MPS Society

What causes Alpha-mannosidosis?

---

Oligosaccharides are chains of sugar molecules used in the building of bones, cartilage, skin, tendons and many other tissues in the body. “Oligo” means a few and “saccharide” is a general term for the sugar part of the molecule. In the course of normal life there is a continuous recycling process of building new oligosaccharides and breaking down old ones. The breakdown and recycling process requires a series of special biochemical tools called enzymes.

People with alpha-mannosidosis are missing or are low in an enzyme called alpha-D-mannosidase which is essential in breaking down oligosaccharides. When oligosaccharides are not completely broken down they remain stored in the body. The symptoms of alpha-mannosidosis are a result of the build-up of oligosaccharides in the tissues in the body. Babies may show little sign of the disease but as more and more cells build-up of partially broken down oligosaccharides, symptoms start to appear.

---

How is Alpha-mannosidosis inherited?

---

Alpha-mannosidosis is an autosomal recessive disease this means that both parents must carry the same affected gene and each pass this same affected gene to their child.

People probably carry from 5 to 10 genes with mutations in each of their cells. Problems happen when the particular gene is dominant or when a mutation is present in both copies of a recessive gene pair. Genes are the unique set of instructions inside our bodies that make each of us an individual. They are the blueprint for our growth and development, as well as controlling how our bodies function. Genes are carried on structures called chromosomes and it is usual to have 23 pairs. A child will inherit half of the chromosomes from the mother and the other half from the father resulting in 23 pairs. 22 of these pairs look the same in both males and females. Pair 23 are the sex chromosomes, and this is the pair that differ between females and males. The X chromosome is inherited from the mother and the Y chromosome is inherited from the father. More information about inheritance is available here.

For each pregnancy the chances of a baby inheriting alpha-mannosidosis are completely independent of whether a previous child was affected with alpha-mannosidosis. With each pregnancy there is a 1 in 4 chance that the baby will be affected by alpha-mannosidosis.

All parents of children with alpha-mannosidosis can benefit from genetic counselling, the counsellor can provide advice on the risk to close relatives and to suggest whether the wider family should be informed. To find out during a pregnancy, if the baby is affected by alpha-mannosidosis, screening tests can be arranged early on during a pregnancy for those families who already have a child with alpha-mannosidosis. Where only one parent is a carrier, they can opt for carrier screening but it is not 100% reliable or accurate and is not possible in all cases. Amniocentesis and chorionic villus sampling are both available during the pregnancy to find out if the baby is affected by alpha-mannosidosis.

It might also be possible to have Pre-implantation genetic diagnosis (PGD) screening to avoid passing alpha-mannosidosis to the baby. PGD is an assisted fertility treatment that involves checking the chromosomes of embryos before they are transferred in the womb using IVF techniques

---

How common is Alpha-mannosidosis?

---

It is estimated that nearly 6% of the UK population (around 3.5million people) will be affected by a rare disease at some point in their lives. A single rare disease may affect up to about 30,000 people however the vast majority of rare diseases affect far fewer than this.

Alpha-mannosidosis is estimated to occur in 1 in 500,000 new-borns. Approximately 200 people have been reported worldwide with alpha-mannosidosis, about 30 of these people are living in the UK.

---

How are people with Alpha-mannosidosis affected?

---

People with alpha-mannosidosis can experience some or many symptoms from a wide spectrum which range from severe to very mild. Alpha-mannosidosis is broken down into three forms:

• Type 1, a mild and slowly progressive form, symptoms may become evident during the teen years.

• Type 2, a moderate form, where symptoms onset before the age of 10.

• Type 3, a severe rapidly progressive and potentially life-threatening form, where symptoms develop shortly after birth.

It is important to note that people with alpha-mannosidosis will not all experience all the symptoms. Infants with type 3 alpha-mannosidosis often do not survive past childhood, while at the other end of the spectrum people that are less severely affected may have a reasonably normal life span.

Appearance

Babies with the severe form, type 3, often appear normal at birth but the disease grows progressively worse in the first year of life. Babies may be larger than average at birth and may grow faster than normal during the first few years of life, however growth is restricted as they get older causing short stature.

The facial features of children with alpha-mannosidosis can resemble each other very closely. The faces may be chubby, a larger than average head with a prominent forehead and the ears are often large and low-set. The neck may be short and the nose broad with a flattened bridge. The lips are often thickened, teeth are widely spaced or unevenly developed, the tongue is thickened and enlarged and the gums are overgrown. The texture of the hair tends to be coarse.

