A brief history of neurological botulinum toxin therapy in Germany.

Botulinum toxin (BT) has long been infamous in food safety and biological warfare. In the early 1970s, Alan B Scott of San Francisco invented its therapeutic use originally in extraocular eye muscles to treat strabismus using a therapeutic BT type A preparation provided by Edward J Schantz and Eric A Johnson. Subsequently a large number of medical indications based on motor and glandular hyperactivity and-most recently-chronic migraine are now treated by BT therapy. BT's highly specific and elaborate mechanism of action represents a completely novel therapeutic principle which will have consequences far beyond existing indications. BT therapy entered neurology through Stanley Fahn in New York from where C David Marsden brought it to London. From here neurological BT therapy came to Germany through Reiner Benecke and Dirk Dressler. Ophthalmological BT therapy was brought directly to Germany by Peter Roggenkämper, a fellow of Scott. By the early 1990s, several users in Germany had learned about BT therapy and made the country one of the most productive countries in clinical BT science-backed up by a long tradition of solid basic BT research. For several years now, however, BT therapy in Germany has been stagnating due to a lack of reimbursement for the medical treatment and due to off-label use challenges.

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.