Kokoro Ozaki1, Ayaka Ansai2, Kouji Nobuhara3, Toshihiko Araki4, Takayuki Kubodera5, Takashi Ishii6, Miwa Higashi7, Nozomu Sato8, Kazumasa Soga9, Hidehiro Mizusawa10, Kinya Ishikawa11, Takanori Yokota12. 1. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: k-oznuro@tmd.ac.jp. 2. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: taguchi161@gmail.com. 3. Department of Neurology, Kubo-Naika Hospital, 11-9 Tawaramachi, Sasebo, Nagasaki, Japan. Electronic address: nobuhara@hakujyujikai.or.jp. 4. Department of Neurology, Kawaguchi Municipal Medical Center, 180 Nishi-Araijuku, Kawaguchi, Saitama, Japan. Electronic address: ut-araki@royal.ocn.ne.jp. 5. Department of Neurology, Nissan Tamagawa Hospital, 4-8-1 Seta, Setagaya, Tokyo, Japan. Electronic address: t-kubodera@ak.em-net.ne.jp. 6. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: i.takashi.212@gmail.com. 7. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: higanuro@tmd.ac.jp. 8. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: nozsat.nuro@tmd.ac.jp. 9. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: kazumasasoga@hotmail.com. 10. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan; The National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, Japan. Electronic address: mizusawa@ncnp.go.jp. 11. (f)The Center for Personalized Medicine for Healthy Aging, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: pico.nuro@tmd.ac.jp. 12. Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan. Electronic address: tak-yokota.nuro@tmd.ac.jp.
Abstract
INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.
INTRODUCTION:Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxiapatients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxiapatients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxiapatients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxiapatients.
Authors: Raghavendra Y Nagaraja; David M Sherry; Jennifer L Fessler; Megan A Stiles; Feng Li; Karanpreet Multani; Albert Orock; Mohiuddin Ahmad; Richard S Brush; Robert E Anderson; Martin-Paul Agbaga; Ferenc Deák Journal: Mol Neurobiol Date: 2021-07-05 Impact factor: 5.590