Rare Disorders: Contact a Family - for families with disabled children: information on rare syndromes and disorders

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Introduction

Individuals and families are devastated when they are told that they, or a child in the family, has any disorder but when it is a very rare condition they face added problems such as difficulties of diagnosis, lack of clear information and variation of advice and treatment around the country. In addition, many people have grown up to adulthood living with such a rare disorder that they have never met another person with the same condition.

David has a very rare disorder called Pallister Killian Mosaic syndrome. It is thought that only 30 people world wide have been identified as having this disorder. Although doctors realised by the age of 6 weeks that David was not developing in the normal way it was 2 years later - 2 years of hospital visits and tests - before a name was given to David's disorder. David has learning, sight and hearing difficulties caused by Pallister Killian Mosaic syndrome. Many families like David's experience the isolation of not knowing anyone going through the same experience as theirs. Contact a Family was able to help David and his family by putting them in touch with a similar family. David is now a teenager with the build of a teenager but the learning age of a six year old. Knowing that there are other families who understand the problems they face is a real help. Many disorders are individually rare but the total burden for such families is enormous.

Margaret is now 65 years old and a grandmother. However, as a baby she was in intensive care fighting bronchial pneumonia and as infection followed infection no one could understand why. Despite this Margaret became a head teacher. 50 years later Margaret was diagnosed at last as having Common Variable Immunodeficiency which lead to a life time of bowel, chest and joint disorders. Today it is known that there are about 600 children and adults in the UK with Common Variable Immunodeficiency. Now children with this disorder are more easily diagnosed and avoid the life time of illness that Margaret experienced. Margaret is now keen to ensure that the issues of diagnosis and lack of knowledge about rare disorders facing individuals and families are addressed as a priority.

What is a Rare Disorder?

There are over 5,000 known rare disorders, a statistic which is continually growing as medical science advances. They affect both children and adults and can occur at any time of life. Many disorders are chronic, progressive and disabling. Some are life threatening.

A range of expert information from verifiable sources such as universities, government libraries or hospitals on rare disorders can be found on the Internet. Information from other sources should give details of date of writing and authorship:

- the National Institutes of Health, US National Library of Medicine http://www.nih.gov/icd

Rare Disorders in the United Kingdom

Contact a Family believes that rare disorders should be a public health priority. The large numbers of people affected, as well as the severity of some of the disorders, means that those with rare disorders have to compete for equal access to health resources and social services. In the UK there is little recognition of rare disorders at a national level. The government has yet to take on board the recommendations of the European Union to consider rare disorders within the context of public health programmes (Article 6(2) of Decision 12951991EC)

There is currently no monitoring or collation of statistics for rare disorders, individually or collectively. Only support groups are keeping any records about how many people are affected by each disorder. This is valuable information which could be used to develop and target services, as well as provide a basis for research. It is common for a family to be told on diagnosis that they are the only one affected by the disorder, only to discover at a later date that there are others with the same diagnosis.

Contact a Family West Midlands undertook an 8 month project during 2003/2004 to help parents of children under 5 years of age with rare conditions access mainstream early years services in Birmingham.

Parents' views were sought on their experiences of using mainstream services, through postal and telephones surveys and a workshop specifically for parents of children with rare disorders. This report gives messages from parents of children of rare disorders to staff working in Early Years settings. Download the report (0.1Mb) in Adobe Acrobat pdf format.

How Rare is Rare?

Out of 15,000 children born with a disability in the UK each year, at least 1,200 will have a rare condition. Most rare conditions are known as "orphan diseases", meaning conditions which are so rare that they have not attracted funding for the development of treatments. Sometimes there is only one known case of a particular condition in the UK; more often numbers range from a few children up to as many as 200. The term 'ultra orphan' is also used to define the rarest conditions.

Some conditions seem to be rare, but as diagnostic techniques improve their incidence turns out to be higher. Receiving a diagnosis can be slow as paediatricians and GPs meet few of these conditions during their career.

Although mapping exercises are very valuable, the majority of rare disorders do not have support groups from which statistics can be gathered.

Undiagnosed?

Many families caring for a child with obvious disabilities never receive a definite diagnosis because the childs' symptoms do not conform to any known disorder, or are not recognised as so doing. The needs of these families can be very similar to those affected by a rare condition. For more details see our Factsheet, Living without a Diagnosis.

Rare Disorders in Europe

Eurordis is the European Organisation for Rare Disorders, a coalition of patient organisations geared toward improving the quality of life for those affected by rare disorders in Europe. It was created in 1996, to carry the voice of as many organisations as possible at a European wide level, to co-ordinate actions and to facilitate exchanges of information. A list of European national organisations can be found at http://www.eurordis.org.

