IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTSClinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURESResults of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCECombined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

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Serum anti-aquaporin 4 (AQP4) antibody is detected with high specificity in patients with neuromyelitis optica (NMO), characterised by recurrent optic neuritis and longitudinally extensive transverse myelitis [1,2]. Three NMO patients with anti-AQP4 antibody were reported to have hypothalamic lesions, showing reduced hypocretin-1 levels in cerebrospinal fluid (CSF) and symptomatic narcolepsy [3]. Although the hypothalamus and hypocretin-1 regulate autonomic functions as well as sleep, autonomic functions in NMO patients with hypothalamic lesions have not been described well. Here we report the case of a patient with anhidrosis and narcolepsy as initial symptoms of disorders related to anti-AQP4 antibody.A 41-year-old woman was experiencing excessive daytime sleepiness. Cataplexy was not evident. One month after, she became aware of anhidrosis on the left side of her body including the face. The following month, she was admitted to our hospital because of hypersomnia and anhidrosis that extended throughout her entire body.Physical and neurological examination revealed hypotension (93/62 mmHg) and dry skin. Brain magnetic resonance imaging (MRI) showed a high signal intensity area around the third ventricle on fluid-attenuated inversionrecovery image (Fig. 1a). Multiple sleep latency test showed shortening of the mean sleep latency (4.8 min; normal: [8 min) and sleep-onset REM periods. Lumbar puncture showed only a decrease of CSF hypocretin-1 levels (177 pg/ml, normal:[200 pg/ml). Serum anti-AQP4 antibody was positive. Although sympathetic skin responses (SSR) were absent in all limbs (Fig. 1c), intracutaneous acetylcholine injection caused normal sweating reaction.The patient was diagnosed with NMO spectrum disorders having narcolepsy and anhidrosis, secondary to hypothalamic lesions associated with anti-AQP4 antibody, and treated with intravenous methylprednisolone (1 g/day) for 3 days, followed by oral prednisolone (1 mg/kg/day). After treatment, her excessive sleepiness and anhidrosis disappeared in a few days. MRI showed improvement of the abnormal intensity area (Fig. 1b), and CSF hypocretin-1 levels had recovered to 213 pg/ml. Moreover, repeated tests of SSR showed positive responses (Fig. 1d).Anhidrosis of the entire body was detected and confirmed by SSR in our patient associated with anti-AQP4 antibody as well as symptomatic narcolepsy. After treatment, the reduced CSF hypocretin-1 levels returned to normal in parallel with improvement of excessive daytime sleepiness, similar to previously reported NMO cases [3]. The hypothalamus is the highest level of integration of autonomic function; tumors, trauma, inflammation, or vascular disorders in this structure are known to cause autonomic dysfunctions such as hypothermia or abnormal

Background: Aquaporin 4 (AQP4) is a water-channel protein predominantly expressed in astrocyte end feet that make up the blood-brain barrier (BBB). Recently, anti-AQP4 antibody has been identified as a specific biomarker of neuromyelitis optica (NMO). However, whether anti-AQP4 antibodies damage the BBB is unclear. Methods: We evaluated BBB damage in patients with NMO and multiple sclerosis by measuring albumin leakage (AL) and studied its correlation with anti-AQP4 antibody. Results: No obvious difference in AL was observed between patients with and without anti-AQP4 antibodies. In the multivariate analysis, anti-AQP4 antibody was not associated with BBB damage. Of the anti-AQP4-positive patients, 58.0% had normal AL values, and the degree of BBB damage was unrelated to the anti-AQP4 antibody titer. In addition, 41.9% of anti-AQP4-positive patients showed no gadolinium enhancement of the MRI. Conclusion: These results indicate that the presence of anti-AQP4 antibody alone in plasma is insufficient to disrupt the BBB.