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Page 88 Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58

The available therapies for AM include enzyme replacement therapies (ERT) and hematopoietic stem cell
transplantation (HSCT), although the latter may prove to be more effective when administered at a younger
[12]
age before the disease has significantly progressed . Therefore, the potential new therapies for this
condition may therefore be developed in the context of the patient’s clinical symptoms consequent to
secondary mitochondrial dysfunction. This review aims to discuss the theorized mechanisms of secondary
mitochondrial dysfunction in AM, and the potential neurocognitive repercussions of this defect, as well as
the potential therapies for AM in the context of its clinical manifestations.

CLINICAL MANIFESTATIONS OF ALPHA-MANNOSIDOSIS
The presentation of AM is highly diverse and features a wide range of clinical manifestations such as
cognitive impairment, skeletal abnormalities, immunodeficiency, hearing impairment, and coarse facial
[13]
features [Figure 1]. The majority of individuals affected with AM appear to be clinically normal at birth,
and start to present at a young age, with their symptoms gradually worsening over time . The disease
[5]
phenotypic presentation also ranges from mild to severe and there are no distinct clinical phenotypes of the
disease due to its wide heterogeneity.

Primary CNS disease is expected in these patients, with neurological symptomatology including poor
coordination, ataxic gait, metabolic myopathy, spastic paraplegia spasticity, rigidity, dyskinesia, slight
strabismus, hydrocephalus, and sensorineural deafness . It is also common for patients to experience
[14]
psychiatric symptoms that predominantly present from puberty into adolescence. These CNS-related
symptoms observed in AM will be discussed in more detail.

Ataxia
Ataxia is the most characteristic clinical manifestation of AM. It describes the impaired coordination of the
patient, stemming partially from cerebellar atrophy and demyelination of the brain , thus affecting areas
[15]
that are responsible for muscular coordination and fine motor function. Ataxia has been described as
predominantly presenting in the second decade of life , but can also present in smaller children, generally
[16]
when they learn to walk, in which affected children appear to learn to walk somewhat later . Initial signs
[17]
include general clumsiness and ataxic gait, with these symptoms often appearing to worsen progressively in
follow-up observations as the patient ages. The cause of the ataxia is multifactorial, with myopathy, joint
involvement, and cerebellar changes being the main contributors . Patients require support while walking
[18]
and gradually become dependent on walking aids. Moreover, their coordination is compromised,
significantly impacting their quality of life.

Myopathy
Myopathic symptoms describe the development of muscular weakness in affected patients, as well as
stiffness, cramps, and spasms. In patients with AM, the progression of myopathies contributes toward their
progressing ataxia. It has been shown that the muscular strength of AM patients slowly deteriorates during
the first decade of life and thereafter . Therefore, their motor function was gradually impaired as they
[17]
aged, and their ataxic manifestations worsened. Muscular hypotonia is also common, as well as spastic
paraplegia , which are consequences of the slow progression of muscle fiber degeneration. The data on
[19]
muscle pathology in AM are limited, but we have learned that vacuoles that can be found in the muscle cells
are identical to those observed in lymphocytes and other cells. They contribute to muscle fiber pathology .
[19]
Reticulofibrillar material or lucent space with sparse granules has been described in muscle tissue from
pediatric AM cases ; these changes were not convincing for the authors to be able to explain the muscle
[20]
weakness. The authors did not comment on mitochondrial changes.