Neurologic manifestations of Kanzaki disease.

We describe the neurologic findings in a patient with alpha-N-acetylgalactosaminidase deficiency (Kanzaki disease). Clinical and electrophysiologic studies revealed sensory-motor polyneuropathy, and sural nerve pathology showed decreased density of myelinated fibers with axonal degeneration. The patient had mildly impaired intellectual function with abnormal brain MRI and sensory-neuronal hearing impairment with repeated episodes of vertigo attacks. These findings suggest that Kanzaki disease may develop neurologic complications in the CNS and peripheral nervous system.

Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease.

OBJECTIVES: To clarify the clinical variability, including central nervous system (CNS) involvement, in X-linked Charcot-Marie-Tooth disease (CMTX) patients. MATERIAL AND METHODS: We clinically, pathologically and genetically studied six CMTX patients with distinct symptoms and four different GJB1 mutations. RESULTS: One patient with Val63Ile had deafness, low intelligence, saccadic eye movement, upper extremity distal dominant muscle weakness and normal sensation. Another patient with Glu186Lys had severe sensorineural deafness at the age of 6 years, but did not develop muscle weakness until the age of 20 years. Two patients with Arg22Gln had typical CMT1A-like clinical features, no CNS symptoms and obvious onion bulb formations. Two siblings with deletion of the entire GJB1 gene had mild to moderate lower extremity muscle weakness and sensory disturbance without CNS involvement. CONCLUSION: These findings suggest that some gain of function mutations of GJB1 may be related to CNS symptoms because the patients with GJB1 deletion only had peripheral neuropathy, although other unknown associated factors may contribute to their clinical phenotypes.

The clinical and pathological features of peripheral neuropathy accompanied with HTLV-I associated myelopathy.

We describe the clinical and pathological studies in HTLV-I associated myelopathy (HAM)/tropical spastic paraparesis (TSP) patients with peripheral neuropathy as proven by sural nerve biopsy. Sural nerve pathology in HAM/TSP patients revealed that the most common type of pathologic change is a combination of both demyelination and remyelination and axonal degeneration and regeneration, and this change is modified by the complications. The pathologic changes were correlated with neither the duration of disease nor human T lymphotropic virus type I (HTLV-I) proviral load. This study suggests that peripheral nerves could be involved in HAM/TSP.

Phenotypes of X-linked Charcot-Marie-Tooth disease and altered trafficking of mutant connexin 32 (GJB1).

To clarify the pathomechanism in three patients with X-linked Charcot-Marie-Tooth disease (CMTX) and unique clinical features, we studied three connexin (Cx) 32 (GJB1) mutants with respect to cellular localization in cultured cells. Wild-type Cx32 and three Cx32 mutants (Va163Ile and Glu186Lys, obtained from CMTX patients with hearing impairment; and Arg22Gln, obtained from a CMTX patient with a fair number of onion-bulb formations) were transfected to rat pheochromocytoma cells (PC12). We investigated the expression of Cx32 protein in each clone by immunoblotting and immunohistochemical staining. While Cx32 protein with the Arg22Gln mutation was detectable immunohistochemically only in the cytoplasm, Cx32 protein with the Va163Ile or Glu186Lys mutation was detected in both the plasma membrane and the cytoplasm. Cx32 protein with the wild-type sequence was detected mostly in the plasma membrane, with plaques indicating the existence of active gap junction formation. These three Cx32 mutations associated with CMTX patients with unique clinical and pathological findings caused altered trafficking of the Cx32 protein. These altered expressions indicated loss of active gap junction formation with different expression abnormalities in these CMTX patients.

Expression of vascular endothelial growth factor in tuberculous meningitis.

