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Parkinsonism and Related Disorders 20 (2014) 1315e1316Contents lists avaiParkinsonism and Related Disorders
journal homepage: www.elsevier .com/locate/parkreldisLetter to the EditorKlinefelter syndrome associated myoclonusKeywords:MyoclonusTremorKlinefelterAneuploidyFragile-X-associated tremor/ataxiaTestosteronehttp://dx.doi.org/10.1016/j.parkreldis.2014.09.0121353-8020/ 2014 Elsevier Ltd. All rights reserved.Sir,
It is with great interest that we have read the report of Koegl-Wallner and colleagues who described three patients with tremorand Klinefelter syndrome (KS), and provided an overview of similarcases described in the literature . Here we report a patient,initially diagnosed with essential tremor (ET), who eventuallyappeared to have testosterone responsive myoclonus and Klinefel-ter syndrome (KS). Myoclonus can be confused with tremor. In pa-tients with atypical essential tremor, thorough history taking,clinical examination and tremor recording may reveal an unex-pected diagnosis. Knowledge of Klinefelter associated tremor andmyoclonus will facilitate recognition of these patients.
A 27-year old man presented with a trembling feelingthroughout the whole body and shaking of both hands, whichhad been present since early childhood. He had been diagnosedwith ET. Because medication failed to suppress his tremor, he wasreferred to our tertiary Movement Disorders Clinic. Alcohol didnot have any effect on his tremulous movements. Past medical his-tory revealed delayed developmental milestones, asthma, mildautism and chronic fatigue. Family history was negative for move-ment disorders. Neurological examination revealed continuousirregular distal jerky movements of the hands and fingers duringaction (video). Movements decreased somewhat upon distraction.These jerky movements were also observed in his legs duringextension. In addition, larger, more isolated proximal jerks wereobserved in his trunk. Heel-to-toe testing was slightly ataxic. Elec-tromyography (EMG) of the arm muscles showed irregular shortbursts (50e100 ms) with a peak frequency around 8 Hz, consistentwith myoclonus (Fig. 1). EEG-EMG coherence analysis showed nocortical drive, and no giant somatosensory evoked potentials orC-reflexes were present. Brain MRI was normal. Serum glucose,copper, ceruloplasmin and TSH were within normal limits. Becauseof the mild autism and ataxia, we tested for Fragile-X-associatedtremor/ataxia (FXTAS). FMR1-gene testing disclosed a normal num-ber of CGG repeats, but on two alleles. This indicated the presenceof two X chromosomes, since the FMR1 gene is located on the Xchromosome. Karyotype analysis confirmed the diagnosis of KS.Further work-up revealed primary hypogonadism (testosterone4.1 nmol/L at 8.30 am, reference value 11e35 nmol/L). Initially,the myoclonus did not improve with suboptimal serum testos-terone levels achieved with administration of testosterone gel50 mg (6.1 nmol/L, Fig. 1). After doubling the dosage the serumtestosterone level was within reference values (17.0 nmol/L) andthe myoclonus had diminished (Fig. 1 and video).
Supplementary video related to this article can be found athttp://dx.doi.org/10.1016/j.parkreldis.2014.09.012.
In this report, we describe for the first time a patient with KSwith myoclonus, who responded to testosterone replacement ther-apy. KS is the most common aneuploidy in men, with a prevalenceof 0.1e0.2% in the general population; although 64% of patients arebelieved to remain undiagnosed . Unlike KS and myoclonus, KSand tremor have previously been associated [1,3e5]. Nevertheless,KS is not usually included in the work-up of patients with tremor ormyoclonus. Up to 63% of KS patients were reported to suffer fromtremor in a recent controlled survey study . Though this surveywas aimed at detecting tremor, patients were not assessed by aphysician, and some patients might have in fact suffered frommyoclonus rather than tremor. Considering the high prevalenceof undiagnosed KS patients, this might be the cause of unexplainedtremulous movements in a significant proportion of male patients.
