Alpha-mannosidosis (OMIM 248500) is a rare entity belonging to the lysosomal storage disease family.
The disorder is caused by a deficiency in the enzyme alpha-mannosidase. Inheritance is autosomal recessive [1–5]. Prevalence is between 1/500,000 and 1/1,000,000 live births [1, 2, 4, 5, 10], with only 7 cases reported to date in Spain.
The gene responsible for the disease is MAN2B1, for which more than 155 mutations have been identified [1, 3, 6, 10, 14]. MAN2B1 is located at chromosome 19 (19 p13.2- q12) [4, 6, 14]. The correlation between genotype and phenotype is still controversial [3, 6].
For years, allogenic stem cell transplant was the only treatment option. However, since 2018, affected patients in Europe have been able to receive ERT based on human recombinant alpha-mannosidase, which reduces serum oligosaccharide levels, thus increasing catabolism and preventing accumulation in tissue [4, 5, 11, 13]. This approach is indicated for the treatment of non-neurological manifestations—it has not been shown to cross the blood-brain barrier—in patients with mild-to-moderate clinical involvement [11]. Borgwardt et al. [15] also recorded an improvement in cognitive and motor function, with reduced oligosaccharide levels in cerebrospinal fluid, blood, and urine [2, 8, 14].
According to the endpoints evaluated in the clinical development of velmanase alfa, the mean relative change in serum oligosaccharides (S-oligo) in the study arm was − 77.6%. In the case we report, urine oligosaccharide levels were measured at the beginning of the treatment, revealing very high values.
Motor disturbance was evaluated using the 3MSCT and the 6MWT. An improvement in these parameters, especially in children and after long-term treatment with velmanase alfa, has been reported [4, 5, 13, 14]. We did not observe motor disturbance at the beginning of treatment because of the patient’s young age, although the condition stabilized and even slightly improved after 12 months of treatment (Table 1).
Table 1
6-minute walk test (6MWT) and 3-minute stair-climb test (3MSCT) from baseline to the last visit
| Baseline | June 2023 |
6MWT | 343.2 m | 396 m |
3MSTC | 240 steps | 254 steps |
The main symptoms in younger patients are impaired hearing, recurrent otitis, and early language delay (as in the case we report), with wide variability in symptoms, ranging from completely nonverbal patients to patients with clear speech that is inappropriate for their age. Cases of dysarthria have also been reported [1, 3, 6]. Patients rarely exhibit symptoms at birth [1, 3, 7], thus hampering early diagnosis. In the present case, and even though the diagnostic delay was short (3.5 years), it was necessary to monitor symptoms before alpha-mannosidosis was suspected.
Impaired language development is characterized by limited vocabulary, poorly intelligible speech, and inappropriate pronunciation [6], as observed at diagnosis in the present case. After 12 months of ERT, the patient’s language ability had improved considerably, with a much larger vocabulary.
Periodic behavioral abnormalities and the presence of psychiatric symptoms (eg, anxiety, depression, hallucinations, and delirium) have been detected in 70% of patients aged 10 to 30 years) [6, 9]. Given the young age of the patient, psychiatric symptoms were not present, although we did detect behavioral deficiencies that were reversed after 12 months of treatment. The patient showed signs of global developmental behavioral disorder (eg, an intermittent inappropriate response to her name, poor interaction in play and social contact, and episodes of inappropriate irritability), although these improved after 1 year of treatment. This finding is in line with the results of a recent study on velmanase alfa in children aged < 6 years, in which quality of life was assessed by administering the PEDI questionnaire to the parents. After at least 24 months of treatment with velmanase alfa, raw and scaled scores improved in all children in all domains compared with baseline [16]. Furthermore, during the clinical development of the drug, quality of life improved, as shown by the EuroQol 5 Dimension-5 Level Questionnaire administered after 48 months of treatment, with absolute change values for the pediatric group of 0.083 (0.136) that exceeded the minimal clinically important difference [17].
Patients with alpha-mannosidosis have macrocephaly and coarse facial features, such as prominent forehead, broad and rounded eyebrows, flat nasal bridge, macroglossia, and widely spaced teeth, as well as prognathism and short neck [1]. In line with the red flags pointing to a lysosomal disorder, coarse facial features were present in the case we report (see above).
Osteo-skeletal abnormalities in alpha-mannosidosis include multiple dysostoses, genu valgum, kyphosis, scoliosis, asymptomatic osteopenia, sclerotic bone lesions, sternal deformities, hip dysplasia, cranial thickening, and malformed vertebrae [1, 6]. In the present case, the main skeletal abnormalities were shortening of long bones and slight metaphyseal widening of the metaphysis. (Fig. 1E, 1F).
Alterations of the immune system have been reported, mainly in the form of respiratory and gastrointestinal infections, especially during the first decade of life [1, 6–8].
The central nervous system abnormalities reported include occipital white matter lesions with local or diffuse signal hyperintensity on MRI, cerebellar or cortical atrophy, and thinning of the corpus callosum [1, 9]. This finding was observed in the MRI scan performed in the present report, which revealed dysgenesis of the corpus callosum. Delayed myelinization and hydrocephaly have also been reported [1].
The patient presented with metopic and coronal craniosynostosis. She underwent surgery and progressed well thereafter. Three cases with craniosynostosis have been reported. Craniosynostosis may be a sign of alpha-mannosidosis and can be considered an extension of the clinical spectrum [3, 8, 18].
Our patient had an umbilical hernia. This condition is observed in a variable number of patients [18].
Despite the diagnostic difficulties, it is very important to diagnose the disease early, given the increasing evidence that the response to treatment is better in children than in adults reinforces the importance of early diagnosis of this disease and treatment with replacement therapy [1, 3, 4, 8, 16]. The long-term prognosis for untreated patients is very poor, with progression of cognitive, skeletal, and neuromuscular impairment over decades. Most patients need a wheelchair for basic mobility and assistance with their activities of daily living [1, 8]. The decrease in life expectancy is determined by neurological involvement and recurrent infection [7].
In order to facilitate early diagnosis of alpha-mannosidosis, the pediatrician should take the condition into account in the case of a child with delayed neurodevelopment and dysmorphic features (usually less obvious than in patients with mucopolysaccharidosis). Therefore, it is important to publish reports of cases of alpha-mannosidosis in pediatrics journals.
Since recently, ERT with velmanase alfa has been funded by the public health system in Spain, thus improving access to the drug. Therefore, it is very important to highlight that this is the only medication available to treat affected children. Without treatment, patients’ quality of life would be considerably impaired, and prognosis would worsen significantly [6, 11].