Abstract
Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is an extremely rare autosomal recessive disorder with distinctive clinical and neuroimaging findings. To date, only 17 patients from 9 unrelated families with BLC-PMG have been reported worldwide. Herein, we describe a series of 13 new patients derived from 10 unrelated Egyptian families. Patients presented at early life with the classic phenotype including severe microcephaly, failure to acquire developmental skills, growth failure and the distinguished calcification patterns involving the cortex, thalami, basal ganglia and pons. Additional features not reported before included calcification of the cerebellum (eight patients: 61.5%) and imperforate anus and undescended testis in a single patient. Molecular studies of the OCLN gene (NM_001205254) identified six distinct candidate mutations. Interestingly, the deletion mutation of the transmembrane domain in exons 3 and 4 (c.51-?_730-?del, p.Lys18_Glu243) was found in five unrelated families (50%), suggesting a founder mutation in our population. On the other hand, five novel truncating mutations (c.809delA (p.K270Rfs*62), c.858_861delTTAT (p.I286Mfs*45), c.1037+5G>C, c.1169C>G (p.S390*) and c.1180delG (p.E394Sfs*91)) were detected, each in one family. To our knowledge, this is the largest series of patients with BLC-PMG. Cerebellum calcification is an additional relevant finding in our series, thus expanding the neuroradiological phenotype of this syndrome.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Livingston, J. H., Stivaros, S., van der Knaap, M. S. & Crow, Y. J. Recognizable phenotypes associated with intracranial calcification. Dev. Med. Child Neurol. 55, 46–57 (2013).
Aran, A., Rosenfeld, N., Jaron, R., Renbaum, P., Zuckerman, S., Fridman, H. et al. Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection. Neurology 86, 2016–2024 (2016).
Gresser, I., Morel-Maroger, L., Riviere, Y., Guillon, J. C., Tovey, M. G., Woodrow, D. et al. Interferon induced disease in mice and rats. Ann. N. Y. Acad. Sci. 350, 12–20 (1980).
Lebon, P., Badoual, J., Ponsot, G., Goutieres, F., Hemeury-Cukier, F. & Aicardi, J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J. Neurol. Sci. 84, 201–208 (1988).
Klok, M. D., Bakels, H. S., Postma, N. L., van Spaendonk, R. M., van der Knaap, M. S. & Bugiani, M. Interferon-alpha and the calcifying microangiopathy in Aicardi-Goutières syndrome. Ann. Clin. Transl. Neurol. 2, 774–779 (2015).
Mochida, G. H., Ganesh, V. S., Felie, J. M., Gleason, D., Hill, R. S., Clapham, K. R. et al. A homozygous mutation in the tight junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am. J. Hum. Genet. 87, 882–889 (2010).
O'Driscoll, M. C., Daly, S. B., Urquhart, J. E., Black, G. C., Pilz, D. T., Brockmann, K. et al. Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am. J. Hum. Genet. 87, 354–364 (2010).
LeBlanc, M. A., Penney, L. S., Gaston, D., Shi, Y., Aberg, E., Nightingale, M. et al. A novel rearrangement of occludin causes brain calcification and renal dysfunction. Hum. Genet. 132, 1223–1234 (2013).
Elsaid, M. F., Kamel, H., Chalhoub, N., Aziz, N. A., Ibrahim, K., Ben-Omran, T. et al. Whole genome sequencing identifies a novel occludin mutation in microcephaly with band-like calcification and polymicrogyria that extends the phenotypic spectrum. Am. J. Med. Genet. 164A, 1614–1617 (2014).
Aggarwal, S., Bahal, A. & Dalal, A. Renal dysfunction in sibs with band like calcification with simplified gyration and polymicrogyria: report of a new mutation and review of literature. Eur. J. Med. Genet. 59, 5–10 (2016).
Abdel-Salam, G. M., Zaki, M. S., Saleem, S. N. & Gaber, K. R. Microcephaly, malformation of brain development and intracranial calcification in sibs: pseudo-TORCH or a new syndrome. Am. J. Med. Genet. 146A, 2929–2936 (2008).
Briggs, T. A., Wolf, N. I., D'Arrigo, S., Ebinger, F., Harting, I., Dobyns, W. B. et al. Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct ‘pseudo-TORCH’ phenotype. Am. J. Med. Genet. 146A, 3173–3180 (2008).
Abdel-Salam, G. M. & Zaki, M. S. Band-like intracranial calcification (BIC), microcephaly and malformation of brain development: a distinctive form of congenital infection like syndromes. Am. J. Med. Genet. 149A, 1565–1568 (2009).
Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., Tsukita, S. et al. A novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777–1788 (1993).
Hamamy, H., Antonarakis, S. E., Cavalli-Sforza, L. L., Temtamy, S., Romeo, G., Kate, L. P. et al. Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report. Genet. Med. 13, 841–847 (2011).
Saitou, M., Furuse, M., Sasaki, H., Schulzke, J. D., Fromm, M., Takano, H. et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).
Temtamy, S. A. & Aglan, M. S. Consanguinity and genetic disorders in Egypt. Middle East J. Med. Genet. 1, 12–17 (2012).
Acknowledgements
We thank all the patients and their family members who participated in our study. This work was funded by a research grant from STDF (project no.5253).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
About this article
Cite this article
Abdel-Hamid, M., Abdel-Salam, G., Issa, M. et al. Band-like calcification with simplified gyration and polymicrogyria: report of 10 new families and identification of five novel OCLN mutations. J Hum Genet 62, 553–559 (2017). https://doi.org/10.1038/jhg.2017.4
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2017.4