Abstract
Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal storage disorder involving the white matter of the peripheral and the central nervous systems. It is caused by a deficiency of galactocerebrosidase enzyme activity. The most common manifestation is the classical early onset KD that leads to patient’s loss before the age of 2. Herein, we report the evaluation of a consanguineous family with three affected children manifesting severe neurological findings that ended with death before the age of 2, in an attempt to provide genetic diagnosis to the family. One of the children underwent detailed physical and neurological examinations, including brain magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) evaluations. GALC genetic testing on this child enabled identification of a novel homozygous variant (NM_000153.3: c.1394C>T; p.(Thr465Ile)), which confirmed diagnosis as KD. Familial segregation of this variant was performed by PCR amplification and Sanger sequencing that revealed the parents as heterozygous carriers. We believe this novel GALC variant will not only help in genetic counseling to this family but will also aid in identification of future KD cases.
Similar content being viewed by others
References
Xu C, Sakai N, Taniike M, Inui K, Ozono K (2006) Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype–phenotype correlation. J Hum Genet 51(6):548–554. https://doi.org/10.1007/s10038-006-0396-3
Graziano AC, Cadile V (2015) History, genetic, and recent advances on Krabbe disease. Gene 555(1):2–13. https://doi.org/10.1016/j.gene.2014.09.046
Africa L, Margollicci M, Salvatore S, Shalbafan B, Peruzzi L, Togha M, Sorrentino V, Federico A (2017) Compound heterozygosity in the GALC gene in a late onset Iranian patient with spastic paraparesis, peripheral neuropathy and leukoencephalopathy. Neurol Sci 38(9):1721–1722. https://doi.org/10.1007/s10072-017-2986-6
Federico A, Rufa A, Battisti C, Bianchi S, Cardaioli E, Da Pozzo P et al (2001) Genetic leukoencephalopathies with unknown metabolic pathogenesis. Neurol Sci 22(Suppl2):S108–S112
Yang Y, Ren X, Xu Q, Wang C, Liu H, He X (2013) Four novel GALC gene mutations in two Chinese patients with Krabbe disease. Gene 519(2):381–384. https://doi.org/10.1016/j.gene.2013.02.010
Camelier M, Civallero G, De Mari J, Burin M, Giugliani R (2015) Galactocerebrosidase assay on dried-leukocytes impregnated in filter paper for the detection of Krabbe disease. Clin Chim Acta 438:178–180. https://doi.org/10.1016/j.cca.2014.08.029
Duffner PK, Barczykowski A, Jalal K, Yan L, Kay DM, Carter RL (2011) Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. Pediatr Neurol 45(3):141–148. https://doi.org/10.1016/j.pediatrneurol.2011.05.007
Köhler W (2008) Diagnostic algorithm for the differentiation of leukodystrophies in early MS. J Neurol 255:123–126. https://doi.org/10.1007/s00415-008-6023-9
Tomás J, Durães J, Lacerda L, Macário MC (2015) Adolescent-onset Krabbe disease with an initial diagnosis of multiple sclerosis and a novel mutation. BMJ Case Rep. https://doi:10.1136/bcr-2015-210625
Trojano M, Policelli D (2001) The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes. Neurol Sci 22(Suppl2):S98–S102
Kwon JM, Matern D, Kurtzberg J, Wrabetz L, Gelb MH, Wenger DA, Ficicioglu C, Waldman AT, Burton BK, Hopkins PV, Orsini JJ (2018) Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis 13:30. https://doi.org/10.1186/s13023-018-0766-x
Saavedra-Matiz CA, Luzi P, Nichols M, Orsini JJ, Caggana M, Wenger DA (2016) Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe’s disease. J Neurosci Res 94(11):1076–1083
Puckett RL, Orsini JJ, Pastores GM, Wang RY, Chang R, Saavedra-Matiz CA, Torres PA, Zeng B, Caggana M, Lorey F, Abdenur JE (2012) Krabbe disease: clinical, biochemical and molecular information on six new patients and successful retrospective diagnosis using stored newborn screening cards. Mol Genet Metab 105(1):126–131. https://doi.org/10.1016/j.ymgme.2011.10.010
Ozkara HA, Topçu M (2004) Sphingolipidoses in Turkey. Brain and Development 26(6):363–366. https://doi.org/10.1016/S0387-7604(03)00195-5
Giorgio A, De Stefano N (2008) Leukoencephalopathies and metabolic diseases. Neurol Sci 29:S323–S326. https://doi.org/10.1007/s10072-008-1008-0
Abdelhalim AN, Alberico RA, Barczykowski AL, Duffner PK (2014) Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype. Pediatr Neurol 50(2):127–134. https://doi.org/10.1016/j.pediatrneurol.2013.10.001
Malandrini A, D’Eramo C, Palmeri S, Gaudiano C, Gambelli S, Sicurelli F, Berti G, Formichi P, Kuqo A, Dotti MT, Federico A (2013) Peripheral neuropathy in late-onset Krabbe disease: report of three cases. Neurol Sci 34(1):79–83. https://doi.org/10.1007/s10072-012-0956-6
Zerkaoui M, Ratbi I, Castellotti B, Gellera C, Lyahyai J, Kriouile Y, Sefiani A (2015) Clinical and molecular report of novel GALC mutations in Moroccan patient with Krabbe disease: case report. BMC Pediatr 15(182):182. https://doi.org/10.1186/s12887-015-0490-9
