Cerebral Magnetic Resonance Spectroscopy Demonstrates Long-Term Effect of Bone Marrow Transplantation in α-Mannosidosis

Abstract

a-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic a-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannosecontaining oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.

Alpha‐mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function

“…We found elevated concentrations of T‐tau, GFAp and NFLp in the majority of our patients, even in the youngest part of our cohort. Elevated concentrations of CSF GFAp are consistent with our MRS results, demonstrating significant elevation of mI/Cr in WM, reflecting gliosis . GFAp is known to be increased in neurodegenerative diseases and increased concentrations reflect astrocytic activation and gliosis.…”

“…MRS has been suggested as a monitoring tool for the effect of BMT in AM . We demonstrated a broad peak between 3.5 and 3.9 ppm in the MR spectrum reflecting mannose complexes in GM, WM and CSO in the majority of the patients.…”

“…These 10 patients were the one included in our first clinical trial [rhLAMAN‐02 (EudraCT number: 2010‐022084‐36)]. MRI/MRS was performed in accordance to Danielsen et al and Provencher (see Fig. S1, Supplementary Information).…”

“…The understanding of the CNS pathology in human AM is limited to isolated case reports describing histopathology changes (8)(9)(10)(11)(12)(13), MRI findings in humans (14)(15)(16)(17) and in animals (13) and MRS spectra in humans (15,18,19) and animals (20). Only one study has previously reported CSF-biomarkers of neurodegeneration and oligosaccharides in CSF (1).…”

Cognitive profile and activities of daily living: 35 patients with alpha‐mannosidosis

“…Reduced myelination, gliosis and white matter changes have been shown in alpha-mannosidosis patients (Borgwardt et al 2015a;Danielsen et al 2013;Dietemann et al 1990;Gutschalk et al 2004). Additional cerebral atrophy have been described in a few cases, but may only develop at a late stage of the disease in some AM patients or earlier in severely affected patients (Borgwardt et al 2015a;Dietemann et al 1990;Gutschalk et al 2004).…”