A case of Marinesco-Sjögren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial.

alpha Pix enhances mutant huntingtin aggregation.

Huntington's disease is caused by polyglutamine-expanded mutant huntingtin (muhtt), an aggregation-prone protein. We identified the Pak-interacting exchange factor (alpha Pix/Cool2) as a novel huntingtin (htt) interacting protein, after screening actin-cytoskeleton organization-related factors. Using immunoprecipitation experiments, we show that alpha Pix binds to both the N-terminal of wild-type htt (wthtt) and mutant htt (muthtt). Colocalization studies revealed that alpha Pix accumulates in muthtt aggregates. Deletion analysis suggested that the dbl homology (DH) and pleckstrin homology (PH) domains of alpha Pix are required for its interaction with htt. Overexpression of alpha Pix enhanced muthtt aggregation by inducing SDS-soluble muthtt-muthtt interactions. Conversely, knocking down alpha Pix attenuated muhtt aggregation. These findings suggest that alpha Pix plays an important role in muthtt aggregation.

Incidence and clinical significances of human T-cell lymphotropic virus type I-associated myelopathy with T2 hyperintensity on spinal magnetic resonance images.

OBJECTIVE: To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI). PATIENTS AND METHODS: We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings. RESULTS: MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation. CONCLUSION: HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%.

Identification of a new homozygous frameshift insertion mutation in the SIL1 gene in 3 Japanese patients with Marinesco-Sjögren syndrome.

Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts, progressive muscular weakness, and developmental and mental retardation. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to be a cause of MSS. We sequenced the entire SIL1-coding region in 3 unrelated Japanese patients with classical MSS and identified a novel homozygous frameshift insertion mutation, 936_937insG, in exon 9 in all 3 patients.

p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity.

Huntington's disease (HD) is caused by a polyglutamine (polyQ) expansion in the huntingtin (htt) protein. While aggregation is a pathological hallmark of HD and related polyQ expansion diseases, the role of aggregates has been disputed. Here we report that p21-activated kinase 1 (Pak1) binds to htt in vivo and in vitro. Pak1 colocalized with mutant htt (muhtt) aggregates in cell models and in human HD brains. Pak1 overexpression enhanced the aggregation of muhtt. Furthermore, we observed SDS-soluble wild-type htt (wthtt)-wthtt, wthtt-muhtt and muhtt-muhtt interactions, which were enhanced by the presence of Pak1. We show that Pak1 overexpression enhanced htt toxicity in cell models and neurons in parallel with its ability to promote aggregation, while Pak1 knockdown suppressed both aggregation and toxicity. Overexpression of either kinase-dead or wild-type Pak enhanced both aggregation and toxicity. Our data reveal a novel mechanism regulating muhtt oligomerization and toxicity and suggest that pathology may be at least partly dependent on soluble muhtt-muhtt interactions.

Vasculitic neuropathy in a patient with hereditary C1 inhibitor deficiency.

OBJECTIVE: To report the clinical, pathological, and mutational features of hereditary C1 inhibitor (C1INH) deficiency as a cause of isolated vasculitic neuropathy. PATIENT: A 35-year-old woman with sensorimotor mononeuritis multiplex and facial palsy. RESULTS: The sural nerve biopsy results showed a decrease of myelinated fibers with axonal degeneration and severe hypersensitivity vasculitis, with deposition of C1q on vessel walls. Mutational analysis of the C1INH gene found a new mutation, a heterozygous 2-base pair deletion in exon 8. The patient was treated with plasmapheresis and intravenous methylprednisolone, followed by oral prednisolone, which resulted in marked improvement. CONCLUSION: Hereditary C1INH deficiency should be included in the differential diagnosis of nonsystemic vasculitis neuropathy.

[An autopsied case of limbic encephalitis associated with extremely high titers of anti-SS-A antibodies in serum and anti-neuronal antibodies in CSF].

A 76-year old man was referred to our department because of several episodes of generalized convulsion followed by a loss of consciousness and the right hemiparesis. The disturbed consciousness and hemiparesis disappeared soon but the personal change persisted thereafter. T2 and diffusion weighted images of MRI taken on the admission showed high intensity lesions in the left medial temporal lobe including the hippocampus. Antibodies (Abs) against herpes simplex virus were not elevated, however, serum titers of antinuclear and anti-SS-A/Ro Abs were extremely elevated. CSF IgG level and IgQ index were increased, and the CSF reacted with 78-kd bands on Western blots of rat brain homogenate. He died of bacterial pneumonia on the 28th day of illness and was autopsied. Malignant tumors were not found in any organs. In the left hippocampus, degeneration and loss of neurons, infiltration of macrophages, and microgliosis were observed. Vasculitis, however, was not found in the lesion. The immunohistochemical study showed that the CSF recognized the cytoplasm of neurons in the human hippocampus and also Purkinje cells. Those immunological and pathological findings thus suggest an antibody-mediated autoimmune limbic encephalitis in our case.

Cloning and functional characterization of a rat Daxx that functions as a corepressor for the androgen receptor.

The androgen receptor (AR), a ligand-activated nuclear transcription factor, plays an important role in endocrine system development and homeostasis. AR-mediated gene transcription is modulated by a wide variety of coregulator proteins, but corepressors of AR have not been well characterized. We have isolated a rat homologue of Daxx, a possible AR repressor. The clone obtained comprised a 2196 bp open reading frame, corresponding to a sequence of 731 amino acids with 80.5% homology to mouse. Basal transcription of the isolated clone was repressed in transient transcription experiments using a Gal4 reporter gene assay. Furthermore, a mammalian two-hybrid assay showed a strong interaction between Daxx and promyelocytic leukemia (PML) protein. These results indicate that the isolated clone is a rat homologue of Daxx. The rat Daxx (rDaxx) interacted with the androgen receptor (AR): in co-immunoprecipitation experiments, AR formed complexes with anti-Daxx antibody. Furthermore, overexpression of Daxx suppressed AR-mediated transcriptional activity in HeLa and CV1 cells in transient transfection experiments. Taken together, our results suggest that Daxx may function as a corepressor for the androgen receptor.

Late-onset familial amyloid polyneuropathy: an autopsy study of two Japanese brothers.

We report an autopsy study of late-onset familial amyloid polyneuropathy with a variant transthyretin Val30Met in 2 brothers living in Kyoto, Japan. The disease onsets were at 64 and 59 years, and they died at 71 and 74 years old, respectively. They exhibited almost the same postmortem findings. Amyloid deposition was remarkable in the hearts, but was not seen in the renal glomeruli. In the peripheral nervous system, amyloid deposition was most prominent in the nerves immediately caudal to ganglia, moderate in the dorsal and sympathetic ganglia, and mild in the spinal roots, sciatic nerves, and distal nerves. The difference between the amyloid deposition in the proximal portion and distal portion of the extremity nerves appeared to be greater in the late-onset type than in the ordinary type, and this proximal deposition of amyloid may have induced severe distal nerve fiber degeneration.

Leber's hereditary optic neuropathy with intracranial arteriovenous malformation: a case report.

We reported a patient with Leber's hereditary optic neuropathy (LHON) with an intracranial arteriovenous malformation (AVM). Genetic analysis of this patient revealed a point mutation in mitochondrial DNA (mtDNA) at nucleotide position 11,778 in the ND4 subunit of complex I. Although the relationship between intracranial AVM and mtDNA mutations remains uncertain, some patients with intracranial AVM may be associated with mitochondrial abnormality. Further study is necessary to confirm whether the above conditions are coincidental or closely interrelated.