Movement disorders in chromosomal aneuploidies …

Asma Malik MD

Movement Disorders

Updated 06.19.2024
Released 06.19.2024
Expires For CME 06.19.2027

Movement disorders in chromosomal aneuploidies

Author: Asma Malik MD

See Contributor Disclosures

Editor: Robert Fekete MD

Movement disorders in chromosomal aneuploidies

In This Article

Quick Link

Introduction

Overview

Chromosomal aneuploidies refer to abnormalities in the total number of chromosomes carried by an individual. The normal number of chromosomes is 46 as established by Joe Hin Tjio in 1956. Because each chromosome carries a large number of genes, the addition or loss of even one chromosome disrupts the normal equilibrium of cells and, in most cases, is incompatible with life.

Broadly speaking, chromosomal abnormalities are associated with dysmorphic features, intellectual delay, seizures, and a shortened life span.

Although there have been isolated case reports and small-scale studies on the presence of movement abnormalities, especially tremor, in people with chromosomal aneuploidies, there is a lack of awareness among clinicians regarding the existence of such disorders. In this article, the authors reviewed data concerning these disorders with the goal of further educating physicians, neurologists, and movement disorder specialists about the extent of abnormal movements in patients with chromosomal aneuploidies. In doing so, the authors hope to increase clinicians’ diagnostic capability and, in turn, help improve the quality of life for these patients with the institution of appropriate management early in the disease course.

Key points

	• The authors scanned the literature for chromosomal aneuploidies that are compatible with life and then systematically looked for the presence of abnormal movements in these people.
	• Trisomy 13, 18, and 21 are the only autosomal aneuploidies reported to be compatible with life; trisomy 21 cases are the most common and, hence, most studied.
	• Patients with trisomy 18 rarely survive beyond childhood, and those with trisomy 13 rarely survive beyond infancy.
	• Other autosomal aneuploidies exist as mosaicisms, notably mosaic trisomy 15 and the Pallister Killian syndrome, none of which have a reported movement disorder. Overall, mosaic abnormalities with subtle features probably go undiagnosed.
	• Compared to autosomal aneuploidies, sex chromosomal aneuploidies are more common, with milder phenotypes and longer life spans, many going undiagnosed owing to the lack of classic textbook signs and symptoms as mentioned above. After noting the preponderance of sex chromosomal abnormalities, the authors focused their search on these syndromes.
	• The sex chromosomal aneuploidies found in the literature are syndromes of supernumerary X and Y chromosomes, with Turner syndrome (monosomy 45X0) being the only complete monosomy compatible with life. The authors did not review chromosomal rearrangement syndromes that resulted from the initial search.
	• The authors then searched PubMed using combinations of the specific chromosomal abnormality (Down syndrome, Turner syndrome, Klinefelter syndrome, Jacob syndrome, 47 XXX, 48XXYY) with a specific movement disorder (tremor, myoclonus, dystonia, and chorea individually).
	• A proposed hypothesis for the relative compatibility of sex chromosomal aneuploidies with life could be the physiological inactivation of one X chromosome in females and the relatively few genes carried by the Y chromosome (32).

Down syndrome (trisomy 21)

Down syndrome is the prototype chromosomal aneuploidy and is the most common genetic disorder in the United States, occurring in around one in 800 live births, with a prevalence of 83,000 (30).

Down syndrome is caused by trisomy 21 (discovered by French geneticist Lejeune in 1958) and is due either to chromosome nondisjunction (94%) or, less often, translocations. It is characterized by intellectual delay, facial dysmorphism, and cardiovascular anomalies.

By virtue of its prevalence, Down syndrome is the most common abnormality noted to be associated with movement disorders.

Stereotypies and orofacial dyskinesias have been reported most commonly in this patient population. Orofacial dyskinesias were shown to occur independent of any neuroleptic exposure and had a strong correlation with the severity of intellectual delay (12).

There has also been a suggestion of orofacial dysmorphology as one possible cause of orofacial dyskinesia, and such cases can successfully be treated with appropriate therapy (14).

