Workshop102nd ENMC International Workshop on Schwartz–Jampel Syndrome, 14–16 December, 2001, Naarden, The Netherlands
Introduction
Schwartz–Jampel Syndrome (SJS, OMIM #255800) is a rare human genetic disorder transmitted with an autosomal recessive mode of inheritance. SJS is characterized by the association of myotonia with osteoarticular deformities. Haluk Topaloglu reviewed major steps which led to the identification of the SJS gene. After initial discussion between Fayçal Hentati and Bertrand Fontaine, the groups of Haluk Topaloglu (Turkey), Peter Beighton (South Africa), Fayçal Hentati (Tunisia) and Bertrand Fontaine (Paris) established a collaboration which resulted in the localization of the SJS gene on chromosome 1 in 1995 [1] and in the demonstration in 2000 that the SJS gene encoded perlecan, a major heparan sulfate proteoglycan of basement membranes [2]. Other muscle disorders with membrane hyperexcitability include myotonic dystrophy types 1 and 2, paramyotonia congenita and myotonia congenita caused by mutations in genes encoding a protein kinase and a transcriptional activator, and voltage-gated ion channels, respectively [3], [4], [5]. The identification of perlecan as the gene responsible for SJS was therefore unexpected since it was the first demonstration that a basement membrane component might cause severe muscle membrane hyperexcitability.
The 102nd ENMC meeting on Schwartz–Jampel syndrome was organized to define diagnostic criteria in light of the identification of the gene, and to discuss pathophysiology and future prospects on the disorder. Eleven participants attended this meeting from four countries, including France, Germany, The Netherlands and Turkey.
Section snippets
Clinical aspects of Schwartz–Jampel syndrome
Bertrand Fontaine (France) reviewed initial descriptions of SJS, and history of naming and diagnosing the disorder. Two siblings were described by ophthalmologists Oscar Schwartz and Robert S. Jampel in 1962 with congenital blepharophimosis and mask-like face, small muscle mass, and joint and pigeon breast deformities [6]. The age at onset was within the first year. Donald C. Aberfeld and colleagues (1965, 1970) described in more detail the same patients [7], [8]. They pointed to the short
Genetic basis of Schwartz–Jampel syndrome
Sophie Nicole (France) discussed on the molecular basis of SJS and the possibility of molecular diagnosis. A positional cloning strategy was performed to identify the gene responsible for SJS. The SJS locus was localized on chromosome 1p35–p36 [1]. No genetic heterogeneity was observed when studying 15 families from numerous countries (Algeria, Belgium, France, Mexico, Saudi Arabia, South Africa, Tunisia, Turkey) indicating that the identified SJS locus was the major, if not unique, SJS locus.
Towards the pathophysiological mechanisms of Schwartz–Jampel syndrome
Sophie Nicole presented two putative pathophysiological mechanisms to account for SJS muscle hyperexcitability (Fig. 2). Perlecan may be a component of the synaptic basal lamina required for clustering of acetylcholinesterase (AChE). Inaccurate localization of this enzyme along muscle membrane would result in a slower hydrolysis of acetylcholine (ACh) and in a subsequent muscle hyperexcitability of neurogenic origin. Another tempting hypothesis would be that perlecan interacts with
Clinical criteria of Schwartz–Jampel syndrome
Participants of the workshop agreed to adopt the clinically oriented classification of SJS shown in Table 1. SJS was defined close as possible to the initial description made by Schwartz and Jampel. The onset of the disease is delayed after birth. To establish the diagnosis of SJS, both myotonia and chondrodysplasia have to be demonstrated and confirmed by EMG and X-ray analysis, respectively. EMG helps to distinguish SJS from another chondrodysplasia. X-rays abnormalities enable to eliminate a
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