To clarify the pathogenesis of cerebrovascular amyloid deposits, histological and immunocytochemical studies were performed on the central nervous system (CNS) in ten cases with type I familial amyloid polyneuropathy (FAP). They commonly suffered from peripheral somatic and autonomic nerve disorders without any CNS dysfunctions. However, all cases showed CNS amyloid deposits, mainly on the leptomeningeal vessels and pia-arachnoid membranes, with arteries and arterioles in the subarachnoidal space being the predominant site of cerebral amyloid accumulation. Using immunocytochemical staining methods with antibodies to amyloid beta-protein, human cystatin C and transthyretin (prealbumin), all of these amyloid deposits were specifically immunolabeled by the anti-human transthyretin antibody. However, there was no transthyretin-related amyloid deposits in the brain parenchyma. It is concluded that CNS transthyretin-immunoreactive amyloid deposition with cerebral amyloid angiopathy (CAA) is a common pathological finding in this disease. Moreover, the patients with type I FAP are known to have an amyloid protein precursor (a variant of transthyretin) in serum. This transthyretin type of CAA, therefore, seems to be an example of cerebrovascular amyloid deposits derived from a serum precursor.

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.

Spinocerebellar ataxia type 31 (SCA31) is known as a late-onset, relatively pure cerebellar form of ataxia, but a longitudinal prospective study on the natural history of SCA31 has not been done yet. In this prospective cohort study, we enrolled 44 patients (mean ± standard deviation 73.6 ± 8.5 years) with genetically confirmed SCA31 from 10 ataxia referral centers in the Nagano area, Japan. Patients were evaluated every year for 4 years using the Scale for the Assessment and Rating of Ataxia (SARA) and the Barthel Index (BI). Of the 176 follow-up visits (91.5%), 161 were completed in this study. Five patients (11.4%) died during the follow-up period, and two patients (4.5%) were lost to follow-up. The annual progression of the SARA score was 0.8 ± 0.1 points/year and that of the BI was -2.3 ± 0.4 points/year (mean ± standard error). Shorter disease duration at baseline was associated with faster progression of the SARA score. Our study indicated the averaged clinical course of SCA31 as follows: the patients develop ataxic symptoms at 58.5 ± 10.3 years, become wheelchair bound at 79.4 ± 1.7 years, and died at 88.5 ± 0.7 years. Our prospective dataset provides important information for clinical trials of forthcoming disease-modifying therapies for cerebellar ataxia. It also represents a useful resource for SCA31 patients and their family members in genetic counseling sessions.

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ABSTRACT16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5'-UTR of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCAIII, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using ICARS and SARA, and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 ± 9.8 years, n = 66) than in SCA6 patients (41.1 ± 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant. GLOSSARY ADCA = autosomal dominant cerebellar ataxia, 16q-ADCA = 16q22.1-linked autosomal dominant cerebellar ataxia, SCD = spinocerebellar degeneration, SCA6 = spinocerebellar ataxia type 6, ICARS = international cerebellar ataxia rating scales, SARA = scales for the assessment and rating of ataxia