Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: a case report

• Published in: BMC medical genetics Vol. 21; no. 1; pp. 68 - 4
• Main Authors: Kume, Kodai, Morino, Hiroyuki, Miyamoto, Ryosuke, Matsuda, Yukiko, Ohsawa, Ryosuke, Kanaya, Yuhei, Tada, Yui, Kurashige, Takashi, Kawakami, Hideshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.03.2020; BioMed Central; BMC
• Subjects: Age; Ataxia; Atrophy; Case Report; Case reports; Cerebellar ataxia; Cerebellar Ataxia - complications; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - genetics; Cerebellum; Consanguinity; Deafness; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA helicase; DNA Helicases - genetics; DNA replication; Families & family life; Female; Gait; Gait Ataxia - complications; Gait Ataxia - diagnosis; Gait Ataxia - genetics; Genes; Gonadal Dysgenesis, 46,XX - diagnosis; Gonadal Dysgenesis, 46,XX - genetics; Health screening; Hearing loss; Hearing Loss - complications; Hearing Loss - diagnosis; Hearing Loss - genetics; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Homozygote; Humans; Japan; Late Onset Disorders - diagnosis; Late Onset Disorders - genetics; Magnetic resonance imaging; Middle age; Middle Aged; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mutation; Neuroimaging; Ophthalmoplegia; Patients; Pedigree; Peripheral neuropathy; Perrault syndrome; Pyruvic acid; Questions and answers; Reflexes; TWNK; Japan; Cerebellar ataxia; Perrault syndrome; TWNK
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-020-01002-4

The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.