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

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Rare Diseases

Background:

• Prosaposin (PSAP) gene mutations affecting the saposin B (Sap-B) domain can lead to a rare variant of metachromatic leukodystrophy (MLD).
• This MLD variant is characterized by normal arylsulfatase A (ARSA) activity, distinguishing it from other forms of MLD.
• Only 10 PSAP mutations have been previously identified in 18 MLD patients globally.

Observation:

• A family of Moroccan origin presented with a proband exhibiting late-infantile onset neurological symptoms and a characteristic tigroid MLD pattern on brain MRI.
• The proband displayed normal ARSA activity but an abnormal urinary sulfatide excretion pattern.
• Genetic analysis revealed a novel homozygous c.909 + 1G > A mutation in the PSAP gene, affecting the intron 8 splice donor site.

Findings:

• The identified PSAP mutation resulted in the skipping of exon 8, leading to the deletion of amino acids p.Gln260_Lys303, including critical cysteine residues.
• Reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed the exon-skipping event.
• This molecular finding explains the Sap-B deficiency and the resulting MLD phenotype in the affected family members.

Implications:

• This study expands the spectrum of known PSAP mutations associated with Sap-B deficiency MLD.
• It underscores the wide variability in clinical presentation (age of onset, symptom severity) of this rare MLD variant.
• Increased awareness of this MLD subtype is crucial for accurate diagnosis, timely genetic counseling, and enabling prenatal diagnosis for affected families.