The pathogenesis of tuberculous meningitis is still unclear. Recently, vascular endothelial growth factor (VEGF) was found to be associated with inflammatory diseases and we found the increased serum level of VEGF in pulmonary tuberculosis. We hypothesized that VEGF might be associated with the pathogenesis of tuberculous meningitis and measured serum and cerebrospinal fluid (CSF) levels of VEGF in 28 patients with tuberculous meningitis and 31 non-tuberculous infectious meningitis patients (13 bacterial meningitis patients, eight fungal meningitis patients and 10 patients with viral meningitis) before therapy. We examined the CSF VEGF levels 3 months after in 12 tuberculous meningitis patients. The serum and CSF levels of VEGF were significantly higher in tuberculous meningitis than in other meningitis. The decrease in titer of CSF VEGF paralleled the clinical improvement of tuberculous meningitis. Immunohistochemical staining of autopsied brains demonstrated the presence of VEGF in the inflammatory mononuclear cells of the dense fibroconnective tissue both in the subarachnoid space and surrounding the vasculitis lesion. We found the expression of VEGF in tuberculous meningitis and think that VEGF reflects its activity.

Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 are increased in POEMS syndrome.

The authors quantitatively measured levels of matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP), and vascular endothelial growth factor (VEGF) in blood samples of POEMS syndrome. Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 were more increased in patients with POEMS syndrome than in patients with other neurologic disorders or in healthy controls. Serum levels of VEGF and TIMP-1 were strongly correlated with each other. Increased circulating levels of MMP-1, -2, -3, -9, and TIMP-1 may lead to a better understanding the pathogenesis of POEMS syndrome.

Clinical phenotype in X-linked Charcot-Marie-Tooth disease with an entire deletion of the connexin 32 coding sequence.

To clarify the clinical phenotype and molecular mechanism in X-linked Charcot-Marie-Tooth disease (CMTX) patients with a deletion of the whole connexin 32 (Cx32) coding sequence, we studied a family with this deletion by electrophysiology, Southern blotting and quantitative PCR analyses. Two brothers with no copy of Cx32, 27 and 25 years old, showed steppage gait, moderate muscle atrophy and weakness, and mild sensory disturbance in the distal parts of the legs. The clinical phenotypes in these brothers were not different from those in patients with other types of severe Cx32 mutations. Their mother, with one copy of Cx32, showed very mild muscle weakness and sensory disturbance. An electrophysiological study showed a nonuniform demyelinating neuropathy with some aspects of an axonal-loss neuropathy. Sural nerve biopsy showed loss of myelinated fibers, many relatively thin myelin sheaths, clusters of small myelinated fibers, and some onion bulb formations. The present findings suggest that both a demyelinating process and an axonal involvement were present in the patients with total defect of Cx32 probably due to loss of the function mechanism of Cx32 as the underlying molecular mechanism, because a dominant negative effect theory is not applicable in these patients.

HTLV-I-associated myelopathy.

HTLV-I was first described as a pathogenic human retrovirus that causes adult T-cell leukemia (ATL). Soon after the discovery of HTLV-I, an association of this virus with a slowly progressive neurological disorder was found independently in Japan and Caribbean islands, and this new clinical entity (HTLV-I-associated myelopathy with tropical spastic paraparesis) was named HAM/TSP. Autopsy findings clarified the chronic inflammatory nature of the disease. Detailed neuropathological analysis demonstrated: (i) T-cell-dominant mononuclear cell infiltration; (ii) diffuse and symmetrical degeneration of the anterolateral and inner portion of the posterior columns involving both myelin and axons; (iii) the presence of cytotoxic T cells and apoptosis of helper/inducer T cells; (iv) in vivo localization of HTLV-I provirus in the perivascular infiltrated T cells; and (v) accentuation of inflammatory lesions at the site with slow blood flow. From these findings it is suggested that a T-cell-mediated chronic inflammatory process targeting the HTLV-I-infected T cells is the primary pathogenic mechanism of HAM/TSP.

Polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis.

A patient with mixed gonadal dysgenesis showed glove and stocking-type sensory impairment and slowing of motor and sensory nerve conduction. Sural nerve biopsy revealed minifascicular formation with decreased density of myelinated fibers. As far as we are aware, this is the first report of polyneuropathy with minifascicular formation in 46XY mixed gonadal dysgenesis.

