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ARTICLES: L. Van Maldergem, M. Yuksel-Apak, H. Kayserili, E. Seemanova, S. Giurgea, L. Basel-Vanagaite, E. Leao-Teles, J. Vigneron, M. Foulon, M. Greally, J. Jaeken, S. Mundlos, and W. B. Dobyns Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type Neurology 2008; 71: 1602-1608 [Abstract] [Full text] [PDF]

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Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type

E. Morava MD PhD, RA Wevers, PhD, MA Willemsen, MD, PhD, D Lefeber, PhD   (10 February 2009)

Reply from the authors

Lionel Van Maldergem, William B. Dobyns, Chicago, IL   (10 February 2009)

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type 10 February 2009
E. Morava MD PhD, Radboud University Nijmegen Medical Centre P.O Box 9101, 6500 HB Nijmegen, The Netherlands., RA Wevers, PhD, MA Willemsen, MD, PhD, D Lefeber, PhD Send Correspondence to journal: Re: Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type e.morava{at}cukz.umcn.nl E. Morava MD PhD, et al.	Van Maldergem et al. reported children with cutis laxa and cobblestone-like brain dysgenesis associated with deficient N- and O-glycosylation. [1] ATP6V0A2 mutation analysis was not reported in these patients. We disagree with the authors’ suggestion that Apolipoprotein-CIII is not released into circulation after its synthesis in the liver. The diagnostic workup of the patients with cutis laxa should rely on simple laboratory screening for glycosylation defects, specifically iso-electric focusing of Apolipoprotein-CIII and transferrin. In our experience, all patients with ATP6V0A2 mutations have abnormal transferrin isoform profiles (N-glycan screening) and the majority of patients also have a characteristic abnormal Apolipoprotein-CIII isoform profile (mucin type O-glycan screening). Alpha-dystroglycan is a membrane bound, non-secreted protein, that is abnormally O-glycosylated (mannosyl-type O-glycan) in congenital muscle dystrophies (CMD). The initial diagnostic work-up relies on muscle histology and immunostaining, while blood transferrin and Apolipoprotein-CIII iso-electric focusing can be performed in the cutis laxa syndromes. The diagnostic approach for CMD and the cutis laxa syndromes, although both caused by the defective protein glycosylation, is completely different due to the tissue-specific expression and presence or absence of the involved proteins in the blood. Since our first description of a novel cutis laxa syndrome with variable cortical anomalies and the genetic defect in ATP6V0A2, several cases have been reported with variable CNS involvement. [2,3] The neuroradiological abnormalities in this syndrome are similar to those seen in O-mannosylation disorders (CMD), like muscle-eye-brain disease. The cerebral abnormalities are dominated by bilateral cortical malformation of the posterior parts of the frontal lobes. In some patients, the affected area includes larger parts of the frontal lobe and the nearest anterior parts of the parietal lobes. Another remarkable feature is the presence of enlarged perivascular spaces. Hypoplasia of the cerebellar vermis is not seen in all patients and very mild when observed. The classification and description of malformations of cortical development is difficult and still evolving. [4] We agree with the authors that the cortical abnormalities in cutis laxa syndrome are strikingly similar to those in CMD. [1] We would include them in category II (malformations due to abnormal neuronal migration), subtype B (cobblestone complex/CMD) of the classification scheme. [4] Currently, this category only includes CMD. Since cutis laxa syndrome with malformations of cortical development is essentially different from CMD, we propose to include a second category, II–B–2, for this group of glycosylation defects. References 1. Van Maldergem L, Yuksel-Apak M, Kayserili H, et al. Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type. Neurology 2008;71:1602-1608. 2. Morava E, Lefeber DJ, Urban Z, et al. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur J Hum Genet 2008;16:28-35. 3. Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 2008;40:32-34. 4. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65:1873-1887. Disclosure: The authors report no disclosures.
Reply from the authors 10 February 2009
Lionel Van Maldergem, Centre de génétique humaine, Université de Liège CHU du Sart-Tilman, B-4000 Liège, Belgium, William B. Dobyns, Chicago, IL Send Correspondence to journal: Re: Reply from the authors vmald{at}skypro.be Lionel Van Maldergem, et al.	We would like to address the three points that Morava et al. make relevant to our article. [1] They mention that the mutation analysis of ATP6V0A2 was not reported in our patients. This is incorrect. The last sentence of our article states: "mutations in the a2 subunit of the V-type H-ATPase (ATP6V0A2) were recently identified in all our patients except for patient 2." We cited the article that includes both their patients and ours. [3] Secondly, we agree with Morava et al. that we incorrectly stated that Apo-CIII is not released into the circulation. Thus, abnormal isoforms profiles should be detected in serum in most patients. However, we were able to obtain reliable results for ApoCIII isoelectric focusing only when testing the index patient and parents together, as seen in Figure 4 (analyses performed in the Jaeken lab). Finally, Morava et al. agree with our conclusion that the cortical malformation found in Debré type cutis laxa closely resembles the cortical malformation of muscle-eye-brain disease and related alpha-dystroglycanopathies. We also agree that it should be added to the group of cobblestone malformations (as category II-B-2) listed in the current classification of cortical malformations. [4] We would also propose that both Debré type cutis laxa brain malformation and the cortical malformation associated with mutations of the heavily glycosylated GPR56 gene be added to category II-B-2. While it would be premature to assign definitively these conditions to this category without knowing the corresponding human brain pathology, this tentative classification is supported by recent studies in the Gpr56-/- mouse model where defective pial basement membrane and other changes similar to alpha-dystroglycanopathies occur in both human and mouse. [5] Reference 5. Li S, Jin Z, Koirala S, et al. GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination. J Neurosci 2008;28:5817-5826. Disclosure: The authors report no disclosures.