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draw firm conclusions, particularly in relation to the use of episiotomy in severe shoulder dystocia. Gurewitsch and Allen state that their aim was “to test the intuited but unproven hypothesis that elimination of soft tissue via episiotomy will—on its own—successfully resolve shoulder dystocia”. This, however, was not stated as the aim of their study,1 which was “to compare neonatal outcomes between shoulder dystocia deliveries managed with episiotomy and those managed with fetal manipulation”. We believe that it is inappropriate to dismiss a statistically significant difference of 5% in birthweight between groups as “clinically insignificant and irrelevant since it would not be appreciable prospectively”. This misses the point. Even if it were not appreciable prospectively, it should be considered as a factor that might have a bearing on manoeuvres required to achieve delivery, and on outcomes such as brachial plexus palsy and anal sphincter trauma. Gurewitsch and Allen assert “our results indicate that this strategy [of internal manoeuvres before episiotomy] will not incur any greater risk of brachial plexopathy, because the injury rate (and mean birthweight) of those managed with episiotomy alone was the same as those managed with episiotomy and fetal manoeuvres”. The results could, however, also be taken to suggest that fetal manoeuvres were of no additional incremental benefit to episiotomy alone. Further, the incidence of brachial plexus palsy and anal sphincter trauma is far lower in the group in which fetal manoeuvres only were used than in those managed by episiotomy with or without fetal manoeuvres. Although it may be reasonable to argue that episiotomy caused the anal sphincter trauma seen, it could surely not explain the increased risk of brachial plexus palsy in the groups managed by episiotomy with or without fetal manoeuvres? Gurewitsch and Allen do not explain why the brachial plexus palsy rate in the two groups managed by episiotomy with and without fetal www.thelancet.com Vol 365 April 2, 2005
manoeuvres (just under 60%) was so much higher than that in the group managed by fetal manoeuvres alone (35%). We would advance the following explanation: that the severity of shoulder dystocia in the former two groups was inherently more severe than in the latter. We believe that this is what most obstetricians would conclude from this work. The results cannot be used to justify the assertions1 that “prompt progression to manipulating the fetus within the birth canal, even without episiotomy, will not increase the risk of fetal injury” and that “the addition of episiotomy alone does not otherwise confer any increased benefit over performance of fetal manipulation alone”. The argument against episiotomy could therefore only be a valid one if, by doing it, internal manoeuvres would be significantly delayed; this is ,however, not the case. Such an interpretation of data cannot in our view be used as an argument against immediate episiotomy to facilitate internal vaginal manoeuvres in the management of severe shoulder dystocia. We declare that we have no conflict of interest.
Andrew C G Breeze, *Christoph C Lees
[email protected] Division of Maternal-Fetal Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK 1
Gurewitsch ED, Donithan M, Stallings SP, et al. Episiotomy versus fetal manipulation in managing severe shoulder dystocia: a comparison of outcomes. Am J Obstet Gynecol 2004; 191: 911–16.
LRRK2 mutations and Parkinsonism William Nichols and colleagues,1 Alessio Di Fonzo and colleagues,2 and William Gilks and colleagues3 report a common pathogenic 6055G A mutation (Gly2019Ser) in the LRRK2 gene associated with Parkinson’s disease. Our group has also identified the same heterozygous mutation in several families and apparent sporadic cases of Parkinson’s disease originating from the USA, Norway, Poland,
and Ireland.4 Together with our results, the three reports in The Lancet indicate that the mutant allele is geographically widespread across European and American populations. In our series of 248 affected probands from families with autosomal dominant parkinsonism, we identified seven (2·8%) carriers of the LRRK2 Gly2019Ser substitution. Subsequent screening of three community-based series of individuals with idiopathic Parkinson’s disease from Norway, Ireland, and Poland identified about 1% with this substitution, in close agreement with Gilks and colleagues.3 The LRRK2 Gly2019Ser mutation may not, however, be as common as reported. This frequency could indicate referral bias; a study of LRRK2 mutations in incident patients is now required. These findings show that even lateonset Parkinson’s disease can have a significant genetic component, especially since LRRK2-associated parkinsonism is clinically indistinguishable from “idiopathic Parkinson’s disease”. In view of these results, a family history of parkinsonism, previously regarded as an exclusion criterion for a diagnosis of Parkinson’s disease, should be reconsidered. As postulated in the Lancet papers, our work in families shows that penetrance is age-dependent, increasing from 21% at the age of 50 years to 81% at 70 years.4 Reduced penetrance may account for the lack of family history in some Gly2019Ser carriers. It may also explain why monozygotic twin studies have not shown concordance in late-onset disease. Although a family history was not always apparent, all mutation carriers in our study share a small ancestral haplotype indicative of an ancient common founder.4 This remarkable finding should be examined in other Gly2019Ser patients. The Gly2019Ser substitution is located adjacent to Ile2020Thr—a substitution identified in a German family in our first report on LRRK2 1229
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mutations in Parkinson’s disease.5 Both Gly2019Ser and Ile2020Thr lie within the highly conserved activation segment of the LRRK2 kinase domain. We postulate that both these pathogenic substitutions have an activating effect on the kinase activity of the LRRK2 protein, causing gain of function, which is compatible with the dominant mode of disease transmission in our families.4 Several highly potent and selective protein kinase inhibitors are now in development and could offer great therapeutic potential. We declare that we have no conflict of interest.
