Alpha-mannosidosis is a lysosomal storage disorder that should be highly suspected in individuals presenting with a combination of mental retardation, skeletal abnormalities, hearing loss, and recurrent infections. Often, children with this condition appear normal at birth, making Alpha-mannosidosis Diagnosis crucial as the condition progressively worsens over time. Early diagnosis is especially vital because bone marrow transplantation (BMT) may be a viable therapeutic option. Given that inborn errors of lysosomal metabolism occur in approximately 1 in 5,000 live births, newborn screening has been advocated as a strategy for early diagnosis and timely treatment initiation [18]. Recognizing the subtle onset and varied clinical presentations is key to prompt alpha-mannosidosis diagnosis.
Recognizing the Onset of Symptoms
Initial reports on alpha-mannosidosis indicated that early psychomotor development seems typical, with the disease pathology unfolding gradually [4, 19]. However, it’s important to note that some infants are born with ankle equinus or may develop hydrocephalus within their first year of life, indicating that the disease can manifest earlier than initially thought [17, 20].
Studies in α-mannosidosis animal models, specifically guinea pigs, have revealed significant insights. Even before overt neurological symptoms appear at around two months, neuropathological changes such as neuronal lysosomal vacuolation and reduced myelination in cerebral white matter are already present. This suggests that complex neuropathological changes in α-mannosidosis begin in utero, well before clinical signs become apparent, and a similar disease progression is highly probable in humans affected by this disorder [21]. Therefore, a high index of suspicion and careful monitoring are essential for early alpha-mannosidosis diagnosis, even in seemingly asymptomatic newborns who may be at risk due to family history or subtle initial signs.
Characteristic Facial Features as Diagnostic Clues
While facial features in alpha-mannosidosis can be subtle, a degree of coarse Hurler-like facial characteristics is consistently observed across all patients, irrespective of their race or genetic background. These features are important indicators for alpha-mannosidosis diagnosis. The classic presentation includes a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia (enlarged tongue), widely spaced teeth, and prognathism (protruding jaw). Additionally, patients often have a short neck (Fig 1). Recognizing these facial traits can be a crucial step in prompting further investigation and confirming an alpha-mannosidosis diagnosis.
Figure 1
Facial features in alpha-mannosidosis. A. Twins aged 18 Months displaying characteristic features like enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. B. Same twins aged 8 years noting slight muscular atrophy of the hands. C. Boy, aged 27 with a hearing aid visible.
Skeletal Abnormalities: A Key Component in Alpha-Mannosidosis Diagnosis
Skeletal abnormalities are highly prevalent in alpha-mannosidosis, with approximately 90% of patients exhibiting clinical or radiographic signs of mild to moderate dysostosis multiplex, according to Chester (1982) [14]. Scoliosis and sternum deformation are among the most frequently observed skeletal issues [22] (Fig 2), and these changes can be present from birth. Genu valgus (knock-knee) is also common and, similar to Gaucher disease, may require surgical intervention like epiphyseal arthrodesis at a young age to correct the deformity before the knee epiphyseal line closes [23].
Over time, typically from the second to fourth decade of life, patients may develop destructive polyarthropathy, particularly coxarthrosis (hip osteoarthritis) (Fig 3) and gonarthrosis (knee osteoarthritis) [24, 25]. These joint issues can become severe enough to necessitate orthopedic corrections [26]. Additional skeletal complications reported include patellar bilateral dislocation, severe synovial hypertrophy, Charcot elbow, and bilateral hip and elbow avascular necrosis in a single patient [27]. The presence of these skeletal abnormalities, particularly in conjunction with other suggestive symptoms, strongly supports the need for further investigation towards alpha-mannosidosis diagnosis.
Figure 2
Radiography of kyphoscoliosis in alpha-mannosidosis before and after orthopedic correction. A. Kyphoscoliosis with skeletal abnormalities evident across all vertebrae. B. Post-orthopedic correction of kyphosis.
Figure 3
Coxarthrosis in alpha-mannosidosis. A. Coxarthrosis evident at 8 years of age. B. Progression of coxarthrosis at age 13 showing increased joint damage.
Hearing Impairment: A Common Finding in Alpha-Mannosidosis
Moderate to severe sensorineural hearing loss appears to be an almost inevitable outcome for individuals with alpha-mannosidosis [12, 22, 28, 29]. This hearing deficit is frequently compounded by otitis or fluid accumulation in the middle ear, adding a mechanical component to the existing sensorineural loss [17]. Therefore, evaluating hearing function is crucial in the diagnostic process, and hearing loss should be considered a significant indicator for alpha-mannosidosis diagnosis, especially when associated with other typical symptoms.
Ocular Changes: Less Common but Noteworthy
While less frequent than other manifestations, certain ocular changes can be associated with alpha-mannosidosis. Slight strabismus (misaligned eyes) is a common finding, and hyperopia (farsightedness) is more prevalent than myopia (nearsightedness) in affected individuals [14, 30]. Less commonly reported ocular manifestations include blurred optic discs [31], superficial corneal opacities, and lenticular changes [4]. While not primary diagnostic indicators, these ocular findings can contribute to the overall clinical picture and support alpha-mannosidosis diagnosis in conjunction with other more prominent symptoms.
Mental Retardation: A Consistent Feature in Alpha-Mannosidosis
Mental retardation is a near-universal finding in alpha-mannosidosis. Once patients reach an age where intelligence quotient (IQ) can be reliably measured, almost all demonstrate some degree of intellectual disability. A clinical study involving eight patients showed symptom onset ranging from 6 months to 3 years of age [10]. The initial presenting symptom was typically delayed development in speech, motor skills, or overall mental function. Across the study group, patients exhibited mild to moderate mental retardation, with IQ scores ranging from 60 to 80, and a tendency for cognitive decline over time. Due to speech difficulties combined with sensorineural hearing loss, patients often perform better on nonverbal cognitive assessments [10].