A wide range of stereotypies has been noted, from hand-wringing movements to gait involvement. The association of stereotypy and regression in Down syndrome has been well established and can be seen in particular in cases of Down syndrome regression disorder, which is an entity that has increasingly been recognized and is distinct from autism spectrum disorder in Down syndrome (04; 24). A case report described a 32-year-old woman with an abnormal repetitive gait pattern consistent with stereotypy and suggested that gait stereotypy could be a marker for neurodegeneration in patients with Down syndrome (27).

Down syndrome has been shown to involve selective reduction of frontal and parietal gray matter volumes in addition to the generalized microcephaly typically observed in this patient population. Relative hyperplasia of the cerebellar white matter has been observed in a patient with Down syndrome and autism spectrum disorder with stereotypies (07).

Patients with Down syndrome suffer from a disturbance in the motor tone due in part to the disrupted motor circuitry, and this may be linked to abnormal gait and posture that can be observed (21).

Another motor disorder that has been reported and frequently overlooked is catatonia. This is probably under-recognized because any unexplained regression in behavior, mood, activities of daily living, motor activities, and intellectual functioning in this patient population is attributed to a natural progression of Down syndrome or the development of Alzheimer disease (15). Again, similar to the onset of stereotypies as part of Down syndrome regression disorder, catatonia can also be seen (29).

The recognition of catatonia is imperative because, with the correct treatment, patients generally do well.

Chorea in Down syndrome has been reported in the setting of Moyamoya disease (35).

Klinefelter syndrome (47XXY syndrome)

Klinefelter syndrome (47XXY syndrome) has an incidence of 1.72 per 1000 male births (25). The syndrome was first described by Dr. Harry Klinefelter in 1942, highlighting the constellation of testicular dysgenesis, microorchidism, eunuchoidism, gynecomastia, and azoospermia (19). The etiology was thought to be due to an endocrine disorder until 1959, when Jacobs and Strong recognized this as a chromosomal disorder with the karyotype 47XXY(18).

Tremor in Klinefelter syndrome was described by Baughman as early as 1969. He described the entity as essential tremor but mentioned in his report that the tremor may have different attributes from essential tremor. Since then, there have been many publications on this phenomenon, and there appears to be a general agreement that it differs from essential tremor in various aspects and, hence, is an entity in itself. A questionnaire-based control study by Harlow and Gonzalez-Alegre demonstrated an increased prevalence of tremor and a younger age of onset in Klinefelter syndrome cases compared to controls and a weaker association with family history (17). Koegl-Wallner and colleagues reported three patients with Klinefelter syndrome in 2013. They detailed the phenomenology of tremor as distinct from essential tremor, pointing out that earlier reports may have likened this tremor to essential tremor due to a lack of formal diagnostic criteria at the time (20).

Their cases also replicated the younger age of onset of tremor and absent family history, as had previous studies. In addition, they also reported a lack of alcohol responsiveness to the tremor in their patients. It is hypothesized that the increased gene dose by virtue of an extra X chromosome and also the effect of genes on the X chromosome that escape inactivation might modify the expression of tremor, perhaps leading to an increased predisposition to tremor.

Increased dose effects of genes on pseudoautosomal regions of X and Y chromosomes have also been theorized to modify tremor expression (03; 11).

It has been proposed that the presence of supernumerary sex chromosomes causes changes in DNA methylation at diverse loci in the genome, resulting in altered gene expression and the distinct phenotypes that ensue (31).

A decrease in cerebellar volume and change in caudate morphology could have some role in the development of tremor; however, more refined studies are needed to look into the functional networks that are disrupted in patients with chromosomal aneuploidies presenting with tremor (33).

There have been conflicting reports on the response of this tremor to testosterone administration. One case report described a jerky action myoclonus, further confirmed with EMG, responsive to testosterone replacement in a patient diagnosed with Klinefelter syndrome (06).

Another case report described rubral tremor associated with Klinefelter syndrome; however, there is a paucity of descriptions of the tremor itself, no central nervous system lesion to account for on MRI, and no associated video that could be found; hence, this may be a chance occurrence (10).

Lastly, there have been several case reports of Parkinson disease in Klinefelter syndrome (01; 22), one case report of parkinsonism in Klinefelter syndrome with a normal DAT scan (02), and one case report of a patient with Klinefelter syndrome presenting with tremor, ataxia, and Parkinsonism (16).