In 1998 the European Union recognised rare disorders as a public health issue faced by 5-8 per cent of the population across Europe. It was agreed that a pan European approach would improve the situation of all those affected by rare disorders. Hence a Programme of Community Action on Rare Disorders (1999 -2003) was produced and funded for this purpose, designed to:

"The very fact of the rarity of low-prevalence diseases and conditions, and the lack of information about them, may mean that people affected by such diseases and conditions do not benefit from the health resources and services that they need." (Article 129 (4))

The number of people affected by rare diseases is, by definition, relatively small in comparison with more commonplace disorders; whereas, these diseases taken together are quite prevalent and affect a significant percentage of the population. (Article 129 (5))

The first goal of Eurordis was to campaign for a European Orphan Medicinal Drug regulation. An Orphan Medicinal Drug Product is a treatment for a rare disorder, where the costs of developing the product are greater than the expected return on the investment. The European Commission ratified the Orphan Medicinal Products Regulations in December 1999. The legislation provides incentives to pharmaceutical companies to develop treatments for rare disorders. The current goals of Eurordis are to:

Genetic Counselling following the Human Genome Project

We are grateful to Professor Sandy Raeburn for his permission to reproduce this article and to Climb who first carried it in ClimbUpdate.

Professor Raeburn works in the City Hospital, Nottingham as part of the genetics service. The hospital laboratories and clinicians are supported by NHS funding. There are close links with the University of Nottingham where there is the Institute of Genetics, (where human genes are identified and mutations investigated), and also the Genetics and Society Unit, conducting social science research. This article hopes to cover two aspects of genetic counselling and to put it in a framework of the new, exciting opportunities presented by molecular investigations and the Human Genome project.

The draft of the structure of the human genome was completed in 2001. The work has produced some surprises as well as some very important points of confirmation. It has filled blanks in what we know about the structure of genes and then how they work and how they sometimes do not work. It has also raised the possibility of gene therapies. However we are very aware of the time it takes to bring new ideas towards treatments in medical practice. (Professor Donnai talked about the Human Genome project at Climb Conference 2001 as reported in Climb Update Volume 1 Number 6 July 2001.)

As a clinical geneticist, Professor Raeburn agrees with the view that families he sees should be able to live and reproduce as normally as possible. For some families, for a multiplicity of circumstances, this may seem unrealistic but geneticists set out to achieve that. The purpose of a genetic counselling interview is to find out from a family with a genetic problem - a baby with a metabolic disease for example - what particular things are important to them and to tell them about the risk of recurrence. It may follow, later, that the family needs to understand other aspects of the problem, for example about prenatal diagnosis and/or carrier testing. But, to begin with, answering questions and establishing what is appropriate for that particular family must be the priority.

It is important to look beyond the human genome project and the intellectual satisfaction of knowing the exact border of the base pairs that form the human genome towards what this is going to achieve for us. DNA consists of two sugar strands joined by pairs of bases, of which there are four - adenine, cytosine, guanine and thymine (A, C, G and T), and twisted together to form a double helix. Adenine and thymine are always paired together and, likewise cytosine and guanine. The two strands can, therefore, easily be separated into single strands (in the laboratory simply by heating) and then copied to give two copies of the same strand. Both public and private bodies using different techniques to work out the sequence have undertaken the human genome project. This is well explained in a book by Kevin Davies called "Sequence" and published earlier in 2001.

If the DNA from a particular person is examined, now that the human genome is known, differences can be identified in relevant genes. This tells us a little but not all that much; when other factors are taken into consideration, for example the age of the person, their previous medical history and the environmental factors, which may have affected them, the genetic result may be better interpreted. With all relevant information available, the interpretation of knowledge of a person's genome is much more useful and exciting.

Genetic counsellors may get quite a lot of their referrals from primary care although some will come from the specialist paediatrician. Specialists have a great deal of knowledge about specific conditions, the disease, specific treatments and management strategies, especially for autosomal recessive conditions and these specialists can easily learn the relevant genetics. Care needs to be taken that the genetic bits are not tacked onto routine clinical appointments concerning the care of an affected child. Otherwise, concerns over treatment and other clinical matters may mask the genetic information. When a referral is made to a specialist genetic clinic the first investigation would be into the immediate family history and the grandparents, aunts and uncles. There would be no need, when dealing with an autosomal recessive disorder, for a complete knowledge family genealogy. A genetic nurse specialist can collect this family information during a home visit. This visit may also give clues about the family's most important queries. Often the request by the referring practitioner (for information on prenatal diagnosis, for example) does not match the family's immediate need for knowledge (for example, why their child has particular neurological features). Clinic appointments are thus matched to individual needs. It also needs to be noted that information from one person does not necessarily give the picture for the whole family. The size and complexity of a family is also important, together with family politics. The support mechanisms available to an individual and within a family need to be considered. People may not understand, especially with autosomal recessive conditions, how carriers of the faulty gene will be on both sides of the family; carriers are healthy and thus have no signs of the disease.

