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Page 94 Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58

Table 2. A summary description of neurodegenerative mechanisms in Alpha-Mannosidosis
Lysosomal Clinical manifestation of
storage neurodegenerative dysfunction in Pathomechanism of CNS involvement Reference
disorder humans
Alpha- Cerebellar dysfunction, developmental delay, Sural nerve biopsies showed neuropathy with myelin [27]
Mannosidosis absent tendon reflexes, spasticity, degeneration and metachromatic deposits [111]
developmental delay, impaired speech, hearing CNS pathology of reduced myelination with elevated mannose [112]
impairment, psychosis, cognitive impairment complexes and gliosis, increased CSF-oligosaccharides. [18]
Impaired visual function, reasoning, visuo- Significant elevations in Cho/Cr and ml/Cr reflect reduced [113]
spatial skills, memory, and attention myelination and gliosis. Raised NFLp concentrations due to [114]
axonal injury, degeneration, and myelin loss
Iron deposits at the basal ganglia
Dilated endoplasmic reticulum, increased levels of aberrant
mitochondria with reduced mitochondrial mass; oxidative stress
with increased ROS
CNS: Central nervous system; CSF-oligosaccharides: cerebrospinal fluid- oligosaccharides; ROS: reactive oxygen species; Cho/Cr:
choline/creatine ratio; ml/Cr: myo-inositol/creatine; NFLp: neurofilament light polypeptide.

of neurodevelopmental delay, by Mynarek , which is also the largest retrospective analysis of HSCT
[119]
treatment in patients with AM. It was reported that the mortality and morbidity of patients were improved,
in addition to developmental improvement observed in all patients. Some patients also displayed improved
hearing ability and preservation of neurocognitive function.

These improvements in neurological function post-HSCT are likely due to the ability of HSCT to cross the
blood-brain barrier (BBB) . However, HSCT treatment is considered to predict better clinical outcomes
[13]
when administered at an earlier age . Nevertheless, this does not necessarily result in the prevention of
[12]
psychosis during adulthood, as this is more likely to develop with age, but there have been reports of
altering the course of the rapid neurological disease progression in infantile Globoid Cell Leukodystrophy
[119]
(GLD) , which may be applied to AM. Despite these reports, there is no evidence to suggest that HSCT
has any significant long-term effects on the outcomes of patient neurological function and psychiatric state
post-treatment and its effects on their long-term development, nor are there many studies using an adult
cohort. It is, therefore, prudent that further study should be carried out into the long-term HSCT in patients
with AM during adulthood, as this is when psychosis and neurological dysfunction are most likely to
develop.

ERT is the most commonly used therapy in the treatment of LSDs. ERT is specifically used in the long-term
treatment of adults, adolescents, and children with mild to moderate AM disease using velmanase alfa (VA),
also known as Lamzede, which is known to not cross the BBB, similar to all other recombinant lysosomal
enzymes used in ERT . There are studies of ERT using VA in the treatment of AM, with many reports of
[118]
improved clinical symptoms and quality of life post-treatment due to the reduction in mannose-rich
oligosaccharide levels in bodily tissues, thereby altering disease progression and abating clinical
complications. There have been reports of reduction in pain and disability in AM patients post-ERT , as
[120]
well as patients showing improved scores in motor proficiency and increased skill acquisition in comparison
[121]
to healthy peers after receiving ERT therapy . This may potentially improve the psychiatry of patients by
positively influencing their behavior as a consequence of their pain improvement. Treatment with VA has
shown clinical benefit that was maintained for up to 4 years in patients with AM . This long-term follow-
[122]
up is specifically important in relation to neurocognitive decline, in which there is a need for the
involvement of a neuropsychiatrist, neurologist, and neuropsychologist. However, the limitation of these
studies discussed is the lack of investigation into evidence of neurocognitive improvement post-ERT, with
the outcomes of these trials focusing mainly on the effects on mobility, ataxia, and respiratory dysfunction.
This is because, unlike HSCT, ERT does not cross the BBB and instead targets the periphery and soft
[12]