Early onset autosomal dominant spinocerebellar ataxia with miosis: Four cases

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  • an

    n

    ris

    bDepartment of Clinical Genetics, Umea University Hospital, SwedencPediatric Clinic, Ostersund Hospital, Sweden

    a b s t r a c t

    Previously, at least 29 different forms of autosomal dominant spinocerebellar ataxias

    (SCAs) have been described. We describe a family with four members through three

    according to their genetic basis of disease, and are termed

    (SCA 13, 67, 17) and DRPLA are known to be caused by

    SCA. Eye symptoms (nystagmus, slow saccades, ophtalmo-

    exia,

    igns,

    athy

    .2,3

    ARTICLE IN PRESS

    E U RO P E A N J O U RNA L O F PA E D I AT R I C N E U RO L O G Y 12 ( 2008 ) 38 40Corresponding author. Tel.: +46 907850000; fax: +46 90123728.cytosine-adenine-guanine (CAG) trinucleotide repeat expan-

    sions in the coding region of the mutated gene leading to

    abnormally long polyglutamine stretches in the protein.

    Anticipation, a phenomenon where an earlier age at onset

    The family whose pedigree is shown in Fig. 1 was identified.

    The four afflicted family members were examined by one

    examiner (NT), and data from earlier hospital visits were

    obtained.

    1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ejpn.2007.03.007

    E-mail address: niklas.timby@vll.se (N. Timby).neurological and psychiatric symptoms as well as age at

    onset and progressiveness are often overlapping but

    every SCA has still its own phenotypic description. Six SCAs 2. Case studyspinocerebellar ataxias (SCAs). At least 29 different forms of

    SCAs have been described so far.1 The SCAs are named in

    order after their gene description (SCA 128) except for

    dentatorubral pallidoluysian atrophy (DRPLA). Additional

    plegia, retinopathy), pyramidal (hyper- and hyporefl

    spasticity) and extrapyramidal (tremor, bradykinesia) s

    dementia, executive dysfunction, and peripheral neurop

    are additional symptoms present in one or several SCAs1. Introduction

    Autosomal dominant cerebellar ataxias have been organized

    and a more severe progression of disease is seen in successive

    generations, is associated with disorders due to expanded

    CAG repeats. Ataxia and dysarthria are present in all forms ofa r t i c l e i n f o

    Article history:

    Received 11 January 2007

    Received in revised form

    15 February 2007

    Accepted 6 March 2007

    Keywords:

    Spinocerebellar ataxia (SCA)

    Autosomal dominant

    Miosis

    Hyperreflexiagenerations with autosomal dominant ataxia in combination with miosis and hyperre-

    flexia. This familys ataxia does not match any of the previously described SCAs and is

    probably a novel form of SCA. To continue with the search for the genetic background of

    this disease, more cases are needed.

    & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Official Journal of the Europe

    Case study

    Early onset autosomal dominawith miosis: Four cases

    Niklas Timbya,, Eva-Lena Stattinb, Ingela KaDepartment of Pediatrics, Umea University Hospital, Swedent spinocerebellar ataxia

    tiansenc, Urban Erikssonc, Anders Eriksona Paediatric Neurology Society

  • noticed that his reflexes were brisk. By the age of 7, he had

    ARTICLE IN PRESS

    IC N2.1. Case IV:1

    Girl, 412 years old. Born slightly preterm (w36+5) with no

    perinatal complications. By the age of 1 year and 2 months

    she was referred to hospital from the child welfare clinic

    because of instability when sitting. She was able to walk

    unaided by the age of 2. Already between 2 and 3 years of age,

    her walking was described as ataxic. MRI of the brain at 312years was normal and eye examination at 412 years showed no

    pathological changes of the retina. When examining her at

    the age of 412 years she has an obvious ataxic gait, trunk ataxia

    and she cannot close her eyes when standing without falling.

    Finger-nose and dysdiadokokinesis are poor and her deep

    tendon reflexes are brisk, both in upper and lower extremi-

    ties. Eye movements are normal and no nystagmus can be

    seen. Further, her pupils are miotic and are not widened in

    I:1 I:2

    II:1 II:2 II:3 II:5 II:6II:4

    III:2 III:4III:3III:1

    IV:1

    I

    II

    III

    IV

    Fig. 1 Family pedigree.

    EUROPEAN JOURNAL OF PAEDIATRdark.

    2.2. Case III:2

    Man, 27 years, father of case IV:1. He was referred to hospital

    by the age of 212 years. No history of perinatal complications.

