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
Open Access
- 24 March 2009
- journal article
- case report
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 149A (4), 613-621
- https://doi.org/10.1002/ajmg.a.32712
Abstract
Prosaposin deficiency (pSap‐d) and saposin B deficiency (SapB‐d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for the 65–70 kDa prosaposin protein, which is the precursor for four sphingolipid activator proteins, saposins A–D. We report on two new patients with PSAP gene defects; one, with pSap‐d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB‐d, who presented with a metachromatic leukodystrophy‐like disorder but had normal arylsulfatase activity. Screening for urinary sphingolipids was crucial to the diagnosis of both patients, with electrospray ionization tandem mass spectrometry also providing quantification. The pSap‐d patient is the first case with this condition where urinary sphingolipids have been investigated. Multiple sphingolipids were elevated, with globotriaosylceramide showing the greatest increase. Both patients had novel mutations in the PSAP gene. The pSap‐d patient was homozygous for a splice‐acceptor site mutation two bases upstream of exon 10. This mutation led to a premature stop codon and yielded low levels of transcript. The SapB‐d patient was a compound heterozygote with a splice‐acceptor site variant exclusively affecting the SapB domain on one allele, and a 2 bp deletion leading to a null, that is, pSap‐d mutation, on the other allele. Phenotypically, pSap‐d is a relatively uniform disease of the neonate, whereas SapB‐d is heterogeneous with a spectrum similar to that in metachromatic leukodystrophy. The possible existence of genotypes and phenotypes intermediate between those of pSap‐d and the single saposin deficiencies is speculated.Keywords
This publication has 27 references indexed in Scilit:
- Non‐neuronopathic Gaucher disease due to saposin C deficiencyClinical Genetics, 2007
- Prosaposin Deficiency - a Rarely Diagnosed, Rapidly Progressing, Neonatal Neurovisceral Lipid Storage Disease. Report of a Further PatientNeuropediatrics, 2005
- A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activityHuman Genetics, 2005
- Urinary Lipid Profiling for the Identification of Fabry Hemizygotes and HeterozygotesClinical Chemistry, 2005
- 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 mouseHuman Molecular Genetics, 2004
- Shotgun lipidomics: Electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samplesMass Spectrometry Reviews, 2004
- Sphingolipid activator protein 1 deficiency in metachromatic leucodystrophy with normal arylsulphatase A activity. A clinical, morphological, biochemical and immunological studyEuropean Journal of Pediatrics, 1991
- Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidosesEuropean Journal of Pediatrics, 1989
- Clinical, pathological, and biochemical studies on an infantile case of sulfatide/GM1 activator protein deficiencyAmerican Journal of Medical Genetics, 1989
- A variant form of metachromatic leukodystrophy without arylsulfatase deficiencyAnnals of Neurology, 1982