Alpha-Mannosidosis

Alpha mannosidosis is an autosomal recessive lysosomal storage disorder due to biallelic variants in MAN2B1, with deficiency of lysosomal alpha mannosidase and accumulation of mannose rich oligosaccharides. It causes hearing loss, immunodeficiency, skeletal disease, intellectual disability and psychiatric disease, over a broad range of severity.

Pathophysiology. Alpha mannosidase hydrolyses mannose residues from glycoprotein oligosaccharides. Deficiency leads to storage in lysosomes of the brain, bone, immune system, and many other tissues.

Early severe forms present in infancy, while mild forms present in adults.

An enzyme replacement therapy for the non-neurological manifestations is available.

• Sensorineural hearing loss (almost universal) and recurrent otitis media
• Recurrent infections from impaired immunity, particularly in childhood
• Intellectual disability, speech delay and psychiatric disease (psychosis, depression, anxiety, confusion) in adults
• Ataxia, tremor and muscle weakness, with myopathy
• Skeletal disease: dysostosis multiplex, scoliosis, genu valgum, joint pain and osteonecrosis
• Coarse facial features, a large head, prominent forehead, and macroglossia
• Hepatosplenomegaly, hydrocephalus in infants, and cataracts
• Angioedema like and immune manifestations in some
• Fluctuating course: slow progression in adults

• Alpha mannosidase enzyme activity in leukocytes: markedly reduced.
• MAN2B1 sequencing with deletion and duplication analysis.
• Urinary oligosaccharides (mannose rich) by thin layer chromatography or mass spectrometry.
• Immune assessment: immunoglobulins and vaccine responses.
• Audiology, skeletal survey and MRI of the brain.
• Neuropsychological assessment.

Differential diagnosis.

• Mucopolysaccharidoses and mucolipidosis
• Fucosidosis, sialidosis and aspartylglucosaminuria
• GM1 gangliosidosis
• Other causes of sensorineural hearing loss with intellectual disability

• Enzyme replacement therapy: velmanase alfa 1 mg/kg intravenously once weekly, as a lifelong infusion, for the non-neurological manifestations. Premedicate with an antihistamine (cetirizine 10 mg orally; children 1 to 5 years 2.5 mg twice daily, 6 to 11 years 5 mg twice daily) and a corticosteroid if infusion reactions occur. Monitor for hypersensitivity and anaphylaxis, and keep adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) available during infusions.
• Haematopoietic stem cell transplantation: an option in early severe disease at specialist centres, with higher risk.
• Hearing: hearing aids, cochlear implants and grommets for persistent middle ear effusion, with speech therapy.
• Infections: prompt antibiotics, vaccination, and prophylaxis for recurrent infection with co-trimoxazole (children trimethoprim 150 mg/m2 daily in two doses on 3 days each week; adults 960 mg three times weekly) when needed. Immunoglobulin replacement 0.4 to 0.6 g/kg intravenously every 3 to 4 weeks if hypogammaglobulinaemia with infection.
• Psychiatric care: treat depression and anxiety with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily, and psychosis with risperidone 1 mg daily increasing to 2 to 4 mg daily (maximum 6 mg daily), with metabolic monitoring.
• Skeletal care: physiotherapy, analgesia with paracetamol 1 g up to four times daily (maximum 4 g), and orthopaedic surgery for deformity.
• Education: special education and occupational support.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Adults: assess for new psychiatric symptoms, ataxia and joint disease at each visit.

Monitoring. Audiology yearly, immunoglobulins and infection history yearly, and skeletal review yearly. Anti-drug antibodies and infusion tolerance during enzyme replacement therapy, and psychiatric review at each visit.

Referral and escalation. Refer to clinical genetics, metabolic medicine and audiology. Urgent for severe infection, anaphylaxis during infusion or acute psychosis.