Alpha-mannosidosis

Alpha-mannosidosis is a rare genetic neurometabolic disorder caused by deficiency of lysosomal alpha-mannosidase, resulting in impaired degradation and accumulation of mannose-rich oligosaccharides in cells and progressive neurodevelopmental and multisystemic manifestations. It occurs as an inherited autosomal recessive genetic condition; absence of a relevant family history does not exclude the diagnosis because the parents of an affected individual are typically unaffected carriers. A distinctive presentation may include the combination of coarse facial features, intellectual disability, hearing loss, and ataxia.

It can present with psychiatric features such as anxiety, depression, sleep disturbance, behavioural dysregulation, irritability, and psychosis. Neuropsychiatric manifestations typically emerge during late puberty or adolescence, although psychosis appears to be more common in adults and may occur as recurrent episodes, sometimes following a physical or psychological stressor.

From a morphologic lens perspective, features include (but are not limited to):

• Macrocephaly

• Coarse face

• Prominent forehead

• Prognathism

• Depressed nasal bridge

• Large tongue

• Widely spaced teeth

Other characteristic features include developmental delay, intellectual disability, speech impairment, hearing loss, ataxia, hypotonia, muscle weakness or myopathy, communicating hydrocephalus, and, in some individuals, progressive motor impairment. Characteristic physical findings may also include highly arched eyebrows.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: cardiomyopathy, valvular disease, and other cardiac abnormalities may occur, particularly in adults.

• Respiratory: recurrent respiratory infections and pulmonary parenchymal disease may occur; airway and sleep-related respiratory complications may also occur.

• Gastrointestinal: diarrhea, swallowing difficulties, aspiration, and other gastrointestinal dysfunction may occur.

• Hepatobiliary: hepatomegaly and splenomegaly may occur.

• Musculoskeletal: dysostosis multiplex, osteopenia, focal lytic or sclerotic bone lesions, osteonecrosis, joint abnormalities, and progressive myopathy may occur.

Early diagnosis is important to recognize potentially treatable neuropsychiatric manifestations, identify hearing loss and developmental difficulties early, detect and manage progressive skeletal, cardiac, respiratory, and visceral complications, provide appropriate psychiatric, developmental, and educational support, guide enzyme replacement or other disease-specific treatment, and enable genetic counselling and screening of at-risk relatives.