Alpha-mannosidosis

Alpha-mannosidosis is a lysosomal storage disorder, first described by Swedish physician Okerman in 1967. In humans it is known to be caused by an autosomal recessive genetic mutation in the gene MAN2B1, located on chromosome 19, affecting the production of the enzyme alpha-D-mannosidase, resulting in its deficiency. Consequently, if both parents are carriers, there will be a 25% chance with each pregnancy that the defective gene from both parents will be inherited, and the child will suffer from the disease. There is a two in three chance that unaffected siblings will be carriers (Figure 1). In livestock alpha-mannosidosis is caused by chronic poisoning with swainsonine from locoweed. Alpha-mannosidosis is a lysosomal storage disorder, first described by Swedish physician Okerman in 1967. In humans it is known to be caused by an autosomal recessive genetic mutation in the gene MAN2B1, located on chromosome 19, affecting the production of the enzyme alpha-D-mannosidase, resulting in its deficiency. Consequently, if both parents are carriers, there will be a 25% chance with each pregnancy that the defective gene from both parents will be inherited, and the child will suffer from the disease. There is a two in three chance that unaffected siblings will be carriers (Figure 1). In livestock alpha-mannosidosis is caused by chronic poisoning with swainsonine from locoweed. Alpha-mannosidosis is a lifelong multi-systemic progressive disease, with neuromuscular and skeletal deterioration over decades. The timing of the appearance of symptoms correlates with the severity of the disease. The onset of the most severe form of the disease occurs within the first months of life and involves skeletal abnormalities and intellectual disability, with rapid progression leading to death from primary central nervous system involvement or myopathy. However, most neonates with lysosomal storage disorders are asymptomatic and only rarely severely affected. This delays diagnosis, particularly as milder forms of the disease involve only mild to moderate intellectual disability, which progresses gradually during childhood or adolescence. The first decade of life is characterised by the development of hearing impairment, psychomotor delay, recurrent infections, especially upper airway infections, pulmonary infections and acute/serous otitis media infections. Significant changes in a number of facial features may occur, such as: protruding forehead; flattened nasal bridge; small nose; wide mouth; and widely spaced teeth. Muscular weakness or spinal abnormalities can occur due to the build-up of storage materials in the muscle. A defective alpha-mannosidase enzyme, which normally helps to break down complex sugars derived from glycoproteins in the lysosome, causes progressive lysosomal accumulation of mannose-rich oligosaccharides in all tissues, resulting in impaired cellular function and apoptosis (Figure 2). Complete absence of functionality in this enzyme leads to death during early childhood due to deterioration of the central nervous system. Enzymes with low residual activity lead to a milder form of the disease, with symptoms such as impaired hearing, cognitive impairment, susceptibility to bacterial infections, and skeletal deformities. The course of the disease is progressive. Depending on the severity of the disease, alpha-mannosidosis has been classified into three proposed subtypes, based on severity and age of onset. However, given the variety of mutations that have been documented, and the broad range and severity of symptoms, the disease is considered clinically as a continuum. Alpha Mannosidosis is a progressive disorder, and its presence should be suspected in patients with cognitive disabilities, skeletal changes (e.g. swollen joints, curved spine), hearing loss and recurrent infections. Although children with the condition are often born seemingly normal, their condition deteriorates with age. Alpha-mannosidosis can impact on a patient's quality of life in many ways, including their ability to live independently, socialise or find employment. Generally, phenotypes of alpha-mannosidosis patients are not clearly distinguishable, which makes a prediction of the clinical course for an individual patient challenging. Patients may present to doctors, nurses or health visitors at different stages of progression, and with different ad hoc symptoms, making the link to suspect a diagnosis of alpha-mannosidosis difficult. The main symptoms can also be shared with those of other lysosomal storage disorders, such as mucopolysaccharidosis. Given the progressive nature of the disease, the earlier a correct diagnosis is achieved the better. The condition is often diagnosed and treated using a multi-disciplinary approach, involving paediatricians, orthopaedics, ophthalmologists, otologists, neurologists, immunologists, neurosurgeons and physiotherapists.