Brain

Intellectual disabilities associated with alpha-mannosidosis can range from mild intellectual impairment to profound intellectual deficiency. Children with alpha-mannosidosis at the severe end of the spectrum usually experience progressive storage of oligosaccharides in the brain. This is primarily responsible for the learning difficulties however the pattern is very varied. People at the less severe end of the spectrum may have mild to moderate learning difficulties.

Children often experience speech impairment including delayed ability to speak. Some children may experience delays in sitting, learning to walk and may appear clumsy and experience difficulty in coordinating movements due to reduced muscle tone.

Almost half of those affected by alpha-mannosidosis are likely to have epilepsy. There are different forms of epilepsy e.g. absence episodes where the person may appear to be staring into space with or without jerking or twitching movements of the eye muscles, or more generalised tonic-clonic seizures, a type of generalised seizure that affects the entire brain. Tonic-clonic seizures are more commonly associated with epilepsy.

Some people with alpha-mannosidosis may experience hydrocephalus, which is water on the brain. This can happen because the fluid that protects and circulates around the brain and spinal cord may become blocked over time. The blockage causes increased pressure in the head which can press on the brain causing headaches and delayed development. Tests to confirm hydrocephalus can be done using a CT or MRI scan, or a lumbar puncture. If hydrocephalus is confirmed it can be treated by an insertion of a small tube in the spinal cord which drains fluid from the brain.

Lungs

Normally the ribs are curved and between the ribcage and breastbone there is flexibility for the chest to move freely. In alpha-mannosidosis the chest cannot move freely to allow the lungs to take in a large volume of air because the ribs are straight and there is limited flexibility between the ribcage and breastbone. The muscles at the base of the chest may be pushed upwards by an enlarged liver and spleen, further reducing the space for the lungs. When the lungs are not fully cleared there is an increased risk of infection which can lead to scarring causing further obstruction.

Typically, the bridge of the nose is flattened and the passage behind the nose is smaller than usual due to poor growth of the bones in the mid-face. Frequent coughs, colds and throat infections are common problems for many people with alpha-mannosidosis. The windpipe (trachea) becomes narrowed by storage material and is often more floppy, or softer than usual due to abnormal cartilage rings in the trachea. Nodules of tissue can further block the airway making swallowing difficult. Removal of tonsils and adenoids may help in some cases to lessen the obstruction and make breathing easier, but adenoid tissue may grow back.

Frequent coughs, colds and throat infections are common problems for many people with alpha-mannosidosis. The white blood cells that are important for fighting off infection do not work very well, this means that there is a higher risk of infection, especially within the respiratory. Medication for controlling cough and cold symptoms is available but it is essential to consult the doctor rather than using ‘over the counter’ medication which may not help. Medications such as antihistamines may dry out the mucus making it thicker and harder to dislodge. Decongestants usually contain stimulants that can raise blood pressure and narrow blood vessels, both are undesirable effects for people with alpha-mannosidosis. Cough medicines that have a sedating effect may cause more problems with sleep apnoea by depressing muscle tone and respiration. It is common for people with alpha-mannosidosis to develop secondary bacterial infections which should be treated with antibiotics.

Liver and Spleen

In most people with alpha-mannosidosis the liver and spleen become enlarged by storage of oligosaccharides. The enlarged liver does not cause problems or lead to liver failure however the size can interfere with eating and breathing.

Bones and joints

The spine bones (vertebrae) of people with alpha-mannosidosis are poorly shaped resulting in a hump on the upper back called kyphosis or the spine may be curved to one side, this is called scoliosis. Some children with alpha-mannosidosis may occasionally experience skeletal pain which should be managed by a specialist.

There are usually significant problems with bone formation and growth. This leads to both bone and brain symptoms if nerves are compressed by bone. Joint stiffness does lead to limited movement, in the shoulders and arms, hips and knees. The limited movement can make everyday activities like getting dressed difficult. Joint stiffness can sometimes cause pain which may be relieved by warmth and painkillers, speak with your doctor to select the most suitable treatment.

Many children with alpha-mannosidosis stand and walk with their knees and hips flexed. The feet are broad and may be stiff with the toes curved under, often the tight Achilles tendon may result in walking on toes. Sometimes children have ‘knock knees’ but this is very unlikely to need treatment until the child has stopped growing.