The press can often be quite destructive in their quest for immediate responses to a family tragedy. Many hours of counselling may be necessary to help families to understand the problems they face, especially when presented with a life limiting diagnosis for their child. The press can often jump in for an immediate response that can seriously upset family members.

Another type of inheritance is that where a disease is passed from parent to child. A small number of metabolic diseases are inherited in this way, as is the non-metabolic disease, Huntington disease. The way the gene for Huntington's behaves gives clues about the way in which genes for more rare diseases will also behave.

A final type of inheritance is that in which an error appears on the X-chromosome. A mother may have the mutation on one of her X-chromosomes but the other, normal X-chromosome protects her from its effects. If her son inherits the altered X he will not have any second X-chromosome to protect him.

From a counselling point of view, some people will have specific questions that are important to them. There will be people with a known diagnosis and the mutation will be known. In these cases the diagnosis may be scary but the family probably know where they are as a result. This is a strength for some families. A known mutation might have been detected. If so, family members could be checked for risk and given a clear 'yes/no' answer.

There may also be a known diagnosis but without a known mutation. The knowledge of the human genome may make identification of the mutation possible in the future. For some conditions this may be five or even ten years away but it will gradually be possible to reduce the number of families for whom there is no known mutation. For some the gene will already have been identified so it is just a matter of learning what the mistake is; for others we might only know the location of the gene roughly and we might not even know that. There will also be families where the diagnosis doesn't fit into any of the known classifications. These will be the people who don't have the reassurance and the comfort of knowing. These people are in uncharted territory and this sort of situation is one of the most scary and difficult situations with which to be involved.

The actions and wishes of the family will to a great extent influence the framework in which genetic tests may be carried out. Many families want to know very soon after a diagnosis is confirmed whether siblings are carriers and if there is any other information that can be discovered. This may be appropriate, but is not something that should be rushed into until all the consequences have been discussed, both good and bad. Parents often wish to know the carrier status of their other children but the children themselves may not either need, or wish to know until a later time. Knowledge of the human genome may not produce treatments immediately so we need to be very careful about the timing of information. We must not do anything that will change the dynamics within a family. It is up to them to share information.

One important element of counselling is to establish what myths or incorrect assumptions there are. A person might be convinced that because the sufferer had a particular feature and because they also share that feature that they will inevitably also be a sufferer. This can occur when people, for example misunderstand the genetic mechanisms.

How do we interpret genetic tests? Normally, we would hope to look at the normal population, divide them into groups, for example, positive and negative and then establish, how many of the people in each group remain healthy. This would give a sound theoretical and scientific basis for the test, but it would take years. However, life is not like that and the ideal is mostly unachievable. What usually happens is that we start off with a group of people with a disease and we find out that a lot of them test positive for a particular chemical or have a low level of an enzyme. This might then be an indicator for the disease but there will always be a small proportion of people who test positive but do not have the disease, or who are negative but do have it. You have to be very careful about creating unnecessary worry and concern for people with false positives.

There is one message I'd like to leave with you following the success of the Human Genome Project. It will teach people that although they may have certain genetic mutations that might seem scary, there are many ameliorating factors. Although a particular mutation may have been found in a lot of people with a particular disease, a person who is 'normal' is not necessarily going to develop that disease if they have the same mutation. They may, for example, have a second gene, which is able to control the defective gene completely. A similar unaffected person with the defective gene, but in a family in which the gene has been expressed, might be much more significant.

The human genome project will, ultimately, enable us to be far more precise with diagnoses than we have been able up until now. This will apply both now and in the future for others. Relatives will be able to find out if they are at risk as carriers. For some conditions and in some people this will be relatively easy but for others the mutation may be much more difficult to detect. In cystic fibrosis, for example, 75 per cent of carriers have just one particular genetic difference but for the other 25 per cent it may be any one of a thousand different mutations. This illustrates that there is still a lot of work to be done, even in a genetic disease that we know quite a lot about.

