Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu).

OBJECTIVE: To determine the clinical and radiologic features of Gerstmann-Sträussler-Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102). METHODS: The authors report 11 patients (nine families) with clinically and radiologically diagnosed GSS102. RESULTS: All patients showed mild gait disturbance, dysesthesia and hyporeflexia of the lower legs, and truncal ataxia, and 9 of 11 patients showed proximal leg muscle weakness during the early stage of the disease. Dementia was not a main symptom during the early stage. Brain MRI and EEG abnormalities were not prominent initially. SPECT (N-isopropyl-p-[(123)I]iodoamphetamine) analyzed by the three-dimensional stereotactic surface projection (SSP) method detected abnormalities in five patients early during the course of the illness. SPECT findings showed diffusely decreased cerebral blood flow, demonstrated by a mosaic pattern, with the lowest perfusion noted in the occipital lobes. In contrast, blood flow to the cerebellum was preserved. These studies suggested sites of pathology in GSS102, with the main lesions probably located in the cerebrum and the spinal cord (posterior horn and spinocerebellar tract) instead of the cerebellum. CONCLUSIONS: Key features for early diagnosis of Gerstmann-Sträussler-Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102) are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings are characters of early GSS102.

Age associated axonal features in HNPP with 17p11.2 deletion in Japan.

OBJECTIVE: To clarify age related changes in the clinicopathological features of hereditary neuropathy with liability to pressure palsy (HNPP) in Japanese patients with deletion of 17p11.2, particularly concerning axonal abnormalities. METHODS: Forty eight proband patients from 48 HNPP families were assessed as to clinical, electrophysiological, and histopathological features, including age associated changes beyond those in controls. RESULTS: Motor conduction studies showed age associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve. Sensory conduction studies revealed more profound reduction of action potentials than motor studies with little age related change. Large myelinated fibre loss was seen in the sural nerve irrespective of age at examination. CONCLUSIONS: Irreversible axonal damage may occur at entrapment sites in motor nerves in HNPP patients, progressing with aging. Sensory nerves may show more profound axonal abnormality, but without age association. The electrophysiological features of HNPP are presumed to be a mixture of abnormalities occurring from early in life and acquired features caused by repetitive insults at entrapment sites. Unlike Charcot-Marie-Tooth disease type 1A, age associated axonal damage may not occur unless the nerves are subjected to compression.

Chronic progressive cervical myelopathy with HTLV-I infection: Variant form of HAM/TSP?

OBJECTIVE: To investigate the role of human T-lymphotrophic virus type I (HTLV-I) infection in four patients who developed slowly progressive myelopathy with abnormal MRI lesions in the cervical cord levels. METHODS: Clinical and neuroradiologic examinations were performed, and the odds that an HTLV-I-infected individual of specified genotype, age, and provirus load had HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were calculated. RESULTS: Anti-HTLV-I antibodies were positive in both the serum and the CSF in all of the patients. Biopsied sample from spinal cord lesions showed inflammatory changes in Patient 1. Patient 2 had a demyelinating type of sensorimotor polyneuropathy. Two of the three patients examined showed high risk of developing HAM/TSP in virologic and immunologic aspects. CONCLUSION: These four cases may belong to a variant form of HAM/TSP, predominantly involving the cervical cord levels.

SET binding factor 2 (SBF2) mutation causes CMT4B with juvenile onset glaucoma.

The authors report a Japanese family segregating autosomal recessive Charcot-Marie-Tooth disease (CMT) with focally folded myelin, juvenile-onset glaucoma, and a nonsense mutation of SET binding factor 2 (SBF2). The consistent phenotypic features associated with SBF2 mutations are early-onset demyelinating neuropathy, myelin folding, and markedly decreased motor nerve conduction velocities; glaucoma associates with SBF2 nonsense mutations.

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.

In vivo protection of a water-soluble derivative of vitamin E, Trolox, against methylmercury-intoxication in the rat.

Methylmercury (MeHg) is a well-known neurotoxicant. MeHg-intoxication causes a disturbance in mitochondrial energy metabolism in skeletal muscle and apoptosis in cerebellum. We report the first in vivo effectiveness of antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carhoxylic acid), a water soluble vitamin E analog, against the MeHg-induced cellular responses. Treatment with Trolox (6-hydroxy-2.5,7,8-tetramethylchroman-2-carboxylic acid) clearly protects MeHg-treated rat skeletal muscle against the decrease in mitochondrial electron transport system enzyme activities despite the retention of MeHg. Tdt-mediated dUTP nick-end-labeling method clarified that Trolox is effective for protecting cerebellum from MeHg-induced apoptosis. These data indicate that MeHg-mediated oxidative stress plays an important role in the in vivo pathological process of MeHg intoxication. Trolox may prevent some of clinical manifestations of MeHg-intoxication in humans.

