complex partial seizure several times a week since age 19. She was born by breech presentation and umbilical cord was coiling around her neck at birth. EEG showed spike foci on P 3, O1 and T5. Cerebral MRI with 4 mm-section inversion recovery image revealed bilaterally symmetrical polymicrogyria involving the posterior portion of sylvian fissure extending posteriorly to the inner cortex of the postcentral gyrus and the supramarginal gyrus, and she was diagnosed as bilateral perisylvian polymicrogyria. 99mTc-ECD SPECT showed increased cerebral blood flow over the bilateral polymicrogyric lesion. On cerebral MRA, bilateral middle cerebral arteries were narrow all way through. Epileptic attacks were controlled with zonisamide and carbamazepin. This is a rare case of bilateral perisylvian polymicrogyria because epileptic attacks were the only manifestation and the patient showed neither mental retardation nor neurological abnormality.

[Primary new daily persistent headache (NDPH): clinical characteristics of forty-three cases in Japan].

Although the primary chronic daily headache is subdivided into chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache (NDPH), the characteristics of NDPH have not been well studied in Japan. The purpose of this study is to investigate the clinical characteristics of the primary NDPH. Twenty-one men and twenty-two women with primary NDPH, aged 14 to 73 years were diagnosed at Toyonaka Municipal Hospital from November 1997 to April 2003. Age of the onset ranged from 13 to 73 years (mean, 34.8). The onset of headache occurred in relation to a stressful life event in 16%, a systemic infection in 12% and an extracranial surgery in 7%. Any precipitating events could not be identified in approximately two-third of patients (65%). Quality of the headache was described as dull and/or pressure-like sensation in 91%, throbbing and/or pulsating sensation in 28%. NDPH needs further study, because it appears to be one of the most refractory headaches.

[A case of CIDP with diabetes mellitus who had good response to intravenous immune globulin].

A 64 year-old man began to feel numbness on his bilateral feet in 1990. He was diagnosed as diabetes mellitus with a high fasting glucose level of 580 mg/dl in 1993 and he received oral hypoglycemic agents. Since then, his blood glucose levels had been in good control under diet therapy and medication. However, his numbness worsened and progressive weakness of bilateral lower legs occurred in 1997. Bilateral anterior tibial muscles were atrophic and deep tendon reflexes were decreased on bilateral upper and lower limbs. Protein level of his cerebrospinal fluid was 63 mg/dl. Nerve conduction study fulfilled the electrophysiological diagnostic criteria of CIDP. Superficial peroneal nerve biopsy showed loss of myelinated fibers, small amount of onion bulbs and thickening of the basement membrane of arterioles. Demyelination was predominant in teased fiber study. These findings were compatible with CIDP combined with diabetes mellitus (DM-CIDP). His numbness and leg weakness improved after intravenous high dose immune globulin therapy. DM-CIDP must be distinguished from diabetic peripheral polyneuropathy because immunological therapy may be effective in DM-CIDP patients.

[A case of possible neuro-Sweet disease with prolonged disturbance of consciousness and no dermal lesion during the course of dementia].

The patient was a 58-year-old man with 1-year history of cognitive decline, which was diagnosed as Alzheimer's disease in another hospital. He was admitted to our hospital for extreme fatigue, weight loss, and dysphagia, subsequent to the left peripheral facial paresis. Brain magnetic resonance (MR) imaging showed bilateral diffuse white matter lesions and hippocampal atrophy. After admission, he presented with sudden high fever, recurrent exacerbations of consciousness, and increased C-reactive protein level with marked neutrophilia, with the result that he underwent mechanical ventilation. Routine cerebrospinal fluid findings at the exacerbation were normal i.e. 4.7 cells/mm(3), 40 mg/dl of protein, but IL-6 concentration was mildly elevated to 22.2 pg/ml. After confirming the positivity of HLA (human leukocyte antigen) B54 and Cw1, we administered steroid to him and his physical activity and state of consciousness significantly improved. During the course of treatment, dermal lesion characterisitic of Sweet disease was absent. We diagnosed this case was possible neuroSweet disease proposed by Hisanaga in 2005.

[Brain abscess mediated through a pulmonary arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia].

The patient is a 66-year-old man with hereditary telangiectasia. He was diagnosed with pulmonary arteriovenous malformation (PAVM), which was revealed by contrast-enhanced chest computed tomography at the age of 65. He developed headache, right homonymous hemianopsia, and right hemiparesis and was admitted to our hospital. Contrast-enhanced magnetic resonance imaging revealed multiple lesions in the left hemisphere, which indicates brain abscesses. Thus, the diagnosis of brain abscess mediated through PAVM was established. Following management with drainage and coil embolization, all neurological symptoms resolved. Therefore, coil embolization should be considered for PAVM at an early stage to prevent brain abscess, even if it is asymptomatic.

Antiphospholipid syndrome complicated by unilateral pleural effusion.

Antiphospholipid syndrome (APS) with pleural effusion is extremely rare. A 75-year-old man was admitted to our hospital for spreading erythema on his trunk and extremities, as well as dyspnea. One year before admission, he had visited us with a 1-year history of erythema and purpura on his legs and occasional fever. Given the diagnosis of APS, we initiated a combination therapy of aspirin and warfarin, but the skin lesions had gradually worsened. A biopsy specimen revealed marked thrombosis in the dermal and subcutaneous small vessels. In addition, chest X-ray and computed tomography demonstrated a large pleural effusion in the left lung. He underwent repeated drainage of the pleural effusion but the effusion recurred. We added oral prednisolone 30 mg daily to his prior anticoagulant therapy. The skin lesions and pleural effusion rapidly improved and disappeared without any complication. Corticosteroids might be a choice of treatment for intractable pleural effusion in APS patients.

Lemierre syndrome with blepharoptosis.

A 51-year-old woman was hospitalized with a high fever, occipital pain, blepharoptosis, and trismus. Enhanced CT showed thrombophlebitis of her left cavernous sinus, maxillary vein, and multiple pulmonary nodular lesions. (18)F-FDG PET/CT showed significant uptakes in the same lesions. Streptococcus constellatus was detected in her blood. Therefore, she was diagnosed as a Lemierre syndrome variant. After administration of antibiotics, all symptoms, inflammatory reactions, and thrombi disappeared. Since Lemierre syndrome has life-threatening potential, early diagnosis and initiation of appropriate therapy are important. In this case, (18)F-FDG PET/CT was useful to detect the focus and extent of infection.

Astrocytic necrosis is induced by anti-aquaporin-4 antibody-positive serum.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system, and humoral immunity is suggested to play an important role in the pathogenesis. The identification of an anti-aquaporin-4 antibody (AQP4-Ab, neuromyelitis optica immunoglobulin G) in the sera of patients with NMO has led to the investigation on the pathogenicity of the autoantibody. Recent immunohistological analyses revealed the primary loss of AQP4 on astrocytes and complement deposition in active lesions of NMO. In this report, we show that astrocytes are susceptible to sera from AQP4-Ab-positive patients and undergo necrosis in a complement-dependent manner. Our results suggest the primary pathogenic role of AQP4-Ab in NMO.