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Dewsbury et al. J Transl Genet Genom 2024;8:85-101 https://dx.doi.org/10.20517/jtgg.2023.58 Page 89

To that end, myopathic changes resulting from secondary mitochondrial dysfunction have been observed in
[7]
muscle biopsies from adults with Fabry and Pompe diseases . We can therefore presume that this
mechanism is present in untreated adult patients with AM as well.

Neurocognitive dysfunction
Neurocognitive impairment is observed in almost all AM patients, with varying severity amongst the
different symptoms, although their early psychomotor development may appear normal. It has been
[21]
suggested that intellectual disability is slowly progressing in AM patients , whereas others have reported
that disease progression halts during puberty in these individuals . Characteristic symptoms that may
[22]
begin to appear first include delayed speech development and motor or mental functions . Affected
[5]
individuals may not initiate speech until their second decade of life and may also have a restricted
vocabulary and may be difficult to understand due to their poor pronunciation. These defects in speech may
[5]
potentially be the result of the patients’ congenital or later-onset hearing loss . This combination of poorly
developed speech and sensorineural hearing loss means that patients generally achieve better scores in non-
verbal tests. However, it is very difficult to measure total mental performance in these patients, particularly
children, where they undergo neurodevelopmental assessment in general intelligence, language, and visual-
spatial skills, as well as their overall adaptive abilities. Conversely, patients with adult-onset disease are
predominantly mild to moderately intellectually disabled, with an IQ of 60-80 . It has been shown that this
[23]
[24]
decline in IQ occurs more drastically in the first decade of life in comparison to the second decade and
depends on the severity of the disease. Although other studies report positive cognitive development until
the ages of 10 to 12 years, there is little development thereafter . Despite this, patients with AM still present
[17]
with a neurocognitive function that is increasingly underdeveloped compared to other non-affected
individuals within the same age group. Behavioral problems, self-harm, emotional instability, and
frustration due to inability to communicate are common features observed in adults with AM (personal
observations).

Psychosis
Signs of psychiatric disorder tend to appear in the second decade of life in patients with AM , usually from
[13]
late puberty to early adolescence. However, these psychiatric symptoms can often be missed or overlooked,
particularly in patients with AM who are intellectually disabled. It has been reported that psychiatric
[25]
symptoms and episodes of psychosis are present in more than 25% of adults affected with AM . Despite
efforts to evaluate the psychiatric syndromes in these patients, this study did not reveal that there was an
underlying cause. Another study has described that periods of psychosis become more pronounced with
age, rising from 33% in patients aged 11 to 20 years, up to 64% amongst patients aged 21 to 30 years .
[17]
These episodes may be recurrent and short in duration, usually lasting 3 to 12 weeks, but medication may
sometimes be necessary to improve the patients’ symptoms. Psychosis in affected individuals may be
preceded by a psychological stressor, inducing states of anxiety, confusion, delusions, hallucinations, and
sometimes depression which precipitates a severe loss of function, such as decreased appetite and weight
loss, or incontinence of both urine and feces . These episodes may then be followed by a longer period of
[5]
hypersomnia, as well as diminishment in their general ability, such as being unable to read or having
difficulty speaking. When assessing individuals with inborn errors of metabolism (IEMs) such as AM,
clinicians should be vigilant in recognizing atypical psychiatric symptoms due to targeted treatments
generally being more effective in the early stages of psychosis, before irreversible neurological damage has
occurred . Importantly, the neurocognitive dysfunction and resulting psychosis occur in adulthood
[25]
irrespective of any ERT, which does not cross the blood-brain barrier, or HSCT, which patients often
undergo in childhood .
[26]