A novel homozygous PSAP mutation identified by whole exome sequencing in a consanguineous family with metachromatic leukodystrophy: a case report

December 12, 2024

The article “A novel homozygous PSAP mutation identified by whole exome sequencing in a consanguineous family with metachromatic leukodystrophy: a case report” describes a rare genetic mutation linked to metachromatic leukodystrophy (MLD), a devastating lysosomal storage disorder. Here’s an explanation of the study and its significance:

What is Metachromatic Leukodystrophy (MLD)?

MLD is a genetic disorder affecting the breakdown of certain fats called sulfatides. These fats build up in cells, particularly in the nervous system, leading to progressive damage to the brain’s white matter, motor function loss, and cognitive decline. The disorder is typically associated with mutations in the ARSA gene, but in rare cases, mutations in the PSAP gene—which affects fat metabolism enzymes—can cause similar symptoms.

Why This Study is Important

While most MLD cases are caused by ARSA mutations, this study identifies a novel mutation in the PSAP gene in a Chinese family, expanding our understanding of the genetic causes of MLD. It also highlights the role of the prosaposin protein, encoded by PSAP, in fat metabolism and lysosomal function, which are central to the disease’s pathology.

What Did the Researchers Do?

  1. Case Study Analysis:
    • The researchers studied a 2.5-year-old girl from a consanguineous family who showed classic MLD symptoms, such as motor regression, difficulty walking, muscle stiffness, limb pain, and tremors. Her older brother exhibited similar but more severe symptoms.
    • MRI scans revealed white matter damage in her brain, consistent with MLD.
  2. Genetic Testing:
    • Using whole exome sequencing, they identified a homozygous c.643A>G mutation in the PSAP gene in both the girl and her brother. The mutation was inherited from their unaffected parents, confirming an autosomal recessive inheritance pattern.
  3. Protein and Cellular Studies:
    • Laboratory experiments showed that this mutation did not disrupt the normal localization of the prosaposin protein in lysosomes, but it caused lysosomal dysfunction.
    • The mutation reduced lysosomal pH and decreased the activity of cathepsin D, an enzyme critical for breaking down cellular waste.
    • Transmission electron microscopy revealed damaged and swollen lysosomes in cells carrying the mutation.

Key Findings

  1. Unique Mutation:
    • The identified mutation, p.N215D, is novel but occurs at the same site as a previously reported mutation, emphasizing its critical role in prosaposin function.
  2. Lysosomal Dysfunction:
    • The mutation impairs lysosomal activity, leading to inefficient breakdown of fats, which likely contributes to the accumulation of harmful substances seen in MLD.
  3. Broader Implications for Fat Metabolism:
    • The study links PSAP mutations to rare “variant forms” of MLD caused by saposin B deficiency, providing new insights into the molecular mechanisms driving these disorders.

What Does This Mean for Patients?

  • This research highlights the importance of genetic testing for rare MLD variants, especially in families with consanguinity.
  • It also demonstrates that PSAP mutations can mimic classic MLD symptoms, which has implications for diagnosis and treatment development.

Future Directions

  1. Better Understanding of Prosaposin Function:
    • Further studies are needed to explore how PSAP mutations affect other cellular processes beyond lysosomal function.
  2. Therapeutic Exploration:
    • Developing treatments targeting lysosomal health or enhancing cathepsin D activity could offer new therapeutic options for patients with PSAP-related MLD.
  3. Broader Screening:
    • Expanding genetic testing to include PSAP mutations may improve the diagnosis and understanding of variant MLD cases.

Conclusion

This study expands the genetic landscape of MLD by identifying a novel PSAP mutation and linking it to lysosomal dysfunction. It underscores the importance of genetic studies in understanding rare diseases and opens doors for future research into targeted therapies for lysosomal storage disorders.

For more detailed information, you can access the full study here.

*The United Leukodystrophy Foundation is not liable for any inaccuracies or gaps in these overviews , which are offered “as is” without assurances on completeness, accuracy, or timeliness. For verification or detailed information, please consult the original articles directly.
As a leukodystrophy related nonprofit, the ULF provides awareness to scientific literature. Inclusion on our website does not imply endorsement of, or agreement with, the contents by the ULF.