Alpha-mannosidosis

Alpha-mannosidosis belongs to the glycoprotein group of lysosomal storage diseases and is closely related to the mucopolysaccharidoses. Oligosaccharides are short chains of sugar molecules used in building bone, cartilage, skin and tendons. The recycling of old oligosaccharides depends on the enzyme alpha-D-mannosidase. When it is missing or low, partially broken-down oligosaccharides remain in cells, and symptoms appear as more cells fill with stored material.

It is autosomal recessive, with a 1 in 4 chance in each pregnancy of two carrier parents. MedlinePlus estimates an occurrence of about 1 in 500,000 people worldwide.

The MPS Society describes a spectrum split into three forms. Type 1 is a mild and slowly progressive form in which symptoms may only become evident during the teen years. Type 2 is moderate, with symptoms starting before the age of 10. Type 3 is a severe, rapidly progressive and potentially life-threatening form, with symptoms shortly after birth. Infants with type 3 often do not survive past childhood, while people at the mild end may have a reasonably normal life span. MedlinePlus adds that people with later-onset disease may live into their fifties.

Babies with the severe form often look normal at birth but worsen during the first year. They can be larger than average at first and grow quickly, then growth is restricted and short stature follows.

Children often have a chubby face with a large head, prominent forehead, large low-set ears, flat nasal bridge, thick lips, widely spaced teeth, overgrown gums and a large tongue. Intellectual disability can range from mild to profound, and speech is often delayed. Delayed sitting and walking and clumsiness from low muscle tone are common.

Almost half of those affected are likely to have epilepsy, and some develop hydrocephalus, which is treated by inserting a drain. Some people have psychiatric symptoms such as depression, anxiety or hallucinations, which can be triggered by stress, surgery or a change in routine.

The chest cannot move freely because ribs are straight and the liver and spleen can be enlarged, so lungs cannot take in a large volume of air. A narrow, floppy windpipe, a small passage behind the nose and white blood cells that do not work well all add to frequent coughs, colds and throat infections. Tonsil and adenoid removal sometimes helps.

Hearing loss is common. Glue ear can be treated with grommets or longer-lasting T-tubes, and nerve deafness is managed with hearing aids. Eye problems such as squint, clouding of the cornea and refractive errors occur, and dental care needs special attention because enamel is fragile.

The society advises that people with alpha-mannosidosis see a doctor rather than rely on over-the-counter cold remedies. Antihistamines can thicken mucus, decongestants contain stimulants that can raise blood pressure, and sedating cough medicines may worsen sleep apnoea by lowering muscle tone and breathing.

Dental treatment under anaesthetic is safer in hospital under an experienced anaesthetist for severely affected children, and the dentist should know about any heart problems, because mouth bacteria can infect heart valves and antibiotics may be prescribed around treatment.

The MPS Society states that haematopoietic stem cell transplantation is the treatment of choice for people with alpha-mannosidosis, with immediate correction of the missing enzyme and longer-term protection of heart, lungs and brain, although the benefit has not been shown to prevent brain damage in severely affected people.

NICE guidance HST29, dated 13 December 2023, recommends velmanase alfa as an option for treating the non-neurological signs and symptoms of mild to moderate alpha-mannosidosis, only if treatment is started in people under 18 years (it can be continued once they turn 18) and the company provides it under the commercial arrangement. NICE notes that trial evidence suggests improvements in functions such as walking, stair climbing and lung capacity, and in quality of life, but the size of benefits is highly uncertain because of the ultra-rare nature of the condition. Treatment already started in the NHS is not affected.

Specialist care for hearing, eyes, bones, breathing, learning and mental health makes up most of day-to-day management.

Call 999 for a seizure that does not stop, severe breathing difficulty, or sudden weakness in the legs. Seek urgent advice for persistent fever or chest infection, new headaches with vomiting or drowsiness, or a sudden change in mood or behaviour.