The shape of the hands is very noticeable, they are short and broad with stubby fingers which gradually become curved over or clawed. People with alpha-mannosidosis sometimes experience pain, weakness or loss of feeling in the fingertips, this is caused by thickening of the ligaments which causes pressure on the nerves. It is called carpal tunnel syndrome and can be relieved by an operation. An electrical test called a nerve conduction study can show whether carpal tunnel syndrome is the cause.

Ears

A degree of deafness is common in people with alpha-mannosidosis. It may be conductive deafness, nerve deafness or both (called mixed deafness) and can be made worse by frequent ear infections.

Conductive deafness is when sound waves that travel through the ear canal, drum and the middle ear are impaired. Correct functioning of the middle ear depends on the pressure behind the ear drum being the same as that in the outer ear canal and the atmosphere. This pressure is kept equal by the eustachian tube which runs from the middle ear to the back of the nose. If the eustachian tube is blocked the pressure behind the eardrum will drop and the transmission of sound waves will be impaired. If this persists, fluid from the lining of the middle ear will build up and in time will become thick like glue, hence the condition being known as glue ear. Glue ear can be treated through surgery by inserting a small ventilation tube called a grommet, however these can fall out quickly and T-tubes, a type of grommet which stays in place longer, are an alternative option.

Nerve deafness is damage to the tiny hair cells in the inner ear. It may happen at the same time as conductive deafness, in which case it is referred to as mixed deafness. Mixed deafness can be managed by grommets or hearing aids. Nerve deafness is managed by fitting hearing aids in most people. More severely affected children may keep pulling out their hearing aids at first, but it is important to persevere at wearing them so that communication can be maintained. Alternatives include radio aids and the loop system which can be helpful at school and at home.

Eyes

People with alpha-mannosidosis may experience a range of eye conditions that can include an inability to align the eyes, clouding of the cornea, farsightedness and near-sightedness.

Dental

Good dental hygiene is very important for children with alpha-mannosidosis, teeth should be well cared for to avoid tooth decay, pain and extractions. Usually teeth are widely spaced and poorly formed with fragile enamel. Cleaning around the mouth with a small sponge or a stick soaked in mouthwash will help keep the mouth fresh and avoid bad breath. If the water in your area has not been treated with fluoride, speak with your dentist about including fluoride tablets or drops as part of the dental management plan. Dribbling is a common problem and can soak through clothes causing soreness, to prevent this choosing a bib that is plastic backed.

Where a child with alpha-mannosidosis is severely affected it may be safer for any treatment to be carried out in hospital. If teeth need to be removed under anaesthetic this should be carried out in hospital under the care of an experienced anaesthetist and never in the dental surgery. It is important to inform the dentist about heart problems when discussing any treatment. This is because certain bacteria in the mouth may get into the blood stream and cause an infection on the heart valves. In most cases antibiotics are usually prescribed before and after any dental treatment.

---

Treatment options for people with Alpha-mannosidosis

---

Haematopoietic Stem Cell Transplantation (HSCT)

For people with alpha-mannosidosis HSCT is the treatment of choice. The immediate benefits include correction of the missing or deficient enzyme. The long-term benefits include a longer life by protecting the heart, lungs and brain from the effects of progression of alpha-mannosidosis. Other organs and tissues can also show benefits from the therapy; these include the eyes and ears, liver, spleen, joints and airways. Therapeutic benefit has not been shown in preventing the damage to the brain that occurs in people severely affected by alpha–mannosidosis.

More information on this and supportive care treatments for people with MPS and related diseases can be found in the treatments section.

---

Research & Clinical trials for people with Alpha-mannosidosis

---

For an up-to-date list of current UK based trials taking place visit Be Part of Research (resource provided by the National Institute for Health Research). For an international search visit Clinical Trials (resource provided by the U.S. National Library of Medicine). This resource provides information on trial status including recruiting, completed or withdrawn and worldwide trial locations. To find out more about past or current trials speak to your doctor and learn about the risks and potential benefits.

---

Living with Alpha-mannosidosis

---

The MPS Society is the only UK charity at the forefront of supporting people and families affected by MPS and related diseases. Our extensive support services offers you a wide range of support and resources. The team can advise and sign post you to adequate needs-led support and services in your local area as well as social care, home adaptions, education and much more. The support team can visit you in your home and provide you with vital support and includes an Advocacy Officer based at Belfast City Hospital supporting members in Northern Ireland.

Get involved and support us in the community, volunteer or support fundraising; we are a small charity but with your support we can continue to offer a highly valued and essential service.

---