Alpha-mannosidosis: Positive Effects of Enzyme Replacement Treatment on Cognitive Function

Case study: A 7-year-old patient presented with developmental delay. The patient’s parents are first-degree cousins. The girl was born at term but during the first months of life, she suffered from frequent upper airway infections, adenoid hypertrophy and bilateral hypoacusia. She underwent an adenoidectomy at the age of two years. She had delayed developmental milestones, was hyperactive from a young age and had an altered sleep pattern. She underwent electroencephalography (EEG) (generalised point-wave abnormalities) and brain MRI, which identified hypoplasia of the cerebellar vermis and thin corpus callosum. Karyotype, array-CGH and urinary glucosaminoglycans results were normal.

At her first evaluation, the patient presented with dysmorphic features, splenomegaly, hyperactivity, aggressivity, hypertonicity of the lower limbs and wide gait deambulation. Heart ultrasound and ophthalmologic evaluation were normal. Urinary oligosaccharides were increased and alfa-mannosidase activity was reduced. NGS sequencing of MAN2B1 identified a homozygous mutation of c.685CT (p.R229W).

The patient was started on Enzyme Replacement Therapy (ERT) with velmanase-alfa, 1 mg/kg once a week. After eighteen months of therapy, the number of annual infections has significantly diminished, hypoacusia has improved, and the patient is less hyperactive and aggressive. Her 6 Minute Walking Test performance has increased by 100 meters and the EEG has normalised. Cognitive skill tests identified moderate cognitive delay.

Conclusions: This case underlines the frequent delay in diagnosing such a rare disease and the importance of early recognition because of the availability of therapy. Finally, even though ERT does not pass the blood-brain barrier, cognitive function and skills improve with therapy, probably due to improved hypoacusia and effects of ERT on hippocampal synaptogenesis as one Dutch study has proved.