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).

Turner syndrome

A review of the literature revealed no association of Turner syndrome with tremor.

Three cases of dystonia associated with Turner syndrome were found. A case of DOPA-responsive dystonia with mutation in the GTP cyclohydroxylase gene was described in a 28-year-old woman who was found to have Turner syndrome on further neurologic evaluation (26).

Dystonia in association with basal ganglia calcification in a patient with Turner syndrome and hypoparathyroidism has also been described (34).

There was one case report of X-linked dystonia-parkinsonism in a patient with atypical Turner syndrome and mosaicism in her cell lines (37).

All these cases were mosaic for 45X0 and 46XX.

Jacob syndrome (47XYY)

Avery Sandberg first described Jacob syndrome in 1961 (28). In 1962, he published a report on a man with 47XYY karyotype, highlighting multiple defects in his progeny and suggesting a possible familial predisposition to nondisjunction. The incidence of Jacob syndrome is 1 in 1000 males.

It was not until 8 years later that Daly published his study on 12 XYY men, detailing their neurologic examination and noting that 10 of them exhibited an intention tremor (08).

Boissen and Rasmussen demonstrated the tremor characteristics in these patients using tremor-recording equipment. This study was a double-blind, double-matched population survey that included 47XXY patients in addition to 47XYY patients and 46XY controls (05). They concluded that the tremor in 47XYY subjects was an intention tremor of a higher amplitude and relatively irregular in amplitude and frequency compared to 47XXY patients. Dystonia, in addition to tremor, has also been reported in Jacob syndrome (09).

48XXYY syndrome

Although similar to 47XXY syndrome, 48XXYY syndrome has been recognized as a distinct phenotype owing to the significant neuropsychological abnormalities in this group of people. It is a rare disorder with an incidence of approximately 1:18,000 to 1:40,000 males (36). The existence of tremor in 48XXYY syndrome was reported as early as 1969 by Baughman in his report on Klinefelter syndrome, and since then, others have also reported on the prevalence of this clinical entity (03; 13; 23).

Tic disorders, along with other neurodevelopmental and neuropsychiatric features, have also been noted in these patients (13).

Outcomes

Chromosomal aneuploidies, particularly sex chromosome aneuploidies, are frequently accompanied by movement disorders. Given the wide phenotypic spectrum of these patients owing to varying DNA methylation status, gene expression, and mosaicisms, they may first present to the neurologist or even the primary care physician, so recognizing movement disorders in this population is increasingly important. This review provides a resource for physicians to institute appropriate diagnostic work-ups so these patients can be identified by karyotyping and, henceforth, be directed for further management to the appropriate specialty.

To our knowledge, although there has been work on neuroimaging, including functional neuroimaging in patients with chromosomal aneuploidies evaluating aspects of neurocognitive and language domains, there have been no dedicated neuroimaging studies on patients with chromosomal aneuploidies and movement disorders. Expanding the use of diagnostic modalities in this group of individuals would be beneficial to understanding the burden of abnormal movements they experience.