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Page 86 Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58

targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic
modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic
severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to
discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the
improvement of neurocognitive symptoms in affected AM individuals.

Keywords: Lysosomal storage disorders, Alpha-Mannosidosis, neurocognitive dysfunction, secondary
mitochondrial dysfunction, oxidative stress, synaptic defects, psychosis, neurological complications

INTRODUCTION
Lysosomal storage disorders (LSDs) are a subgroup of metabolic disorders that can be characterized by a
range of deficiencies of different components within lysosomal function. Specific LSDs themselves are
individually rare, but collectively are one of the most prevalent groups of metabolic diseases and have been
[1]
estimated to affect approximately 1 in 5,000 live births . These inherited diseases stem from lysosomal gene
defects, resulting in deficient or dysfunctional lysosomal enzymes, activator proteins, or transmembrane
[2]
proteins . This leads to the unwanted accumulation of biomolecules within the lysosome. This excess
storage of macromolecules is thought to start during the stages of early embryonic development, but the
clinical presentation of LSDs is highly variable, ranging from mild to severe phenotypes that may have
[3]
either early or late onset . It is the accumulation of undigested biomolecules within the lysosome that
causes disruption to normal cellular function, resulting in the symptomatic presentation of LSDs, including
neurocognitive impairment, worsening developmental delay, and abnormal neurological symptoms.

The involvement of the Central Nervous System (CNS) within this group of disorders is highly prevalent
and these neurological symptoms most commonly have a slow and subtle progression. This is observed in
the autosomal recessive LSDs such as Alpha-Mannosidosis (AM). The condition is a highly rare, progressive
[4]
LSD that is estimated to affect 1:250,000 to 1:1,000,000 live births . AM is caused by a deficiency in
lysosomal alpha-mannosidase enzyme activity, consequent of mutations present in the MAN2B1 gene on
chromosome 19 (19p13.13) . This deficiency of alpha-mannosidase activity affects the degradation of
[5]
glycoproteins, resulting in the accumulation of intracellular mannose-rich oligosaccharides in various
tissues and organs, thus leading to defective cellular functions and apoptotic mechanisms . AM is an
[5]
abundantly heterogeneous condition that is defined by a wide variety of presentations regarding disease
severity and progression, clinical manifestations, and genetic mutations.

There are currently 183 different disease-causing pathogenic variants of the MAN2B1 gene that have been
[6]
identified . However, AM is a highly heterogeneous condition with no clearly defined genotype-phenotype
correlation , and despite having distinguished clinical subtypes , it is difficult to predict disease
[7]
[5]
progression in patients with AM. Three clinical subtypes have been reported: a mild form (type 1)
recognized after 10 years of age with the absence of skeletal abnormalities, myopathy, and slow progression
[Figure 1], a moderate form (type 2) recognized before 10 years of age with the presence of skeletal
abnormalities, myopathy, and slow progression, and a severe form (type 3) manifested as prenatal loss or
[5]
early death from progressive CNS involvement or infection . However, the disease manifestations of AM
display a continuum of clinical severity; therefore, this classification into three phenotypic subtypes is now
[8]
rarely used .
It has been hypothesized that secondary mitochondrial dysfunction may contribute to the progression of
neurological symptoms of AM, such as myopathy, white matter changes [Figure 2], psychosis, or seizures.