Symptoms and red flags

Hearing loss (bone and conductive) is seen in all patients affected by Alpha-Mannosidosis: the impaired hearing is predominantly due to sensorineural damage, but because it may result also from early ear infections it represents a mixture of conductive and neurosensory components.¹

Hearing loss is an important and early manifestation of Alpha-Mannosidosis: especially when associated with learning or cognitive difficulties, with or without dysmorphic features, it should raise a possible diagnosis of lysosomal storage disorder, in particular Alpha-Mannosidosis, as suggested by Lehalle and colleagues in 2019.²

The authors reported cases of 7 patients referred to clinical geneticists for syndromic hearing loss and moderate cognitive impairment that were diagnosed with Alpha-Mannosidosis.²

The findings of this study emphasized that the clinical diagnosis of Alpha-Mannosidosis can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.²

Among other symptoms, in Alpha-Mannosidosis patients the first decade of life is characterised by frequent recurrent infections, especially:²

• upper airway infections;
• pulmonary infections;
• acute/serous otitis media infections.

The number of infections diminishes in the second and third decades, when ataxia, reduced balance and gait distance, facial coarsening and muscular weakness become more prominent clinical findings.²

In a quantitative analysis, 111 patients were idenified and the relative frequency of respiratory tract infections in the total study population with Alpha-Mannosidosis was assessed at 53,1%.³

Cognitive impairment is one of the most common manifestations of Alpha-Mannosidosis.¹

As soon as the age of the patients makes intelligence quotient (IQ) measurements feasible, almost all patients show some degree of mental retardation.² Alpha-Mannosidosis patients show rapid decline in cognitive function during the first two decades of life.³

In a study of clinical course of mannosidosis performed in 8 patients (age at onset of symptoms 6 months-3 years), the first symptom was usually delayed development of speech or motor or mental functions and was often accompanied by recurrent infections.⁴

Regarding speech disabilities, some patients are mute, other speaks monosyllables or bi-syllables and other have a fair speech though not age-appropriate.⁵

In a 2015 study, authors showed that intellectual disability is a consistent finding in patients with alpha-mannosidosis but with extensive variation: in a cohort of 35 patients aged 6-35 years the IQ ranged 30-81.⁶

Moreover, Alpha-Mannosidosis is associated with an increased risk of psychiatric symptoms, affecting 25% of patients: first onset is often in late puberty to early adolescence.⁵ The episodes are mostly of limited duration, lasting 3-12 weeks, and may be recurrent. The symptoms are often:⁵

• confusion;
• hallucinations;
• anxiety;
• depression.

Alpha Mannosidosis is characterized by a severe immunodeficiency, the patients being prone to various bacterial, mycobacterial, and viral infections.¹

In Alpha-Mannosidosis, there are increased levels of oligosaccharides in plasma.
Oligomannosides with five and six mannose residues bind to interleukin-2 (IL-2) receptors, which can activates T-, B-, and NK cells, disturbing the IL-2-dependent responses. It can therefore be speculated that blockage of this receptor is the mechanism causing the immune deficiency seen in mannosidosis.²

Evidence of reduced phagocytosis and impaired leukocyte chemotaxis has also been found in alpha-mannosidosis patients.²

Bone anomalies are one of the most common manifestations of Alpha-Mannosidosis.^1,2

In Alpha-Mannosidosis patients, 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.³

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.³

The most frequent abnormalities are scoliosis and deformation of the sternum.⁴ Over time, from the second till the fourth decade of life patients may develop destructive polyarthropathy, especially coxarthrosis but also gonarthrosis which are often so serious that orthopedic corrections are needed. Patellar bilateral dislocation and severe synovial hypertrophy have also been described along with Charcot elbow and bilateral hip and elbow avascular necrosis.⁴

In a multicenter, multinational prospective study, the musculoskeletal area showed typical abnormal findings for this disease such as macrocephaly, contractures, scoliosis, genua valga, hip dysplasia and deformities of feet. In the younger age group (patients < 18 years) 62% of the patients had abnormal findings for this body area. In the older patients pathological signs and symptoms of the musculoskeletal system were observed at an even higher rate than in the younger age group: in this population 92% of the patients had abnormal findings for this body area at baseline. After two years 94% of adult patients had abnormal findings.²