The Spectrum of Krabbe Disease in Greece: Biochemical and Molecular Findings
Krabbe disease is an autosomal recessive neurodegenerative lysosomal storage disease caused by the deficiency of β-galactocerebrosidase. This deficiency results in the impaired degradation of β-galactocerebroside, a major myelin lipid, and of galactosylsphingosine. Based on the age of onset of neurological symptoms, an infantile form (90% patients) and late-onset forms (10% patients) of the disease are recognized. Over 130 disease-causing mutations have been identified in the β-galactocerebrosidase gene. We present the biochemical and molecular findings in 19 cases of Krabbe disease, 17 of them unrelated, diagnosed in Greece over the last 30 years. β-Galactocerebrosidase activity assayed in leukocyte homogenates using either the tritium-labeled or the fluorescent substrate was diagnostic for all. Increased plasma chitotriosidase activity was found in 11/15 patients.
Mutational analysis, carried out in 11 unrelated cases, identified seven different mutations, four previously described (p.I250T, c.1161+6532_polyA+9kbdel, p.K139del, p.D187V) and three novel mutations (p.D610A, c.583-1 G>C, p.W132X), and seven distinct genotypes. The most prevalent mutation was mutation p.I250T, first described in a patient of Greek origin. It accounted for 36.4% (8/22) of the mutant alleles. The second most frequent mutation was c.1161+6532_polyA+9kbdel that accounted for 22.7% (5/22) of the mutant alleles. The observed frequency was lower than that described in Northern European countries and closer to that described in Italian patients.
KeywordsLysosomal Storage Disorder Lysosomal Storage Disease Infantile Form Chitotriosidase Activity Plasma Chitotriosidase Activity
We are grateful to Prof. Zafeiriou, Dr. Garoufi, Dr. Skiadas, Dr. Lourbopoulos, and all the clinicians that collaborated with us in the diagnosis of the Krabbe patients. We are also grateful to A. Bayona for technical help. This work was partially supported by grants SAF2011-25431 from the Spanish Ministry of Science and Innovation and 2009SGR971 and 2014SGR932, from the Catalan Government.
- Foss AH, Duffner PK, Carter RL (2013) Lifetime risk estimators in epidemiological studies of Krabbe disease: review and Monte Carlo comparison. Rare Dis 1:e25212Google Scholar
- Wenger DA (2008) Krabbe disease. In: Gene reviews and gene tests: medical genetics information resource (database on line). Copyright, University Washington, Seattle. 1997–2010. http://www.genetest.org
- Wenger DA, Suzuki K, Suzuki Y (2001) Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Chilids B, Vogelstein D (eds) The metabolic and molecular bases of inherited disease. McGraw Hill, New York, pp 3669–3694Google Scholar
- Wenger DA, Escolar MI, Luzi P, Rafi MA (2013) Krabbe disease (globoid cell leukodystrophy). In: Valle D, Beaudet AL, Vogelstein D, Kinzler KW, Antonarakis SE, Ballabio A (eds) The online metabolic and molecular bases of inherited disease. McGraw Hill, New YorkGoogle Scholar