title: Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation.
abstract: 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.
authors.affiliation: 1] Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan [2] Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.affiliation: Department of Neurology, Kenwakai Hospital, 1936 Kanaenakadaira, Iida 395-8522, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ushiyama
authors.affiliation: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.affiliation: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Tani
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: 1] Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan [2] Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda-Yuzawa
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Medicine (Neurology &Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging; D005260:Female; D005787:Gene Frequency; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009128:Muscle Spasticity / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D010740:Phospholipases / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011859:Radiography; D017422:Sequence Analysis, DNA; D020754:Spinocerebellar Ataxias / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology
chemical_list: D010740:Phospholipases; C541017:DDHD2 protein, human