[A case of neuro-Behcet's disease with transient cerebral ischemia evoked by smoking].

We present a 63-year-old male case of neuro-Behçet's disease with transient cerebral ischemia evoked by smoking. He first noticed genital ulcer after the operation of colon cancer, and then recurrent oral aphtha and skin erythema. From these symptoms and other laboratory data, we diagnosed him as suffering from Behçet's disease. He also showed dysbasia, dysarthria, pseudo-bulbar palsy, and changes in character, characteristic to neuro-Behçet's disease. After smoking, he showed disturbance of consciousness, dysequilibrium, and bilateral adynamia in upper and lower extremities, so we performed SPECT study. Compared with routine SPECT, less blood perfusion in frontal lobe, temporal lobe, and basal ganglia was observed after smoking. Mild vasculitis was observed in skin biopsy, but no such signs were observed in cerebral angiography. After steroid therapy, these symptoms evoked by smoking faded away. Previous studies reported that vasculitis is an important predisposing cause of vasospasm, and that smoking causes transient cerebral ischemia by vasospastic mechanisms. In this case, mild vasculitis was thought to be predisposed to vasospasm by smoking.

Activation of macrophages/microglia with the calcium-binding proteins MRP14 and MRP8 is related to the lesional activities in the spinal cord of HTLV-I associated myelopathy.

Macrophages and microglia may play an important role in the pathogenesis of chronic inflammatory process in HTLV-I associated myelopathy (HAM) and tropical spastic paraparesis (TSP). However, the etiology and cellular mechanism of chronic inflammation are poorly understood in HAM/TSP. To help to define the roles of macrophages and microglia we analyzed the various patterns of macrophage and microglia activation in the central nervous system (CNS) of HAM/TSP using several monoclonal antibodies recognizing the different states of activation. The results indicate that a large number of macrophages and microglia express both MRP14 and MRP8 in active-chronic inflammatory lesions of the patients with a short duration of illness (2.5 years). In the patient whose duration of illness was 4.5 years, perivascular and parenchymal macrophages and microglia were reactive for MRP8 but not for MRP14. In contrast, MRP14 and MRP8 were negative on the perivascular and parenchymal macrophages and microglia in inactive-chronic lesions and in controls. This study suggests that (a) activated macrophages and microglia as well as CD4+ T lymphocytes and CD8+ cytotoxic T lymphocytes are main components of the inflammatory process in the CNS in HAM/TSP, (b) activation of macrophages and microglia is related to the amount of HTLV-I proviral DNA in situ.

[Acute isolated levator palpebral myositis].

A 17-year old man developed acute onset blepharoptosis of the right upper eyelid with swelling. On examination, the patient exhibited right blepharoptosis without limitation of eye movement. MRI revealed swelling of right levator palpebral muscle. Oral steroid administration led to complete resolution of the blepharoptosis within 3 weeks. Isolated levator palpebral myositis is a rare disease, but, it is important for differential diagnosis on patients with blepharoptosis.

Accumulation of mitochondrial ATP synthase subunit c in muscle in a patient with neuronal ceroid lipofuscinosis (late infantile form).

We report a case late infantile neuronal ceroid lipofuscinosis (NCL). Abnormal granules were found in the skeletal muscle fibers, Schwann cells, perineurial cells, endothelial cells, fibroblasts, and perivascular smooth muscle cells in the sural nerve. Electron microscopy revealed that these granules showed fingerprint profiles, curvilinear profiles or membrane-bound membranous structures. Acid phosphatase reaction was increased in these cells. Immunohistochemical studies for mitochondrial ATP synthase subunit c showed a strong reaction in these cells, suggesting abnormal accumulation of subunit c. Immunohistochemistry for subunit c in muscle may be useful in the diagnosis of late infantile NCL.

Neuropathology of HTLV-1-associated myelopathy (HAM/TSP).