Mathias Toft, Ignacio F Mata, Jennifer M Kachergus, Owen A Ross, *Matthew J Farrer
[email protected] Mayo Clinic College of Medicine, Department of Neuroscience, Jacksonville, FL 32224, USA 1
2
3
4
5
Nichols WC, Pankratz N, Hernandez D, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005; 365: 410–12. DiFonzo A, Rohe CF, Ferreira J, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005; 365: 412–15. Gilks WP, Abou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005; 365: 415–16. Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism; evidence for a common founder across European populations. Am J Hum Genet 2005; Feb 22, Epub. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601–07.
William Nichols and colleagues,1 Alessio Di Fonzo and colleagues,2 and William Gilks and colleagues,3 report the identification of a Gly2019Ser sequence variation contained in leucine-rich repeat kinase 2 (LRRK2; dardarin). Although this variant seems to be associated with Parkinson’s disease in a relatively large proportion of patients, an Ile2020Thr variant, which occurs adjacent to Gly2019Ser, has also been seen to segregate with Parkinsonism.4 Structural and functional analyses of LRRK2 lend support 1230
to the proposed pathogenicity of these variants. LRRK2 is a large protein with multiple domains including several ankyrin, leucine-rich, and WD40 repeats, a Raslike small GTPase family domain named Roc, and a non-receptor tyrosine kinase-like MAPKKK-related domain. Gly2019Ser and Ile2020Thr are contained in the well studied kinase activation segment of the MAPKKK-related domain (figure).5 Phosphorylation of specific residues within this segment regulates kinase activity. In particular, the Gly2019 residue is part of the highly conserved DFG-like motif (DYG in LRRK2) at the N-terminus of the activation segment. The invariant aspartate of the DFGlike motif chelates a magnesium ion that positions the phosphates for phosphotransfer.5 This magnesiumbinding site forms a loop in the active cleft at the interface between the small and large lobe of the kinase domain. Residues in and around the DFG-like motif make essential contributions to the contact surface of the magnesium-binding loop (in the large lobe) to the functionally relevant Chelix of kinases (in the small lobe).5 Therefore, mutations of Gly2019 and Ile2020 within LRRK2 presumably affect the proper positioning of the
C-helix and its catalytically important aminoacids, possibly impairing kinase activity. The additional insights provided into the molecular cause of Parkinson’s disease should direct experimental studies and drug design towards the protein kinase activity of LRRK2. I declare that I have no conflict of interest.
Mario Albrecht
[email protected] Max-Planck-Institute for Informatics, 66123 Saarbrücken, Germany 1
2
3
4
5
Nichols WC, Pankratz N, Hernandez D, et al, for the Parkinson Study Group-PROGENI investigators. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005; 365: 410–12. Di Fonzo A, Rohé CF, Ferreira J, et al, and the Italian Parkinson Genetic Network. A frequent LRRK2 mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005; 365: 412–15. Gilks WP, Abou-Sleiman PM, Gandhi S, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005; 365: 415–16. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601–07. Nolen B, Taylor S, Ghosh G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 2004; 15: 661–75.
Figure: Three-dimensional model of LRRK2 based on the B-RAF protein kinase domain
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