In the future we will be able to identify carriers more easily and the possibilities for prenatal diagnosis will also exist although this may or may not be appropriate for a particular family. There may be pre-implantation tests, which take us further into the science of artificial reproductive technology, testing someone who may undergo IVF treatment to ensure the implanted egg is healthy.

Another future development will be in the area of opportunities for treatment. We must remember that genetic variation is all around us. It is what makes us individual. The human genome will show us what is associated with 'normal' and what is associated with 'disease'. This must not be allowed to create an underclass of people who don't deserve to have the resources of medicine available to them. There is so much natural variation, even within a metabolic disorder. It would be interesting to know whether carrier status confers any benefits, whether physical, psychological or whatever, on the carrier, as has been found in some populations with a high prevalence of a particular genetic disorder. This would be adding another dimension to the Human Genome Project and its usefulness to medicine and mankind.

British Paediatric Surveillance Unit

Rare disease and infections are by definition individually uncommon, but collectively they are an important cause of morbidity and mortality in childhood. With this in mind the British Paediatric Surveillance Unit (BPSU) was set up in 1986 under the auspices of the Royal College of Paediatrics and Child Health, the Health Protection Agency, and the Institute of Child Health (London) to address this. Through the simple methodology of circulating monthly report cards to all paediatric consultants the Unit has enabled paediatricians in the United Kingdom and the Republic of Ireland to participate in the surveillance and further study of uncommon disorders affecting children. It has also increased awareness within the medical profession of such disease.

British Paediatric Surveillance Unit Report Card NOTHING TO REPORT June 2003 [203-06] Specify in box number of cases seen CODE No [ ]
	HIV & AIDS
	Progressive Intellectual & Neurological Deterioration
	Congenital Rubella
	Suspected Fatal Adverse Drug Reactions
	Congenital Toxoplasmosis
	Severe Complications of Varicella
	Invasive fungal infections in VLBW infants
	Severe Hyperbilirubinaemia in the newborn
	Langerhans Cell Histiocytosis

Over the past 17 years the BPSU has facilitated the study of over 50 rare paediatric diseases. Data from over 15,000 patients have been collated and analysed and have led to the publication of over 200 papers in peer review journals and 150 presentation here and abroad. The educational role of the Unit extends further to the publication of an annual report, quarterly bulletin, (both are available free from our website http://bpsu.inopsu.com) presentations and the holding of scientific seminars.

The BPSU has in its achievements surpassed its original expectations. Not only has the Unit supported researchers in the study of rare disorders but also the outcomes have had a substantial impact on public health. As early as 1986 the BPSU was monitoring the effects of new warnings about aspirin and Reye's syndrome, funded by the Reye's syndrome Foundation. The Unit has kept under surveillance diseases targeted by vaccination programmes. Examples include the surveys on congenital rubella, meningoencephalitis after MMR vaccine, acute flaccid paralysis, Haemophilus influenzae b vaccine failures. One of the aims of the Unit is to have a 'rapid response' to emergencies. Recently the BPSU has been involved in the monitoring of variant Creutzfeldt Jacob disease in children through the Progressive and Intellectual Neurological Disorder survey; also the monitoring of E.coli 0157 outbreaks and its impact on the level of haemolytic uraemic syndrome in children. Other studies currently being surveyed include congenital rubella, congenital toxoplasmosis, severe complications of chickenpox, invasive fungal infections in low birth weight infants, hyperbilirubinaemia and Langerhans cell histiocytosis.

The BPSU is currently funded by the Department of Health and through a charge levied on the research teams, they in turn in many cases are funded by patient support groups. Groups such as the Stroke association (cerebrovascular disease), Children's Liver Foundation (biliary atresia), the Meningitis Research Fund (Group b streptococcus disease), Reye syndrome Foundation (Reye syndrome), the British Diabetic Association (paediatric diabetes), Rett syndrome association and the Crohn's & Colitis Research Fund (Inflammatory Bowel disease) have all funded research facilitated by the BPSU.

Such has been its success, other medical specialities within the UK have developed similar units. Overseas has seen the development of 13 other national units. These Units cover a child population of over 48 million. Over 10,000 clinicians have now linked up to form the International Network of Paediatric Surveillance Units. Between us we have surveyed over 100 rare paediatric conditions; information is available from their website http://www.inopsu.com.

Over the years the BPSU has had a close association with Contact a Family, attending conference, giving presentations and helping with enquiries from the public. We very much hope that this association will continue and strengthened still further in the future. To learn more about the BPSU and the studies it has facilitated please visit our website as detailed above.