Kofler J, Beltran-Quintero ML, Rugari A, et al. Improved Brain Pathology and Progressive Peripheral Neuropathy in a 15-Year-Old Survivor of Infantile Krabbe Disease Treated With Umbilical Cord Transplantation. Front Mol Neurosci. 2022;15:888231.
Hematopoietic stem cell transplantation (HSCT), most commonly in the form of umbilical cord blood transplantation (UCBT), is currently the only available treatment option that has shown to have a positive impact and alter the disease course by improving lifespan and functional abilities of those affected by Krabbe disease. To be effective, HSCT must be performed when only mild clinical symptoms are present, typically before 30-days of life. The parents of two patients with infantile Krabbe disease agreed to autopsy and tissue donation to the University of Pittsburgh Neurodevelopment in Rare Disorders (NDRD) Brain and Tissue Bank. This study is the first study to show that UBCT was able to make a difference in the natural course of the disease in the central nervous system (CNS) but less so in the peripheral nervous system (PNS).
Summary and Important Findings
- The first patient was a male diagnosed at 9 months of age following several months of progressive clinical symptoms and signs, starting at 6 months of age with changes in muscle tone and stiffness in his lower extremities. At 7 months, he lost his ability to hold his head up and to reach for objects. He was not considered a candidate for UBCT and passed away at age 7.
- In comparison, patient 2 was a female who was diagnosed with infantile Krabbe disease as a newborn due to family history in an older sibling who died from disease progression at 12 months of age. She was treated with a UBCT by one month of age. She eventually died at 15 years of age due to respiratory depression and cardiac arrest, and severe scoliosis.
- These findings suggest that long-term engraftment of donor-derived cells into the CNS occurred.
- The brain clearly showed an improvement in myelination but did not reach the levels expected for a normal brain. It is likely that some areas of the brain were already involved before transplant, as confirmed by early MRI findings as no evidence of active demyelination after her transplant was seen in the CNS.
- While areas of the brain showed an increased neuronal loss in the untreated male patient, only subtle changes were present after transplantation in the female.
- Both clinical and brain pathological findings indicate stabilization of CNS disease.
- PNS disease, while still present, resulted in a significant change in disease progression in the long-term transplant survivor.
This is the first evidence looking back that UCBT has beneficial effects in preclinical Krabbe disease by leading to halting progressive demyelination and loss of neurons in the brain. Looking forward, clinical trials combining UCBT with gene therapy have been shown to have a complementary effect with better outcomes than each therapy alone. Early diagnosis and treatment are important considerations for improved outcomes.