References

01: Bach JP, Oertel WH, Sommer N., Möller C, Dodel R. Klinefelter syndrome and parkinsonism. Aktuelle Neurologie 2007;34:S 2.
02: Bach JP, Sommer N, Möller JC, Oertel WH, Dodel R, Gasser T. Parkinson's syndrome in a young patient with Klinefelter's syndrome--a case report. Mov Disord 2008;23(5):771-2. PMID 18265006
03: Baughman FA. Klinefelter's syndrome and essential tremor. Lancet 1969;2(7619):545. PMID 4184860
04: Bernad Ripoll S. Developmental regression in children with Down syndrome. University of Kansas: KU ScholarWorks 2011.
05: Boisen E, Rasmussen L. Tremor in XYY and XXY men. Acta Neurol Scand 1978;58(1):66-73. PMID 360758
06: Buijink AW, Koelman JH, Meissner A, Stegenga ME, van Rootselaar AF. Klinefelter syndrome associated myoclonus. Parkinsonism Relat Disord 2014;20(11):1315-6. PMID 25258330
07: Carter JC, Capone GT, Kaufmann WE. Neuroanatomic correlates of autism and stereotypy in children with Down syndrome. Neuroreport 2008;19(6):653-6. PMID 18382280
08: Daly RF. Neurological abnormalities in XYY males. Nature 1969;221(5179):472-3. PMID 5784429
09: Davis JL, Kurek JA, Morgan JC, Sethi KD. Tremor and dystonia in Jacob's syndrome (47,XYY). Mov Disord Clin Pract 2019;7(1):107-8. PMID 31970224
10: Dehghani R, Agah E, Falsafi Z, Tafakhori A. Rubral tremor associated with Klinefelter syndrome: a case report and literature review. Arch Neurosci 2017;4(4):e55065.
11: Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007;130(Pt 6):1456-64. PMID 17353225
12: Dinan TG, Golden T. Orofacial dyskinesia in Down's syndrome. Br J Psychiatry 1990;157:131-2. PMID 2144461
13: Donati F, Gasser S, Mullis P, Braga S, Vassella F. 48,XXYY-syndrom bei einem knaben mit essentiellem tremor. Vergleich mit 120 Fällen aus der Literatur [48,XXYY syndrome in a boy with essential tremor. Comparison with 120 cases from the literature]. [German.] Monatsschr Kinderheilkd 1992;140(4):216-9. PMID 1614446
14: Faulks D, Veyrune JL, Hennequin M. Consequences of oral rehabilitation on dyskinesia in adults with Down's syndrome: a clinical report. J Oral Rehabil 2002;29(3):209-18. PMID 11896836
15: Ghaziuddin N, Nassiri A, Miles JH. Catatonia in Down syndrome; a treatable cause of regression. Neuropsychiatr Dis Treat 2015;11:941-9. PMID 25897230
16: Gopalakrishnan B, Friedman JH. Klinefelter's syndrome with tremors, ataxia and parkinsonism. R I Med J 2023;106(3):56-7. PMID 36989100
17: Harlow TL, Gonzalez-Alegre P. High prevalence of reported tremor in Klinefelter syndrome. Parkinsonism Relat Disord 2009;15(5):393-5. PMID 18977683
18: Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 1959;183(4657):302-3. PMID 13632697
19: Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a-leydigism, and increased excretion of follicle-stimulating hormone. J Clin Endocrinol Metab 1942;2(11):615-27.
20: Koegl-Wallner M, Katschnig-Winter P, Pendl T, et al. Tremor associated with Klinefelter syndrome--a case series and review of the literature. Parkinsonism Relat Disord 2014;20(3):323-7. PMID 24345964
21: Lauteslager PE, Vermeer A, Heldres PJ. Disturbances in the motor behaviour of children with Down's syndrome: the need for a theoretical framework. Physiother 1998;84(1):5-13.
22: Lee KS, Lee JE, Cho AH, Kim JS, Oh YS. A case of Parkinson's disease in a patient with Klinefelter's syndrome. Acta Neurol Belg 2020;120(4):971-2. PMID 31667793
23: Lote H, Fuller GN, Bain PG. 48, XXYY syndrome associated tremor. Pract Neurol 2013;13(4):249-53. PMID 23487807
24: Mircher C, Cieuta-Walti C, Marey I, et al. Acute regression in young people with Down syndrome. Brain Sci 2017;7(6):57. PMID 28555009
25: Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 2008;16(2):163-70. PMID 18000523
26: Nitschke M, Steinberger D, Heberlein I, Otto V, Müller U, Vieregge P. Dopa responsive dystonia with Turner's syndrome: clinical, genetic, and neuropsychological studies in a family with a new mutation in the GTP-cyclohydrolase I gene. J Neurol Neurosurg Psychiatry 1998;64(6):806-8. PMID 9647318
27: Pedroso JL, Vale TC, Barsottini OG. Are gait stereotypies a marker for neurodegeneration in Down syndrome? A prospective observation. Tremor Other Hyperkinet Mov (N Y) 2016;6:403. PMID 27761302
28: Sandberg AA, Koepf GF, Ishihara T, Hauschka TS. An XYY human male. Lancet 1961;2(7200):488-9. PMID 13746118
29: Santoro SL, Cannon S, Capone G, et al. Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database. Genet Med 2020;22(4):767-76. PMID 31767984
30: Shin M, Besser LM, Kucik JE, et al. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics 2009;124(6):1565-71. PMID 19948627
31: Skakkebaek A, Nielsen MM, Trolle C, et al. DNA hypermethylation and differential gene expression associated with Klinefelter syndrome. Sci Rep 2018;8(1):13740. PMID 30213969
32: Skuse D, Printzlau F, Wolstencroft J. Chapter 24 - Sex chromosome aneuploidies. In: Geschwind DH, Paulson HL, Klein C. Handbook of Clinical Neurology 2018;147:355-76.
33: Steinman K, Ross J, Lai S, Reiss A, Hoeft F. Structural and functional neuroimaging in Klinefelter (47,XXY) syndrome: a review of the literature and preliminary results from a functional magnetic resonance imaging study of language. Dev Disabil Res Rev 2009;15(4):295-308. PMID 20014370
34: Suzuki Y, Watanabe H, Haeno S, et al. Primary hypoparathyroidism in Turner's syndrome. Intern Med 1995;34(11):1071-3. PMID 8774966
35: Takanashi J, Sugita K, Honda A, Niimi H. Moyamoya syndrome in a patient with Down syndrome presenting with chorea. Pediatr Neurol 1993;9(5):396-8. PMID 8292217
36: Tartaglia N, Davis S, Hench A, et al. A new look at XXYY syndrome: medical and psychological features. Am J Med Genet A 2008;146A(12):1509-22. PMID 18481271
37: Westenberger A, Rosales RL, Heinitz S, et al. X-linked dystonia-Parkinsonism manifesting in a female patient due to atypical Turner syndrome. Mov Disord 2013;28(5):675-8. PMID 23389859
38: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Asma Malik MD

