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Page 90 Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58

Psychiatric symptoms distinct from intellectual disability may impact 25% or more of individuals with
untreated AM. Typically, these symptoms manifest from late puberty to early adolescence, with psychosis
[27]
seeming to be a more common feature of adult individuals with AM . Recurrent episodes of limited
duration may occur in these patients, and medication may be required in order to alleviate these symptoms.
In nine individuals with AM and psychiatric symptoms, the rapid onset of confusion, delusions,
[28]
hallucinations, anxiety, and depression occurred following a physical or psychological stressor . This led to
a significant loss of function, typically lasting 3 to 12 weeks, followed by a subsequent period of somnolence,
[28]
asthenia, and prolonged sleep . Among the nine individuals, four underwent evaluation for the psychiatric
syndrome, but no underlying cause was identified .
[28]
Neuroimaging
Brain MRI in untreated individuals with AM reveals evidence of cerebellar atrophy, a partially empty sella
turcica, and white matter signal modifications. Progressive cortico-subcortical atrophy, especially in the
cerebellar vermis, has been described . High signal abnormalities involving the parieto-occipital white
[29]
matter are identified on axial T2-weighted scans in some individuals and may be associated with
demyelination and gliosis as described by Dietemann et al. in 1990 .
[15]

Upon the analysis of MRI brain images of 13 patients with AM, Majovska et al. concluded that white matter
changes and cerebellar atrophy are proposed to be the characteristic brain MRI features in this condition
[Figure 2] .
[30]

Malaquias et al. have observed hyperintensities on symmetrical T2-weighted images or superior aspects of
both thalami and dentate nuclei or cerebellum. However, this research group did not observe cerebellar
atrophy and periventricular white matter hyperintensity on T2-FLAIR sequence was only mild .
[31]

In addition, Borgwardt et al. have demonstrated in a large cohort of 97 patients that the combination of
MRS/MRI changes, elevated concentrations of cerebrospinal fluid (CSF) biomarkers, and CSF-
oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM .
[32]
Leukodystrophy is a feature of other LSDs as well as mitochondrial diseases, and given that secondary
mitochondrial dysfunction and autophagy have been postulated as a cause of lysosomal dysfunction, it is
postulated that they are also responsible for neurodegenerative dysfunction and psychosis in AM [Table 1].

POTENTIAL MECHANISMS OF NEURODEGENERATION IN ALPHA-MANNOSIDOSIS
Current therapies in AM and psychosis
The current therapeutic options for the treatment of AM include ERT with velmanase alfa and allogeneic
HSCT, as well as best supportive care that addresses symptoms as they arise [Table 2]. However, there is still
a lack of studies on the monitoring of treatment response and associated complications outside of clinical
trials and published case reports . HSCT is an effective therapy commonly used in the treatment of several
[115]
metabolic diseases with associated neurological dysfunction. Post-HSCT treatment, the normal donor stem
cells are able to differentiate into different cell lineages, which can colonize a range of organs and tissues.
These differentiated cells have the capacity to secrete the normally functioning enzyme that is otherwise
deficient or dysfunctional in the patient, which is then widely distributed due to cell-to-cell contact amongst
the transplanted cells . This was first tested in the treatment of AM in cat models, in which it was shown
[116]
that HSCT has the ability to significantly increase the levels of alpha-mannosidase within the neuronal cells
of the CNS . There have since been further trials into the effectiveness of HSCT in patients with AM, with
[25]
one study showing that patients who had undergone HSCT had a significantly higher recorded IQ post-