How is Fabry inherited?

People probably carry from 5 to 10 genes with mutations in each of their cells. 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.

The inheritance pattern for Fabry is called X linked semi-dominant inheritance. Males only have one X chromosome, if it contains the faulty gene which cannot make enough enzyme alpha-GAL they are more likely to develop Fabry symptoms. Males can only pass the faulty gene to the daughters, so the daughters will be carriers of the disease, sons will not be affected by Fabry.

Females may have less severe Fabry symptoms than males but this is not always the case. This is because females have two X chromosomes, one of which will be active and one inactive. It is a matter of chance which chromosome is active or inactive in a particular cell. If the X chromosome with the faulty gene is active then a female is likely to show many of the classic features of Fabry. There is a 1 in 2 chance that that faulty gene will be passed on to the children, regardless of whether they are male or female.

All parents of children with Fabry 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 Fabry, screening tests can be arranged early on during a pregnancy for those families who already have a child with Fabry. 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 Fabry.

It is also possible to have Pre-implantation genetic diagnosis (PGD) screening to avoid passing Fabry 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.

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How are people with Fabry affected?

Disease progression is influenced by the sex of the person (male or female) and whether the disease presents as either non-classical (mild form) or classical (severe form). People with the classic form often demonstrate the full spectrum of symptoms. Early onset begins in childhood or adolescence and include cloudiness of the front part of the eye (cataracts), ringing in the ears (tinnitus) and hearing loss, clusters of small dark red spots on the skin (angiokeratoma), pain in the extremities, and decreased ability to sweat (hypohidrosis). In addition, they may have chronic abdominal pain and diarrhoea. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Other symptoms can include tiredness that is not relieved by rest or sleep, intolerance to heat or cold and a feeling of burning in the hands and feet. Sometime people can feel dizzy (vertigo) and signs of depression are present. People with Fabry often have difficulties in managing weight, feeling sick or being sick and pain or bloating after eating, difficulty managing weight and feeling full after eating a small amount of food. Some people with the milder forms of the disease that appear later in life and affect only the heart or kidneys. Death, as a result of renal failure, heart failure, or strokes, commonly occurs by the fourth or fifth decade of life.

Treatment options for Fabry

Chaperone therapy Chaperones are small molecules that assist enzymes in becoming functional by helping them take the correct shape and stay stable. With chaperone therapy, some faulty forms of alpha-GAL enzyme can be corrected and delivered to the lysosomes so that the excess GL3 can be broken down. The name for the chaperone therapy treatment in Fabry is migalastat and the brand name is Galafold®. Galafold® was licensed as the first oral chaperone therapy in Fabry and has been available in the UK since 2016 for adults and adolescents 16 years of age and older. Patients must have a confirmed diagnosis of Fabry and the mutation in the galactosidase alpha (GLA) gene that produces an alpha-GAL enzyme that responds to the treatment. Galafold® is an oral capsule taken every other day. More information about Galafold® can be found at www.galafold.com and a European version of the patient information leaflet is here. Further information on this treatment is available from the electronic medicines compendium. Enzyme Replacement Therapy (ERT) For people with Fabry ERT is a long-term therapy whereby the missing or deficient enzyme is given via an intravenous infusion. Currently Fabrazyme ® (agalsidase beta) and Replagal ® (agalsidase alpha) are both ERTs for the treatment of Fabry and both are approved in the UK. ERT helps to normalise kidney and heart function, and blood supply to the brain. Fabrazyme ® is an infusion administered every other week at home for patients aged 8 years and older. More information about Fabrazyme® can be found at www.fabrazyme.com and a UK version of the patient information leaflet is here. Further information on this treatment is available from the electronic medicines compendium. Replagal® is an infusion administered every other week over 40 minutes and is usually administered at home for patients aged 7 years and older. More information about Replagal® can be found at www.shire.com and a UK version of the patient information leaflet is here. Further information on this treatment is available from the electronic medicines compendium.

How common is Fabry?

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. It has been estimated that Fabry affects between 1:40,000 people, in Caucasian males it is around 1:17,000. Fabry is seen across all ethnic groups, including African Americans and in persons of Hispanic or Asian descent but the population-specific incidence rates are unknown.

Research and clinical trials in Fabry

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 Fabry

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; the MPS Society is a small charity but with your support we can continue to offer a highly valued and essential service.

Why mental health and Fabry are related

This is an area which many of you struggle with whether you are a young person or an adult. There are many reasons for this, but for many, it is the impact of the symptoms making it difficult to engage in activities.

Things to consider

• Try to do something that you enjoy on the days when you are more able, such as meeting friends, going to the cinema, watching a funny film, going for a short walk in some green space, painting, and singing.

• Talk to other Fabry members, sometimes it’s easier to talk to someone who is not a family member. The society can put you in touch with other members

• Try to get outside wherever possible, even for a short time

• Talk to your specialist centre if your mental health is suffering, they will either have therapists who can help or be able to sign post you to the services who can help in your area

What else you can do

• Speak to your GP who can help with local services and next steps

• The charity MIND may be able to help and put you in touch with local services

• ‎Our conferences are always a good place to come and meet and engage with members and clinicians from the Fabry community and have fun at the same time

Points to remember

• Having DLA does not automatically mean you will get PIP
• A child potentially needs more support than a young person/adult, that is why the claim may be reduced or refused
• Mobility component is more stringent, walking distances have reduced
• You have to be UNABLE to perform activities for 182 days of the year, this has Implications for Fabry members who only experience periodic “Fabry Crisis”

Medical Assessment

• Generally your assessor will not be a doctor, they can be nurses, physiotherapist, occupational therapists, paramedics, but all have some medical background

• They may have read about Fabry but it’s how it affects you as an individual that you need to tell them

• They will ask you about how you manage the everyday tasks such as cooking a simple meal, you need to explain why you cannot do this

• Fabry condition varies so it is important to say when you are unable to function; is it all the time, or just when you have a crisis

Hints and Tips

• Be prepared – refresh your memory on what is written on PIP form

• Take someone with you who knows your condition and can speak up if you forget things

• Remember you are observed from the time you arrive

• Remind the assessor TODAY IS A GOOD DAY - otherwise you would not be attending

• You will be asked to perform some physical movements remember: IF IT HURTS DON’T DO IT YOU WILL NOT BE PENALISED FOR THIS

Appeals and Tribunals

• A revision request must be made in writing – This is a Mandatory Reconsideration- MPS Society can help you go through the reasons refused and look at the descriptors, additional medical evidence may need to be supplied

• A right to appeal will arise once the revision request is considered, appeals are made in writing directly to the First-tier Tribunal and again we can help with this

Moving from DLA to PIP

Many of you may have received DLA and then found that allowance had reduced or been withdrawn when you changed to PIP at 16 years old. I would suggest that if you have previously completed the forms yourself it would be helpful to ask me first to help with the PIP form rather than waiting till you have been turned down, and then struggle to do a Mandatory Reconsideration. I have generally found that you need to put in a lot more specific examples than members generally do.