    A non-symptomatic valvular stenosis of the pulmonary artery

    was found, but needed no treatment. At 212 years of age, his

    ataxia was obvious, especially in trunk and legs. He could

    walk unaided by the age of 2, and ride a bicycle by the age of 7.

    At 16 years of age, bilateral miosis was observed. His

    education was 9 years at comprehensive school and 2 years

    at college of forestry, and he is now working with forestry. His

    ataxia has not shown any progression and he has learnt to

    adapt to his balance problems. The ataxia is worsened by

    fatigue and in dark. On examination at 27 years of age, he has

    an ataxic gait. He cannot stand on his left foot alone (but can

    stand on his right foot with some problems). He does small

    failures in fingernose and heelknee tests. His speech reveals

    a mild dysarthria. Deep tendon reflexes in the legs are brisk,

    in the arms normal and plantar responses are flexor. The

    pupils are miotic and do not dilate in the dark. No abnormal

    eye movements are observed. When his daughter showeddeveloped bilateral miosis. As for his brother, the ataxia has

    not been progressive and is worsened by fatigue. He has

    found out that his balance problems are improving by small

    amounts of alcohol. After 9 years at comprehensive school

    and 4 years at secondary school, he is now working as a lorry

    driver. On examination at 26 years of age, he shows, like his

    brother, an ataxic gait, difficulties in fingernose and knee

    heel tests, a mild dysarthria and bilateral miotic pupils not

    widened in the dark. Deep tendon reflexes in the legs are

    brisk, in the arms normal. Plantar responses are flexor.

    2.4. Case II:5

    Woman, aged 61, mother of cases III:2 and III:4. She suffered

    from balance problems during childhood, problems that have

    been consistent through her life. She has never been referred

    to hospital for her balance problems. She could walk by the

    age of 3, but has never learnt to ride a bicycle. The older

    she gets, the more she has learnt to adapt her life to her

    balance problems. When she moves slowly, her ataxia is less

    obvious, and when fatigued or under stress, the problems are

    worsened. She has suffered from depression in adulthood.

    When examining her at 61 years of age, she has ataxia of

    about the same degree as her sons. Her speech is mildly

    dysarthric, and she also has small pupils that do not dilate in

    the dark. Her reflexes in the legs are brisk, in the arms

    normal. Plantar responses are flexor.

    2.5. Deceased and unaffected family members

    Case II:5 is the first case in the family. Both her parents

    (I:1 and I:2) and her only brother (II:1) are deceased. None of

    them had balance problems. All of her sisters (II:2, II:3, II:6),

    5155 years old, and her only daughter (III:3), 35 years old, are

    also unaffected with no balance problems.

    3. Discussion

    We describe four patients in a family with an autosomal

    dominant ataxia. Additional symptoms are bilateral miosis

    and hyperreflexia, especially in the lower limbs. The ataxia is

    present from the first years of life, seems not to be

    progressive, and shows no obvious anticipation. The miosis

    is not present from birth, but starts by the age of 416.

    Inherited ataxia combined with pupil anomaly without

    retinal changes is seldom described in literature. In 1892, Drsigns of ataxia, genetic testing was made for SCA 13 and SCA

    68, all negative.

    2.3. Case III:4

    Man aged 26, brother of case III:2. No history of neonatal

    complications. He was referred to hospital at 2 years and 3

    months, which was at the same time he started to walk

    independently. At that age he showed signs of ataxia,

    especially when handling objects with his hands. It was also

    EUROLOGY 12 (2008) 38 40 39Sanger Brown described 21 patients through four generations

    with inherited ataxia and pyramidal symptoms. Three of

  • these patients had pathological pupil reaction to light, but

    none were described as having miosis.4 The only description

    of inherited ataxia combined with miosis we could find is a

    case report of a mother and three of her five children in the

    age of 44, 25, 24 and 17 who all had a spastic ataxia with

    bilateral miosis. The ataxia was present from early life and

    not progressive. All four had bilateral miosis and nystagmus.5

    None of the 29 SCAs previously described have miosis as an

    additional symptom.3 The miosis in our four cases is so

    obvious, so it is not likely that it would not have been

    mentioned if present in any of the thoroughly made

    investigations of the previously described SCAs. We believe

    that the family we present, has a previously unknown form of

    SCA where miosis and hyperreflexia are additional symp-

    toms. The family described by Dick et al. before the genomic

    era5 had probably a similar defect as