Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene
- 46 Downloads
Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the PSAP gene. Only ten pathogenic variants were described in the PSAP gene in MLD patients to date. We report on two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A–D) or whole prosaposin. The patient’s phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.
KeywordsMetachromatic leukodystrophy Saposin B deficiency PSAP gene
We are grateful to scientists from Laboratory of Genetics Center Bratislava, Slovak Republic and colleagues from the Institute of Inherited Metabolic Disorders Charles University in Prague, Czech Republic.
All authors contributed to the study design and reviewed the manuscript critically and approved the final version. M.K., P.J., M.S., and S.M. researched data and wrote the manuscript; T.F. researched data; J.Ch. and D.G. reviewed and edited the manuscript.
This work was supported by APVV-17-0296.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- Deconinck N, Messaaoui A, Ziereisen F, Kadhim H, Sznajer Y, Pelc K, Cécile Nassogne M, Vanier MT, Dan B (2008) Metachromatic leukodystrophy without arylsulfatase a deficiency: a new case of saposin-B deficiency. Eur J Paediatr Neurol 12:46–50. https://doi.org/10.1016/j.ejpn.2007.05.004 CrossRefPubMedGoogle Scholar
- Elleder M, Jeřábková M, Befekadu A, Hřebíček M, Berná L, Ledvinová J, Hůlková H, Rosewich H, Schymik N, Paton BC, Harzer K (2005) Prosaposin deficiency -- a rarely diagnosed, rapidly progressing, neonatal neurovisceral lipid storage disease. Report of a further patient. Neuropediatrics 36:171–180. https://doi.org/10.1055/s-2005-865608 CrossRefPubMedGoogle Scholar
- Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/. Accessed July 2018)
- Golchin N, Hajjari M, Malamiri RA, Aminzadeh M, Mohammadi-Asl J (2017) Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder. Genet Mol Biol 40:759–762. https://doi.org/10.1590/1678-4685-GMB-2016-0110 CrossRefPubMedPubMedCentralGoogle Scholar
- Kretz KA, Carson GS, Morimoto S, Kishimoto Y, Fluharty AL, O’Brien JS (1990) Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect Proceedings of the National Academy of Sciences of the United States of America 87:2541–2544Google Scholar
- Kuchar L et al (2009) Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A 149A:613–621. https://doi.org/10.1002/ajmg.a.32712 CrossRefPubMedPubMedCentralGoogle Scholar
- Matsuda J, Kido M, Tadano-Aritomi K, Ishizuka I, Tominaga K, Toida K, Takeda E, Suzuki K, Kuroda Y (2004) Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse. Hum Mol Genet 13:2709–2723. https://doi.org/10.1093/hmg/ddh281 CrossRefPubMedGoogle Scholar
- Regis S, Filocamo M, Corsolini F, Caroli F, Keulemans JL, van Diggelen OP, Gatti R (1999) An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity. Eur J Human Genet: EJHG 7:125–130. https://doi.org/10.1038/sj.ejhg.5200266 CrossRefGoogle Scholar
- Richards S et al. (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genetics in medicine : official journal of the American College of Medical Genetics 17:405–424 doi: https://doi.org/10.1038/gim.2015.30
- Siri L, Rossi A, Lanza F, Mazzotti R, Costa A, Stroppiano M, Gaiero A, Cohen A, Biancheri R, Filocamo M (2014) A novel homozygous splicing mutation in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers. Neurogenetics 15:101–106. https://doi.org/10.1007/s10048-014-0390-4 CrossRefPubMedGoogle Scholar
- Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S, Yona Shneor, Mandel H, Zeigler M (2005) A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab 84:160–166CrossRefGoogle Scholar
- Vaccaro AM, Motta M, Tatti M, Scarpa S, Masuelli L, Bhat M, Vanier MT, Tylki-Szymanska A, Salvioli R (2010) Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting. Hum Mol Genet 19:2987–2997. https://doi.org/10.1093/hmg/ddq204 CrossRefPubMedGoogle Scholar