The movement disorders of Coffin–Lowry syndrome

doi:10.1016/j.braindev.2003.11.010

Brain and Development

Volume 27, Issue 2, March 2005, Pages 108-113

https://doi.org/10.1016/j.braindev.2003.11.010 Get rights and content

Abstract

Coffin–Lowry syndrome (CLS) is an X-linked semi-dominant condition with learning difficulties and dysmorphism caused by mutations in the gene RSK2. Originally, epilepsy was reported as a feature. We and others have since described predominantly sound-startle induced drop attacks that have been labelled ‘cataplexy’, abnormal startle response and hyperekplexia. We sought to clarify why there should be controversy over the type of paroxysmal events. Review of the literature and our patients confirmed that each centre had studied only a small numbers of individuals (mean=2). The type of movement disorder varied both with age and between individuals. One individual might have more than one movement disorder. One of our adult patients had several types of movement disorder and epilepsy that merged seamlessly: there was true cataplexy triggered by telling a joke, something close to cataplexy (‘cataplexy’) triggered by sound-startle, a predominantly hypertonic reaction varying from hyperekplexia to a more prolonged tonic reaction resembling startle epilepsy, and true unprovoked epileptic seizures. In the large database of the Coffin–Lowry Syndrome Foundation family support group, 34 of 170 (20%) individuals with CLS and known age had ‘drop attacks’ and an additional 9 (5%) of these had additional epileptic seizures. The onset of such events was usually after age 5 years, prevalence peaking at 15–20 years (27%). Many became wheelchair bound as a result. This unique combination of more than one non-epileptic movement disorder and epilepsy deserves further semiological and genetic study both for the patients with CLS and for the wider implications.

Section snippets

Background

Coffin–Lowry syndrome (CLS) is an X-linked semi-dominant condition with dysmorphism and cognitive difficulties, more severe in affected males, due to mutations in the RSK2 protein kinase gene. The expression of this RSK2 gene has been mapped in human and mouse brain and reported to be prominently expressed in brain structures essential for cognition and learning [1]. It has recently become clear that an important neurological complication of CLS is some form of drop attack, beginning on

Clinical observations

We have made some further clinical observations and video recordings on two further individuals with CLS known to us.

Epidemiological observations

One of us (MH) started the Coffin–Lowry syndrome Foundation (CLSF) as a support group in 1991 after her son was diagnosed with CLS. Families of those diagnosed as CLS by a physician or geneticist make contact via the web site. Of 265 affected individuals on the CLSF database, 8 have a confirmed RSK2 defect, 5 do not, and the remainder have a clinical diagnosis of CLS.

Table 3 gives the age distribution of those on the database with known age, both with and without a history of drop attacks. From

Discussion and future proposals

The mechanisms of the movement disorders of Coffin–Lowry syndrome have been controversial. It seems that there are four reasons for this. One is that the movement disorder varies from individual to individual, so that one may have something more like cataplexy and another something more like hyperekplexia (Table 1). Secondly, more than one movement disorder may be present in the same individual with CLS [11], [13] as in the patient in Case 2 in the present paper. Thirdly, the movement disorder

Acknowledgements

We thank the families for permission to report clinical details and to include the photographs shown in the figures. Thanks to Dr R. Holden for referring the patient in Case 2 to the first author. Alastair Irwin, Chief of Medical Illustration, Yorkhill Hospitals, Glasgow kindly prepared the figures. The web site for the Home Page of the Coffin–Lowry Syndrome Foundation is http://www.clsf.info/.

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There are more references available in the full text version of this article.

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The overall prevalence is approximately 10–14% [5]. Data from the CLS Foundation’s database revealed a higher overall prevalence of 20% and a peak prevalence of 21–27% between ages of 10–20 [10]. It should be mentioned that, although the majority of reported cases with SIDEs appear to be male, about one-third are female cases (7/22) [4,8–12].
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Four novel RSK2 mutations in females with Coffin-Lowry syndrome
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Coffin–Lowry syndrome (CLS) is an X-linked semi-dominant disorder caused by mutations in the RSK2 gene and characterized by moderate to severe mental retardation, characteristic facial features, skeletal deformities, and tapering fingers in males. Females are usually much more mildly and variably affected thus more difficult to diagnose. In this study, molecular genetic analysis was carried out in four female patients presenting features of Coffin–Lowry syndrome. The probands were sporadic cases with no affected males in their families. The molecular analysis of the RSK2 gene revealed four novel mutations, including two frameshift and one missense mutation identified by sequencing, and one large deletion detected by multiplex ligation-dependent probe amplification (MLPA) analysis. Females exhibited a random X-chromosome inactivation pattern. To our knowledge, this is the first report of applying MLPA in the diagnostics of CLS and the first description of a large deletion in a CLS female. These results support including screening for large rearragements in the genetic analysis of female CLS patients.
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^☆: The paper is based on the lecture given at the sixth annual meeting of the Infantile Seizure Society, Tokyo, March 15–16, 2003.

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Original articleThe movement disorders of Coffin–Lowry syndrome☆

Abstract

Section snippets

Background

Clinical observations

Epidemiological observations

Discussion and future proposals

Acknowledgements

Pediatr Neurol

Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin–Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning

Hum Mol Genet

The Coffin syndrome

Hum Genet

The radiology of Coffin–Lowry syndrome

Br J Radiol

‘Cataplexy’ and muscle ultrasound abnormalities in Coffin–Lowry syndrome

J Med Genet

Cataplexy in Coffin Lowry Syndrome

Eur J Paediatr Neurol

Hyperexplexia in Coffin–Lowry syndrome

Ann Neurol

‘Cataplexy’ in Coffin–Lowry syndrome

J Med Genet

Original article
The movement disorders of Coffin–Lowry syndrome☆