Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.

BACKGROUND: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects. METHODS: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment. RESULTS: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 µM; Post = 38.1 µM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ±â€Š9.3; Post = 24.7 ±â€Š10.8; mean ±â€ŠSD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment. CONCLUSIONS: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.

Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan.

Type I (transthyretin Val30Met) familial amyloid polyneuropathy (FAP ATTR Val30Met) has been reported in relation to two endemic foci in Japan. These cases are characterized by a relatively young age at onset, between the second and third decade, high penetrance rate, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. In contrast to these endemic cases, because of advances in DNA diagnosis, late-onset cases of FAP ATTR Val30Met with symptoms appearing at or over 50 years of age are now recognized to occur widely throughout Japan. These cases have a male preponderance, low penetrance rate, no relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. This type of FAP ATTR Val30Met has been overlooked because its clinical and genetic features differ from those of "typical" early-onset cases. Anticipation of age at onset is known to occur in pedigrees from the two endemic foci in Japan, with age at onset becoming younger in patients of successive generations. On the other hand, age at onset of patients in late-onset families seems to be uniformly late among the patient siblings when family history is present. Pathologic findings of the peripheral nervous system also differ in accordance with differences of clinical features. Loss of dorsal root and sympathetic ganglion neurons was severe in the early-onset cases, whereas it was only mild to moderate in the late-onset cases. Unmyelinated fibers in the biopsied sural nerve specimens of late-onset cases seemed to be relatively well preserved compared to those of previously reported early-onset cases.

Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals.

Mutations of the neurofilament-light (NEFL/NF-L) gene were examined in 124 unrelated Japanese patients with Charcot-Marie-Tooth disease (CMT) without known gene mutations, and 248 normal Japanese individuals. A new method, which can detect basepair mismatches with RNase cleavage on agarose gel electrophoresis, coupled with DNA sequencing, identified 8 novel sequence variations in the NF-L gene. In these sequence variants, 5 variants were polymorphisms, including 3 single nucleotide polymorphisms (SNPs), and 3 other missense mutations (Pro22Thr, Asn97Ser and Ala148Val) were found in the patients with CMT phenotype. The variant alleles in the NF-L gene could influence the developing process of CMT phenotype and also might cause CMT phenotype.

Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form.

BACKGROUND: Type I (transthyretin Met30) familial amyloid polyneuropathy (FAP TTR Met30) occurs in 2 endemic foci in Japan. We have also reported late-onset Japanese cases unrelated to an endemic focus and showing distinctive clinicopathologic features. OBJECTIVE: To compare clinical and geographic features of FAP TTR Met30 between patients with onset before and after 50 years of age. DESIGN AND SETTING: Clinical information was obtained through a nationwide survey by the Study Group for Hereditary Neuropathy in Japan. RESULTS: Families with early-onset disease in this study numbered 82, and those with late onset, 59. In families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. Families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. CONCLUSIONS: This study confirmed differences in clinical and geographic features between early- and late-onset FAP TTR Met30. Late-onset cases may be more prevalent and widespread than previously believed.

Mortality and morbidity in peripheral neuropathy associated Churg-Strauss syndrome and microscopic polyangiitis.

OBJECTIVE: Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA) are commonly characterized by systemic necrotizing vasculitis and frequent occurrence of axonal neuropathy. We investigated whether the neuropathy in these 2 diseases reveals differences in clinicopathologic features and predicts survival and functional outcome. METHODS: We compared 30 patients with CSS associated neuropathy with 26 patients with MPA associated neuropathy in terms of clinical, laboratory, electrophysiologic, and outcome data. RESULTS: MPA cases showed a significantly higher age at onset, a higher male/female ratio, and more extensive systemic organ involvement than CSS. Inflammatory markers including antimyeloperoxidase antibody titers were also significantly higher in MPA. Both CSS and MPA showed similar neuropathic symptoms, electrophysiologic findings, and sural nerve biopsy findings representing acute axonal changes. Functional disability assessed by modified Rankin score, muscle strength, and nerve conduction variables were similar in CSS and MPA, both in the acute peak phase and during longterm followup. However, survival was significantly worse in MPA than CSS. CONCLUSION: Neuropathy associated CSS and MPA shared common neuropathic features throughout the course, but systemic organ involvement, inflammatory marker concentrations, and relapse rates were significantly higher in MPA, which showed a poorer survival rate.