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.

A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy.

We describe a patient with 46,XY partial gonadal dysgenesis (PGD) who presented with polyneuropathy. Sural nerve pathology revealed peculiar findings characterized by extensive minifascicular formation within the endoneurium and with a decreased density of myelinated fibers. We found, in the patient, a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog (DHH) gene, which predicts a failure of translation of the gene. The same heterozygous mutation was found in the patient's father. This is the first report of a human DHH gene mutation, and the findings demonstrate that mutation of the DHH gene may cause 46, XY PGD associated with minifascicular neuropathy.

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.

Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system.

Although brain lesions have been described in some cases with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the nature of brain lesion and its relation to the spinal cord lesion. In the present study, we performed histopathological analysis of the brain and the spinal cord of four autopsied cases with HAM/TSP to clarify the relationship between the brain and the spinal cord lesions. In two cases with active-chronic inflammation in the spinal cord, perivascular inflammatory infiltration was also seen in the brain, and the composition of cell subsets was similar both in the spinal cord and in the brain. No active inflammatory change was seen in the brain in two cases with inactive-chronic spinal cord lesions. Inflamed vessels were distributed mainly in the deep white matter and in the area between cerebral cortex and white matter of the brain. In the spinal cord inflamed vessels were mainly seen in the bilateral lateral and the ventral posterior columns. Parenchymal infiltration was diffused in the spinal cord but very sparse in the brain, suggesting the importance of parenchymal infiltration in the destruction of tissues. These results suggest that inflammatory changes occurred simultaneously in the spinal cord and in the brain, and that distribution of inflamed vessels closely correlated with the characteristics of vascular architecture of the brain and the spinal cord, which lead to a slow blood flow. This study may help promote a better understanding of the pathogenesis of HAM/TSP.

Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma.

OBJECTIVE: We describe three patients from a family with motor and sensory neuropathy accompanied by open-angle glaucoma. BACKGROUND: Autosomal recessive demyelinating hereditary motor and sensory neuropathies (HMSN) include different disorders. To our knowledge, autosomal recessive HMSN has not been associated with juvenile onset glaucoma. METHODS: Sural nerve pathology of the three patients were examined, and genetic analysis of the family was performed. RESULT: - The most prominent pathologic finding was a highly unusual myelin abnormality consisting of irregular redundant loops and folding of the myelin sheath. The family survey supports autosomal recessive inheritance. The molecular analysis failed to demonstrate either linkage of the disease to MPZ gene, PMP22 gene, Cx32 gene, orEGR2 gene. Analysis did not establish linkage of the disease to the locus of CMT4A, 4B, and 4C genes. CONCLUSION: The present cases may represent a new type of HMSN accompanied by juvenile onset glaucoma.

Axonal damage revealed by accumulation of beta-amyloid precursor protein in HTLV-I-associated myelopathy.

We investigated the localization and extent of beta-amyloid precursor protein (APP) immunoreactivity as a sensitive marker for impairment of fast axonal transport in the spinal cords of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The results from this study show that APP, used as a marker of early axonal damage in HAM/TSP lesions, is more intensively expressed in areas of active-inflammatory lesions than those of inactive-chronic lesions. The close localization to the areas containing inflammation (activation of macrophage/microglia) is striking and suggests that axonal damage is closely associated with inflammation in active-chronic lesions. Although inflammatory cell infiltration in the central nervous system (CNS) is rarely found in inactive-chronic lesions, a few clusters of APP+ axons are found in the spinal cord white matter in some cases. The presence of APP+ axons without relation to inflammatory cells in inactive-chronic lesions, suggest that soluble neurotoxic factors might induce axonal changes in the CNS of HAM/TSP. The occasional myelinated fibers in the anterior and posterior spinal roots in lower thoracic to lumbar levels had APP+ axons, suggesting that spinal nerve roots can be affected in HAM/TSP, especially in lower thoracic to lumbar levels. Impairment of fast axonal transport may contribute to the development of disability in patients with HAM/TSP.