Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene

Area of Science:

• Genetics
• Biochemistry
• Neurology

Background:

• Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease often caused by saposin B deficiency.
• The PSAP gene encodes saposins A, B, C, and D, which are essential for lysosomal enzyme activity.
• Previously, only ten pathogenic variants in the PSAP gene were documented in MLD patients.

Observation:

• This study reports two previously undescribed pathogenic variants in the PSAP gene: c.679_681delAAG in exon 6 (saposin B) and c.1268delT in exon 11 (saposin D).
• These variants were identified in a patient diagnosed with MLD.
• The identified variants lead to a PSAP null allele, impacting saposin B function.

Findings:

• The presence of PSAP null alleles can lead to a spectrum of lysosomal storage diseases, including MLD, Gaucher disease (saposin A deficiency), and Krabbe disease (saposin C deficiency), depending on the second allele.
• A patient with two PSAP null alleles exhibits the most severe form of prosaposin deficiency.
• Accurate assessment of variant impact is essential for correct diagnosis and management.

Implications:

• Accurate genetic variant assessment is critical to prevent misdiagnosis or delayed diagnosis in patients with PSAP mutations.
• This research expands the known spectrum of PSAP gene variants associated with MLD and related disorders.
• Understanding genotype-phenotype correlations in PSAP mutations is vital for clinical management and genetic counseling.