While some researchers have suggested a stabilization of the disease during puberty [32], most long-term observations indicate a gradual deterioration of mental, motor, and speech abilities with age. Longitudinal studies of affected siblings have shown mild cognitive deficits without significant progressive decline, except in receptive language skills [33]. However, some patients are reported to have profound retardation even at a young age [19, 34]. Notably, there can be considerable variability in cognitive function even among siblings with alpha-mannosidosis [28, 35, 36].
Language development is significantly delayed, with some patients only starting to speak in their second decade. This impaired language development, characterized by limited vocabulary and poor pronunciation, may be attributable to congenital or later-onset hearing loss. Many individuals learn to read but struggle with abstract concepts and comprehension (Malm D: personal observation). The presence of intellectual disability, especially in combination with other described features, is a strong indicator necessitating further investigation for alpha-mannosidosis diagnosis.
Motor Function Disturbances: Progressive Impairment
Motor function development in patients with alpha-mannosidosis is typically slow, and affected children often appear clumsy. This is a result of a combination of factors, including muscle weakness, joint abnormalities, and ataxia stemming from cerebral atrophy and cerebral demyelination [37].
Motor impairment is generally progressive, with a gradual worsening observed in the second and third decades of life [10]. However, similar to mental retardation, there is considerable variability in the clinical progression of motor deficits. Some long-term studies have noted no progression of neurological function in certain patients [28], while other researchers suggest that disease progression may halt after puberty [32]. Further research into the natural course of motor function decline in alpha-mannosidosis is needed. Motor function disturbances contribute to the clinical picture and are important considerations in alpha-mannosidosis diagnosis.
Psychiatric Disease: Often Overlooked Comorbidity
Psychiatric symptoms in intellectually disabled patients can easily be missed or attributed to their underlying cognitive impairment. However, a systematic survey revealed psychiatric symptoms in over 25% of adult patients with mannosidosis [38]. These symptoms typically emerge during adolescence or early adulthood. In mentally retarded patients, psychiatric manifestations are often part of a broader clinical presentation involving systemic, cognitive, or motor neurological signs. Psychiatric symptoms can manifest as acute and recurrent episodes of confusion, sometimes accompanied by anxiety, depression, or hallucinations. These episodes may be associated with functional decline, such as decreased appetite leading to significant weight loss, or incontinence. Periods of psychosis typically last 3 to 12 weeks and are often followed by prolonged hypersomnia and, in some cases, a loss of previously acquired abilities like speech or reading. Investigations into underlying organic causes for these psychiatric episodes have been inconclusive [38]. Given that specific treatments are likely to be most effective in the early stages of the disease, before irreversible neurological damage occurs, clinicians should be vigilant for atypical psychiatric symptoms in patients with suspected inborn errors of metabolism [39]. Recognizing these psychiatric manifestations is important for comprehensive alpha-mannosidosis diagnosis and management.
Immunodeficiency and Autoimmunity: Increased Susceptibility
Patients with mannosidosis are prone to recurrent infections, particularly during the first decade of life. Studies have shown impaired leukocyte chemotaxis and reduced phagocytosis in some patients [9]. A study comparing immunological function in mannosidosis patients to healthy controls revealed lower post-immunization antibody levels in patients, indicating a reduced capacity to produce specific antibodies after antigen exposure. Interestingly, a serum factor present in patient plasma was found to inhibit phagocytosis [40]. Mannosidosis is characterized by elevated levels of oligosaccharides in plasma [41]. Oligomannosides with five and six mannose residues can bind to interleukin-2 (IL-2) receptors, disrupting IL-2-dependent immune responses [42]. Since IL-2 activates T-cells, B-cells, and NK cells, it is hypothesized that blockage of this receptor contributes to the immunodeficiency observed in mannosidosis.
This same mechanism might also contribute to the increased incidence of autoimmune disorders in mannosidosis patients ([13] and Malm D: personal observations). Animal models of alpha-mannosidase II deficiency in mice have shown reduced complex-type N-glycan branching, leading to an autoimmune disease resembling human systemic lupus erythematosus (SLE), including the development of antinuclear antibodies reactive to histone, Sm antigen, and DNA [43]. Recurrent infections and signs of autoimmunity should raise suspicion for alpha-mannosidosis diagnosis, especially in individuals with other suggestive symptoms.
Renal and Cardiac Complications: Rare but Documented
End-stage kidney failure has been reported in a single case, an Italian patient who successfully underwent kidney transplantation [44]. Studies in mannosidosis mice have indicated that enzyme replacement therapy can reduce storage material deposits in the myocardium [45]. While heart murmurs have been noted in some case descriptions, there are currently no documented reports of overt heart disease directly attributed to alpha-mannosidosis. Although renal and cardiac complications are not primary features for alpha-mannosidosis diagnosis, their potential presence should be considered in the comprehensive clinical evaluation and management of affected individuals.
Conclusion: The Importance of Recognizing Key Indicators for Alpha-Mannosidosis Diagnosis
Early and accurate alpha-mannosidosis diagnosis is paramount for effective management and potential therapeutic interventions like bone marrow transplantation. Clinicians should maintain a high level of suspicion for this lysosomal storage disorder in individuals, especially children, presenting with a constellation of symptoms including mental retardation, skeletal abnormalities, hearing loss, and recurrent infections. Characteristic facial features, while subtle, can provide important diagnostic clues. While individual symptoms may vary in severity and presentation, recognizing the common patterns and associated complications is crucial for prompt diagnosis. Continued research and increased awareness are essential to improve early detection rates and optimize outcomes for patients with alpha-mannosidosis.
