A novel homozygous splicing mutation in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers

Laura Siri, Andrea Rossi, Federica Lanza, Raffaella Mazzotti, Anna Costa, Marina Stroppiano, Alberto Gaiero, Amnon Cohen, Roberta Biancheri, Mirella Filocamo

Research output: Contribution to journalArticlepeer-review


Prosaposin (PSAP) gene mutations, affecting saposin B (Sap-B) domain, cause a rare metachromatic leukodystrophy (MLD) variant in which arylsulfatase A (ARSA) activity is normal. To date, only 10 different PSAP mutations have been associated with a total of 18 unrelated MLD patients worldwide. In this study, we report for the first time a family with Moroccan origins in which the proband, presenting with a late-infantile onset of neurological involvement and a brain MRI with the typical tigroid MLD pattern, showed normal values of ARSA activity in the presence of an abnormal pattern of urinary sulfatides. In view of these findings, PSAP gene was analyzed, identifying the newly genomic homozygous c.909 + 1G > A mutation occurring within the invariant GT dinucleotide of the intron 8 donor splice site. Reverse transcriptase-polymerase chain reaction (RT-PCR), showing the direct junction of exon 7 to exon 9, confirmed the skipping of the entire exon 8 (p.Gln260-Lys303) which normally contains two cysteine residues (Cys271 and Cys265) involved in disulfide bridges. Our report provides further evidence that phenotypes of patients with Sap-B deficiency vary widely depending on age of onset, type, and severity of symptoms. Awareness of this rare MLD variant is crucial to prevent delayed diagnosis or misdiagnosis and to promptly provide an accurate genetic counseling, including prenatal diagnosis, to families.

Original languageEnglish
Pages (from-to)101-106
Number of pages6
Issue number2
Publication statusPublished - 2014


  • Lysosomal disorder
  • Metachromatic leukodystrophy
  • Prosaposin
  • Saposin B
  • Splicing mutation
  • Tigroid pattern
  • White matter disorder

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics
  • Medicine(all)


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