Dr. Malik of the University of Missouri has no relevant financial relationships to disclose.
See Profile

Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
See Profile

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Movement disorders in chromosomal aneuploidies

Associated Disorders

48XXYY syndrome
Catatonia
Chorea
Down syndrome
Dystonia
- Jacob syndrome
- Klinefelter syndrome
- Orofacial dyskinesia
- Stereotypies
- Tremor
- Turner syndrome

Also Relevant

Colpocephaly
Down syndrome
Executive dysfunction
Incontinentia pigmenti
Intellectual disability
- Molecular diagnosis of neurogenetic disorders

Clinical Categories

Movement Disorders

Movement disorders in chromosomal aneuploidies …

Movement disorders in chromosomal aneuploidies

Introduction

Overview

Key points

Down syndrome (trisomy 21)

Klinefelter syndrome (47XXY syndrome)

Turner syndrome

Jacob syndrome (47XYY)

48XXYY syndrome

Outcomes

References

Contributors

Author

Editor

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

Movement disorders in chromosomal aneuploidies

Introduction

Overview

Key points

Down syndrome (trisomy 21)

Klinefelter syndrome (47XXY syndrome)

Turner syndrome

Jacob syndrome (47XYY)

48XXYY syndrome

Outcomes

References

Contributors

Author

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

This is an article preview.
Start a Free Account
to access the full version.