In order to clarify pathogenesis of HAM/TSP, we performed a detailed neuropathologic analysis of seven autopsy patients with HAM/TSP. Inflammatory infiltrates of mononuclear cells and degeneration of myelin and axons were noted in the middle to lower thoracic spinal cords and were continuously extended to the entire spinal cord. Horizontal distribution of inflammatory lesions was symmetric at any spinal levels. Immunohistochemical analysis demonstrated T-cell dominance. The numbers of CD4+ T cells and CD8+ T cells were equally present in patients with shorter clinical course. Apoptosis of helper/inducer T cells were observed in the presence of TIA1+ cytotoxic T cells in these active inflammatory lesions. Inflammatory infiltrates were markedly decreased and CD8+/TIA1- T cells were predominated over CD4+ cells in patients with prolonged clinical course. HTLV-1 proviral DNA amounts in the freshly frozen spinal cord measured by quantitative PCR were well correlated with the numbers of infiltrated CD4+ cells. In situ PCR of HTLV-1 proviral DNA using multi-primary pairs demonstrated the presence of HTLV-1 infected cells exclusively in the mononuclear infiltrates of perivascular areas. From these findings, it is suggested that the target of the inflammatory process seen in HAM/TSP lesions may be HTLV-1 infected CD4+ T cells infiltrating the spinal cord.

Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family.

Three adult patients (38-year-old male, 86-year-old female, and 61-year-old male) in a family with mucolipidosis III (ML-III) were described. They had characteristic features of ML-III and they survived a long time. N-acetylglucosaminyl 1-phosphotransferase activity was low in fibroblasts of a patient, but its residual activity remained at a relatively high level (24.5-35.3% of controls), which may explain the benign clinical course. Odontoid dysplasia and atlanto-axial dislocation was found in one patient, and surgical treatment improved his physical disability. Bilateral carpal tunnel syndrome as well as claw hand deformities were common in all of the patients. The clinical manifestations were important for the diagnosis and the management of the patients.

[A case of myasthenia gravis associated with systemic lupus erythematosus and pemphigus erythematosus].

A 34-year-old woman was admitted to our hospital because of ptosis, dysarthria, muscle weakness of upper limbs and skin lesions. At the age of 22 years, she was diagnosed as having systemic lupus erythematosus (SLE) due to the presence of arthritis and high titer of antinuclear antibody. On admission, the high antiacetylcholine receptor antibody titer, along with the positive tensilon test and electromyography established a diagnosis of myasthenia gravis (MG). The demonstration of anti-intercellular antibodies both in cutaneous tissue and blood confirmed the diagnosis of pemphigus. MRI showed hypertrophic thymus. After thymectomy, the myasthenic symptoms aggravated and SLE and pemphigus erythematosus relapsed despite anti-cholinesterase treatment with plasmapheresis. She was then placed on corticosteroid therapy with an improvement of her all symptoms. This very rare case of MG associated with SLE and pemphigus erythematosus suggests that these diseases share common immunological abnormalities.

[Clinical features of allergic granulomatosis and angiitis (Churg-Strauss syndrome). Association with asthma symptoms].

We reported clinical and laboratory findings of 5 patients with Churg-Strauss syndrome (CSS), especially association with asthma symptoms. Subjects included 3 males and 2 females with a mean age of 53.8 year-old. In all 5 patients symptoms of neuropathy; mononeuritis multiplex and in some patients, other vasculitic symptoms; fever, diarrhea, abdominal pain and skin eruptions, were noted. These clinical features and laboratory findings; marked peripheral eosinophilia and elevation of serum ECP were normalized after steroid therapy. We investigated the relation between the occurrence of CSS and the symptoms of asthma. The mean duration of asthma in this series was 17.2 years, and 4 cases were atopic and one was non-atopic asthma. In previous publications, asthmatic symptoms were severe at the onset of the disease and progressed thereafter. In our 5 cases, however, the severities of bronchial asthma were mild of two cases, moderate of two and severe of only one, moreover severe asthmatic attacks were shown in only 2 cases when the manifestation of systemic vasculitis occurred. In conclusion, although CSS has been thought that one of complications of bronchial asthma, the occurrence of CSS are not necessarily correlated with symptoms of bronchial asthma.