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PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation

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Abstract

Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI). Female FMR1 premutation carriers rarely develop motor features. Dual pathology is an emerging phenomenon among FMR1 premutation carriers. Here, we describe a family affected by FMR1-related disorders in which the female index case has developed a rapidly progressive and disabling syndrome of atypical parkinsonism. This syndrome consists of early onset postural instability, echolalia, dystonia, and varying types of apraxia like early onset orobuccal apraxia and oculomotor apraxia. She has also developed supranuclear gaze palsy, increased latency of saccade initiation, and slow saccades. These features are compatible with progressive supranuclear palsy (PSP) of a corticobasal syndrome (CBS) variant. Imaging displays a marked reduction of presynaptic dopaminergic uptake and cerebrospinal fluid analysis showed reduced dopamine metabolism; however, the patient is unresponsive to levodopa. Midbrain atrophy (“hummingbird sign”) and mild cerebellar atrophy were found on brain MRI. Her father was affected by a typical FXTAS presentation but also displayed dopamine deficiency along with the hummingbird sign. The mechanisms by which FMR1 premutations predispose to atypical parkinsonism and dopamine deficiency await further elucidation.

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Abbreviations

CBS:

Corticobasal syndrome

CSF:

Cerebrospinal fluid

DAT:

Dopamine transporter

DOPAC:

3,4-Dihydroxyphenylacetic acid

FMR1 :

Fragile X mental retardation 1

FXTAS:

Fragile X-associated tremor/ataxia syndrome

5-HIAA:

5-Hydroxyindoleacetic acid

HVA:

Homovanillic acid

MCP:

Middle cerebellar peduncles

POI:

Primary ovarian insufficiency

PSP:

Progressive supranuclear palsy

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Acknowledgments

Financial support for this study was obtained from the CBD solutions AB and Stockholm City Council. We thank Dr Vesna Jelic for referring the index case to us.

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Authors and Affiliations

  1. Department of Neurology and Clinical Neuroscience, Karolinska University Hospital and Karolinska Institutet, 141 86, Stockholm, Sweden

    Martin Paucar, Stanislav Beniaminov, Wojciech Paslawski & Per Svenningsson

Authors
  1. Martin Paucar
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  2. Stanislav Beniaminov
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  3. Wojciech Paslawski
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  4. Per Svenningsson
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Corresponding author

Correspondence to Per Svenningsson.

Ethics declarations

All participants have given oral and written consent for this work. The study has been approved by the local ethical committee (2011/500-31/1).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Video 1

Episodic echolalia of the index case (II:2) when examined at 46 years of age. (MP4 1161 kb)

Video 2

Eye movement disorder of the index case (II:2) when examined at 46 years of age. (MP4 3060 kb)

Video 3

Unsteadiness and balance problems of the index case (II:2) when examined at 46 years of age. (MP4 1794 kb)

Video 4

Unsteadiness and falls of the index case (II:2) when examined at 49 years of age. (MP4 1658 kb)

Video 5

Severe speech problem and severe eye movement disorder of the index case (II:2) when examined at 49 years of age. (MP4 3596 kb)

Video 6

Tremor of the father (I:1) of the index case. (MP4 1785 kb)

Video 7

Unsteadiness and balance problems of the father (I:1) of the index case. (MP4 2666 kb)

Video 8

Lack of vertical supranuclear gaze palsy of the father (I:1) of the index case. (MP4 1672 kb)

Video 9

Action tremor of the sister (II:1) of the index case. (MP4 3329 kb)

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Paucar, M., Beniaminov, S., Paslawski, W. et al. PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation. Cerebellum 15, 636–640 (2016). https://doi.org/10.1007/s12311-016-0793-x

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  • DOI: https://doi.org/10.1007/s12311-016-0793-x

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