Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy

Here we report what is to our knowledge the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. The index case is a 52-year-old man with almost 40 years of progressive proximal muscle weakness. High urinary β2 microglobulin, normal serum β2 microglobulin, autophagic vacuoles with sarcolemmal features, and a hemizygous c.164–7T>G mutation in the VMA21 gene were found. His two maternal uncles had similar clinicopathological findings. High urinary β2 microglobulin without obvious renal dysfunction might result from decreased urine acidification in the distal convoluted tubules caused by the VMA21 gene mutation. These findings might prove to be useful as a preliminary marker suggestive of X-linked myopathy with excessive autophagy.     

Lack of differential motor outcome with subthalamic nucleus region stimulation in Parkinson’s disease

Deep brain stimulation (DBS) has emerged as a viable therapy for Parkinson’s disease (PD). The impact of subthalamic nucleus (STN) lead placement (lateral versus medial) on motor outcome, however, has not been systematically evaluated. Forty-eight patients with PD underwent STN-DBS surgery and were evaluated postoperatively for 48 weeks for motor improvement as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (standardized motor examination) and levodopa equivalent daily dose (LEDD). Postoperative MRI was used to identify the location of the active stimulating contact and motor outcome was analyzed. STN-DBS was associated with significant improvement in motor outcome as determined by a reduction in the UPDRS part III subscore from 34.44 ± 1.29 at baseline to 18.76 ± 1.06 at end visit (p < 0.0001) and a reduction in LEDD from 1721 ± 152 mg/day at baseline to 1134 ± 119 mg/day at end visit (p = 0.0024). Patients with stimulating contacts in the medial STN compared to the lateral STN did not demonstrate any significant differences in motor outcome (UPDRS, p = 0.5811; LEDD, p = 0.7341). No significant differences were found in motor outcome between patients with STN stimulation compared to stimulation of surrounding fiber tracts (p = 0.80). No significant difference in stimulation voltage was noted with respect to lead location. Our study did not find a significant effect for the location of active contact and motor outcome neither within the subregions of the STN nor between the STN and surrounding fibers. Further research is needed to better understand the neurophysiological basis for these results.     

Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct

Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein‐transgenic rats and were labeled with quantum dots. The BMSCs (1 × 10⁵ or 1 × 10⁶) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post‐ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post‐transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post‐ischemia, but such therapeutic effects were observed only when the high‐dose BMSCs were transplanted at 4 weeks post‐ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri‐infarct area when the high‐dose BMSCs were transplanted at 1 or 4 weeks post‐ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.     

Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases

Matrix metalloproteinases (MMPs) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation; however, it remains unclear how MMPs act in lesion formation and whether MMP‐targeted therapies are effective in disease suppression. In the present study, we attempted to treat experimental autoimmune encephalomyelitis (EAE) by administration of small interfering RNAs (siRNAs) for MMP‐2, MMP‐9, and minocycline, all of which have MMP‐inhibiting functions. Minocycline, but not siRNAs, significantly suppressed disease development. In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline‐treated animals, while significant gelatinase activities were measured in the EAE lesions of control animals. However, MMP‐2 and MMP‐9 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated. At the same time, mRNA for tissue inhibitors of MMPs (TIMP)‐1 and ‐2 were also upregulated. The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues. Finally, double immunofluorescent staining demonstrated that MMP‐9 immunoreactivities of treated rats were almost the same as those of control rats and that MMP‐9 and TIMP‐1 immunoreactivities were colocalized in the spinal cord. These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs. Thus, MMP‐targeted therapies should be designed after the mechanisms of candidate drugs have been considered.     

Contiguous ABCD1 DXS1357E deletion syndrome: Report of an autopsy case

Contiguous ABCD1 DXS1357E deletion syndrome (CADDS) is a contiguous deletion syndrome involving the ABCD1 and DXS1357E/BAP31 genes on Xq28. Although ABCD1 is responsible for X‐linked adrenoleukodystrophy (X‐ALD), its phenotype differs from that of CADDS, which manifests with many features of Zellweger syndrome (ZS), including severe growth and developmental retardation, liver dysfunction, cholestasis and early infantile death. We report here the fourth case of CADDS, in which a boy had dysmorphic features, including a flat orbital edge, hypoplastic nose, micrognathia, inguinal hernia, micropenis, cryptorchidism and club feet, all of which are shared by ZS. The patient achieved no developmental milestones and died of pneumonia at 8 months. Biochemical studies demonstrated abnormal metabolism of very long chain fatty acids, which was higher than that seen in X‐ALD. Immunocytochemistry and Western blot showed the absence of ALD protein (ALDP) despite the presence of other peroxisomal proteins. Pathological studies disclosed a small brain with hypomyelination and secondary hypoxic‐ischemic changes. Neuronal heterotopia in the white matter and leptomeningeal glioneuronal heterotopia indicated a neuronal migration disorder. The liver showed fibrosis and cholestasis. The thymus and adrenal glands were hypoplastic. Array comparative genomic hybridization (CGH) analysis suggested that the deletion was a genomic rearrangement in the 90‐kb span starting in DXS1357E/BACP31 exon 4 and included ABCD1, PLXNB3, SRPK3, IDH3G and SSR4, ending in PDZD4 exon 8. Thus, the absence of ALDP, when combined with defects in the B‐cell antigen receptor associated protein 31 (BAP31) and other factors, severely affects VLCFA metabolism on peroxisomal functions and produces ZS‐like pathology.     

Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP‐43‐positive inclusions in patients with sporadic amyotrophic lateral sclerosis

Overexpression of BTBD10 (BTB/POZ domain‐containing protein 10) suppresses G93A‐superoxide dismutase 1 (SOD1)‐induced motor neuron death in a cell‐based amyotrophic lateral sclerosis (ALS) model. In the present study, paraffin sections of spinal cords from 13 patients with sporadic ALS and 10 with non‐ALS disorders were immunostained using a polyclonal anti‐BTBD10 antibody. Reduced BTBD10 expression in the anterior horn cells was more frequent in spinal cords from ALS patients than in cords from patients with non‐ALS disorders. We further investigated the relationship between the level of BTBD10 immunoreactivity and the morphology of the Golgi apparatus (GA) and the presence of phosphorylated TAR‐DNA‐binding protein 43 (pTDP‐43). Mirror sections of spinal cords from five sporadic ALS cases were immunostained with antibodies against BTBD10 and trans‐Golgi‐network (TGN)‐46 or pTDP‐43. Whereas 89.7–96.5% of the neurons with normal BTBD10 immunoreactivity showed normal GA morphology and no pTDP‐43 cytoplasmic aggregates, 86.2–94.3% of the neurons with reduced BTBD10 expression showed GA fragmentation and abnormal pTDP‐43 aggregates. These findings suggest that reduced BTBD10 expression is closely linked to the pathogenesis of sporadic ALS.