title: Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study.
abstract: BACKGROUND
  The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2).
  
  
  METHODS
  We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments.
  
  
  RESULTS
  We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively).
  
  
  CONCLUSIONS
  Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease.
  
  
  BACKGROUND
  Cuban Ministry of Public Health.
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba. Electronic address: velazq63@gmail.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Velázquez-Pérez
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodríguez-Labrada
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Nalia
authors.initials: N
authors.lastname: Canales-Ochoa
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Jacqueline Medrano
authors.initials: JM
authors.lastname: Montero
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Sánchez-Cruz
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Raúl
authors.initials: R
authors.lastname: Aguilera-Rodríguez
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Almaguer-Mederos
authors.affiliation: Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.
authors.forename: José M
authors.initials: JM
authors.lastname: Laffita-Mesa
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000067528:Ataxins; D016022:Case-Control Studies; D002648:Child; D003462:Cuba; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009460:Neurologic Examination; D012189:Retrospective Studies; D012306:Risk; D012720:Severity of Illness Index; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018911:Trinucleotide Repeats / Q000235:genetics*; D055815:Young Adult
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins