Clinical Description
The clinical phenotype of alpha-mannosidosis varies considerably with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [Malm & Nilssen 2008]. Most individuals described fit into the moderate type.
Mild form. Clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities (type 1)
Moderate form. Clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities (type 2)
Severe form. With obvious progression leading to early death from primary central nervous system involvement or infection (type 3)
Motor function. Affected children learn to walk somewhat later than normal. They are generally clumsy; ataxia is the most characteristic and specific motor disturbance. In addition to joint abnormalities and a metabolic myopathy [Alroy et al 1984], the disease particularly affects those areas of the brain responsible for fine motor function and muscular coordination. Muscular hypotonia is common. Spastic paraplegia has also been described [Kawai et al 1985], but in general, spasticity, rigidity, and dyskinesia are not observed. Follow-up observations have also suggested progressive impairment of motor function with age [Autio et al 1982]. A longitudinal clinical study on a brother and sister indicated no progression over a period of 25 years [Ara et al 1999]. However, as their basic neuropsychological impairment was described as severe, progression would be difficult to detect.
Intellectual disability. Early psychomotor development may appear normal, but intellectual disability occurs in all individuals. Individuals with adult-onset disease are usually mildly or moderately intellectually disabled with an IQ of 60-80 [Aylsworth et al 1976, Bach et al 1978]. The measurement of total mental performance is very complex, and individuals tend to score better in nonverbal tests. Individuals are late in initiating speech (sometimes as late as the second decade) and have restricted vocabulary and difficult-to-understand pronunciation – possibly the results of congenital and/or later-onset hearing loss.
Most affected individuals described have been children; therefore, information on the natural course of alpha-mannosidosis is based on a limited number of observations. Some investigators suggest that intellectual disability progresses slowly [Autio et al 1982]; others suggest that disease progression ceases after puberty [Yunis et al 1976]. In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [Noll et al 1989]. In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [Ara et al 1999].
Psychiatric symptoms distinct from the intellectual disability may affect 25% or more of persons with alpha-mannosidosis. Onset is typically from late puberty to early adolescence. Episodes may be recurrent and of limited duration; medication may be necessary to alleviate symptoms.
In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [Malm et al 2005]. In four of the nine individuals, evaluation of the psychiatric syndrome did not reveal an underlying organic cause.
Neuroimaging. Brain MRI including sagittal T1 and axial T2 sections reveals a partially empty sella turcica, cerebellar atrophy, and white matter signal modifications. Progressive cortico-subcortical atrophy, especially in the cerebellar vermis, has been described [Ara et al 1999]. High signal abnormalities involving the parieto-occipital white matter are identified on axial T2-weighted scans in some individuals and are probably related to demyelination and associated gliosis as described by Dietemann et al [1990].
Hearing loss. Most individuals appear to have early-childhood-onset non-progressive hearing loss. In many if not most individuals, the hearing loss is partly conductive and partly sensorineural [Autio et al 1982]. Individuals typically experience early ear infections with fluid in the middle ear, probably the result of immunodeficiency and bony abnormalities of the skull leading to closure of the eustachian tubes. If untreated in early childhood, reduced hearing contributes to disturbances in speech and mental function.
Facial features. Independent of family and ethnicity, individuals have typical Hurler-like facies (see Mucopolysaccharidosis Type 1) or coarse facial features, macrocephaly with a prominent forehead, highly arched eyebrows, depressed nasal bridge, widely spaced teeth, macroglossia, and prognathism. The features can also be so subtle that they may be overlooked by an inexperienced observer.
Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis. Clinical or radiographic evidence of mild-to-moderate dysostosis multiplex occurs in 90% of individuals diagnosed with alpha-mannosidosis [Chester et al 1982]; intrafamilial variation is considerable. Conventional radiographs (x-rays) may reveal thickened calvaria; ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; hypoplasia of the inferior portions of the ilia; and mild expansion of the short tubular bones of the hands.
Knock-knee is common and contributes to the gait disturbance.
The skeletal abnormalities may decrease with age [Spranger et al 1976].
Cranial MRI, including sagittal T1 and axial T2 sections, demonstrates several skeletal abnormalities including brachycephaly, thick calvarium, and poor pneumatization of the sphenoid body [Dietemann et al 1990].
Immunodeficiency. Individuals with alpha-mannosidosis have frequent infections. Malm et al [2000] compared humoral and cellular immunocompetence in six affected individuals to that of six healthy controls. They determined that individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation. Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. In addition, leukocytes have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.
Hepatosplenomegaly. The liver and spleen are often enlarged, especially in more severely affected individuals; however, this has no clinical significance. Liver function is normal. Liver biopsy reveals the same vacuoles in hepatocytes as described in several hematologic cell lines.
Ocular features. Hyperopia, myopia, or slight strabismus is common. Lenticular changes, superficial corneal opacities [Bach et al 1978], and blurred discs [Kjellman et al 1969] have been reported. Most of these ophthalmologic findings can be remedied (see Management).
Other
Cardiac and renal complications are rarely observed; however, aortic regurgitation may be more common in individuals with alpha-mannosidosis.
Systemic lupus erythematosus has been frequently observed in individuals with alpha-mannosidosis.
Natural course of the disease. The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial.
The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described [Kawai et al 1985, unpublished personal data].
Pathophysiology. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack or deficiency of a hydrolase, such as lysosomal alpha-mannosidase, results in the multisystemic accumulation of undigested oligosaccharides in the lysosomes. However, the pathophysiology of lysosomal storage disorders is complex, and accumulation of storage material alone cannot fully explain disease mechanisms.