Wenger DA, Luzi P, Rafi MA (2014) Krabbe disease: are certain mutations disease-causing only when specific polymorphisms are present or when inherited in trans with specific second mutations? Mol Genet Metab 111(3):307–308. https://doi.org/10.1016/j.ymgme.2013.12.009
David RB (2009) Clinical pediatric neurology. Third Edition New York, NY
Wenger DA, Rafi MA, Luzi P, Datto J, Costantino-Ceccarini E (2000) Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab 70(1):1–9. https://doi.org/10.1006/mgme.2000.2990
Kleijer WJ, Keulemans JL, van der Kraan M, Geilen GG, van der Helm RM, Rafi MA et al (1997) Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin. J Inherit Metab Dis 20(4):587–594
Luzi P, Rafi MA, Wenger DA (1995) Characterization of the large deletion in the GALC gene found in patients with Krabbe disease. Hum Mol Gen 4(12):2335–2338
Rafi MA, Luzi P, Chen YQ, Wenger DA (1995) A large deletion together with a point mutation in the GALC gene is a common mutant allele in patients with infantile Krabbe disease. Hum Mol Genet 4(8):1285–1289
Gucev Z, Tasic V. Compound galactosylceramıdase gene (GALC) heterozygosity in a boy with infantile Krabbe disease (KD) (2015) Pril (Makedon Akad Nauk Umet Odd Med Nauki) 36(3):99–101. 10.1515/prilozi-2015-0084
Tuncer FN, Gormez Z, Calik M, Altiokka Uzun G, Sagiroglu MS, Yuceturk B, Yuksel B, Baykan B, Bebek N, Iscan A, Ugur Iseri SA, Ozbek U (2015) A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family. Epilepsy Res 113:5–10. https://doi.org/10.1016/j.eplepsyres.2015.02.020
Hossain MA, Takanobu Otomo T, Saito S, Ohno K, Sakuraba H, Hamada Y et al (2014) Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form. Gene 534:144–154. https://doi.org/10.1016/j.gene.2013.11.003
Vargiami E, Papathanasiou E, Batzios S, Kyriazi M, Dimitriou E, Anastasiou A, Michelakakis H, Giese AK, Zafeiriou DI (2016) Neuroradiological, neurophysiological and molecular findings in infantile Krabbe disease: two case reports. Balkan J Med Genet 19(1):85–90. https://doi.org/10.1515/bjmg-2016-0011
Rafi MA, Luzi P, Zlotogora J, Wenger DA (1996) Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. Hum Genet 97(3):304–308
Güngör O, Güngör G, Özkaya AK, Dilber C, Aydın K (2017) A new mutation in an infant with Krabbe disease accompanied by enlargement of the optic nerves. Acta Neurol Belg 117(1):319–321. https://doi.org/10.1007/s13760-016-0637-y
Kardas F, Uzak AS, Hossain MA, Sakai N, Canpolat M, Yıkılmaz A (2013) A novel homozygous GALC mutation: very early onset and rapidly progressive Krabbe disease. Gene 517(1):125–127. https://doi.org/10.1016/j.gene.2012.12.040
Kabadayı A (2016) İstatistiklerle Aile, Türkiye İstatistik Kurumu (TUIK) (updated May 10, 2017). Available at: http://www.tuik.gov.tr/HbPrint.do?id=24646. Accessed June 01, 2018
Bongarzone ER, Escolar ML, Gray SJ, Kafri T, Vite CH, Sands MS (2016) Insights into the pathogenesis and treatment of Krabbe disease. Pediatr Endocrinol Rev 13:689–696
Potter GB, Santos M, Davisson MT, Rowitch DH, Marks DL, Bongarzone ER, Petryniak MA (2013) Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease. Hum Mol Genet 22(17):3397–3414. https://doi.org/10.1093/hmg/ddt190
Acknowledgements
The authors are grateful to the patients and their relatives for their participation in this study.
We would like to acknowledge Advanced Genomics and Bioinformatics Research Center (IGBAM), TUBITAK MAM-GMBE, for kindly providing variant frequency data of 1182 exome sequenced individuals from Turkey with varying disorders, which was used as a population control set towards the evaluation of the novel GALC variant. We would also like to acknowledge Sedef Iskit, PhD, for technical assistance towards the construction of the artwork.
Funding
This work was supported by the grant of The Scientific and Technology Research Council of Turkey (TUBITAK) Project Number: 113S331. Biobanking support was provided by Istanbul Development Agency (ISTKA) Project Number: TR10/15/YNK/0093.
Author information
Authors and Affiliations
Contributions
Feyza Nur Tuncer (FNT) and Sibel Aylin Ugur Iseri (SAUI) were involved in genetic evaluation of the recruited family members, data acquisition, and analyses. FNT has written the original draft, which subsequently was edited by SAUI. Mahmut Demir (MD), Meryem Karaca (MK), and Mustafa Calik (MC) were involved in clinical evaluations of the patients, interview with the available family members and in commenting of several drafts of the manuscript. Zuhal Yapici (ZY) took role both in the evaluation of the patients’ MRI and writing the clinical findings in the main draft. MC mentored the study.
Corresponding author
Ethics declarations
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Accordingly, informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Tuncer, F.N., Iseri, S.A.U., Yapici, Z. et al. A novel homozygous GALC variant has been associated with Krabbe disease in a consanguineous family. Neurol Sci 39, 2123–2128 (2018). https://doi.org/10.1007/s10072-018-3556-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-018-3556-2