The pathophysiology and treatment options of myoclonus andtremor in KS remain to be elucidated. Koegl-Wallner and colleaguesreported normal DAT-SPECT of F-DOPA-PET scans in patients withtremor and KS, which supports the integrity of the nigrostriatal sys-tem in these patients . In our patient, the myoclonus improvedupon restoring normal serum testosterone levels. Previously, acase of KS and tremor also showed a patient respond to testos-terone replacement therapy . However, it was not effective inthe cases described by Koegl-Wallner and colleagues, althoughserum testosterone levels were not mentioned in these cases,meaning it remains unclear whether testosterone treatment wasoptimal . It is not possible to draw a definite conclusionregarding differences between pathophysiology of tremor andmyoclonus in KS based on medication response. Studying tremorand myoclonus in an etiologically homogeneous group of patients,such as with KS, could provide valuable insight into similarities anddifferences between the pathophysiology of these movementdisorders.
In conclusion, in male patients with unexplained tremor ormyoclonus, one should keep in mind clues that might indicate
Fig. 1. A: Spiral drawing before and under sufficient testosterone replacement therapy. Improvement is observed upon reaching a normal serum testosterone level. B: Electromy-ography of the left extensor carpi radialis muscle, before treatment. The irregular nature of the jerks suggests myoclonus and not tremor.
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1315e13161316KS, including mild developmental delay in childhood, inability tofather a child, reduced muscle tone, reduced facial and body hair,breast growth and very small volume testicles, and considerscreening for hypogonadism (FSH, LH and testosterone) and aneu-ploidies. Myoclonus in KS might improve with testosteronereplacement therapy.
The authors are grateful to the patient for approving the publi-cation of this case. No financial support was received for this study.We report no conflict of interest.References
 Koegl-Wallner M, Katschnig-Winter P, Pendl T, Melisch B, Trummer M, Holl E,et al. Tremor associated with Klinefelter syndrome e a case series and reviewof the literature. Parkinsonism Relat Disord 2014;20:323e7.
 Abramsky L, Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY: estimatedrates of and indication for postnatal diagnosis with implications for prenatalcounselling. Prenat Diagn 1997;17:363e8.
 Harlow TL, Gonzalez-Alegre P. High prevalence of reported tremor in Klinefeltersyndrome. Parkinsonism Relat Disord 2009;15:393e5.
 Kinoshita H, Ohkubo T, Kaneko M, Satoh N, Mizutani S, Yasuda M, et al. Tremorin Klinefelter's syndrome improved by testosterone administration. J Neurol2009;256:1924e5.
 Harlow TL, Rodnitzky RL, Gonzalez-Alegre P. From essential tremor to Klinefel-ter through Fragile X, an unexpected journey. Mov Disord 2008;23:1328e9.Arthur W.G. Buijink, Johannes H.T.M. KoelmanDepartment of Neurology and Clinical Neurophysiology,
Academic Medical Center, University of Amsterdam,Amsterdam, The Netherlands
Andreas MeissnerCenter for Reproductive Medicine and Department of Urology
Academic Medical Center, University of Amsterdam,Amsterdam, The Netherlands
Michiel E. StegengaDepartment of Endocrinology and Metabolism, Academic Medical
Center, University of Amsterdam, Amsterdam, The Netherlands
Anne-Fleur van Rootselaar*
Department of Neurology and Clinical Neurophysiology, AcademicMedical Center, University of Amsterdam,
Amsterdam, The Netherlands
* Corresponding author. Academic Medical Center, Dept. ofNeurology and Clinical Neurophysiology,
Room D2-113, P.O. Box 22660, 1100 DD Amsterdam,The Netherlands. Tel.: 31 20 5663415; fax: 31 20 5669187.
E-mail address: email@example.com (A.-F. van Rootselaar).
5 June 2014
Klinefelter syndrome associated myoclonusAcknowledgmentReferences