Condition AZ: f

Also known as: Lipoprotein lipase and apo C-II deficiencies

Background

Triglycerides (TGs) are the main form of fat present in the diet and are a substantial source of energy for daily activity. TGs from the gut are transported in the blood as chylomicrons, which are complex fat globules also containing cholesterol and protein, including the protein apo C-II. An enzyme called lipoprotein lipase, found on the wall of blood vessels, removes the TGs from chylomicrons, to be used by muscle or fat cells. TGs also travel in the blood within very-low-density lipoproteins (VLDL) which are similar to chylomicrons. VLDL carries fat made in the liver to the tissues such as muscle and fat.

Hypertriglyceridaemia occurs when there is too much triglyceride in the blood, but the cholesterol level is normal or only slightly elevated.

Credits

Medical text written September 2014, by Dr M Sharrard, Consultant Paediatrician with Special Interest in Metabolic disease, Sheffield Children’s Hospital, Sheffield, UK.

What are the symptoms?

The most serious complication of hypertriglyceridaemia is acute pancreatitis. This occurs when the pancreas becomes inflamed and releases digestive enzymes into the abdomen causing damage. Pancreatitis causes very severe abdominal pain and can be life-threatening.

Many people with hypertriglyceridaemia experience abdominal pain because of long term inflammation of the pancreas. The liver and spleen may be enlarged and there may be fatty lumps in the skin (called eruptive xanthomas) often round the elbows and knees.

What are the causes?

Hypertriglyceridaemia with excessive chylomicrons in the blood is usually a genetic disease. There may be an inherited deficiency of the enzyme lipoprotein lipase caused by mutation in the LPL gene, or more rarely of the protein apo C-II caused by mutations in the APOC2 gene. These disorders are very rare, affecting about 1 in every one million people in the UK, although more people from Asia are affected.

How is it diagnosed?

Hypertriglyceridaemia is diagnosed by a blood test to measure triglyceride levels. Special blood tests can be used to measure lipoprotein lipase and apo C-II levels, or genetic testing may be used to find the gene defect.

Some children are diagnosed when they have a blood tests and their blood plasma looks abnormally creamy.

How is it treated?

Treatment is aimed at lowering blood triglycerides to a safe level. A very low fat diet is the main part of treatment. This should be supervised by an experienced dietician. Special fats called medium chain triglycerides (MCT) can be used in infant formulas or as dietary supplements to provide energy and MCT may help to reduce triglyceride levels. Fat soluble vitamins and essential fatty acids (often as walnut oil) should be given as supplements.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
Lipoprotein lipase and apo C-II deficiencies are recessively inherited – both parents carry one copy of a mutant LPL or APOC2 gene, and the affected child inherits the mutated gene from each unaffected carrier parent.

Prenatal diagnosis
Prenatal diagnosis is possible if the gene mutation is known, although it is rarely requested as effective treatment is available.

Is there support?

Information and support in the UK for organic acidaemias is provided by Metabolic Support UK (see entry Inherited Metabolic diseases).

Also known as: Recessive Spino-cerebellar Degeneration

Background

Friedreich’s ataxia (also called FA or FRDA) is a rare genetic condition that causes damage to the nervous system, the spinal cord, peripheral nerves and cerebellum (part of the brain that coordinates balance and movement). This results in progressive disability including weakness, imbalance, incoordination and difficulties with speech, swallowing, vision, hearing and sensation (such as sense of position of the body). Some of the people affected develop cardiac (heart) problems and diabetes.

Credits

Last updated January 2015 by Dr P Giunti, Principal Clinical Research Associate, Ataxia Centre, National Hospital for Neurology and Neurosurgery, UCLH/UCL, Institute of Neurology, London, UK.

What are the symptoms?

Onset is usually between the ages of 4 and 16 years (but occasionally between 18 months and 50 years). The first symptom is usually gait ataxia or difficulty in walking.

The ataxia gradually worsens and spreads but the arms may remain relatively unaffected for a long period. The legs are most commonly affected, so that individuals often have to use a wheelchair in the advanced stages of the condition. There is often loss of position sense in the hands and feet. Individuals who develop FA at a young age may also develop skeletal problems such as curvature of the spine (called scoliosis) or high-arched feet (called pes cavus).

Dysarthria (slowness and slurring of speech) and dysphagia (problems with swallowing) can develop and become progressively worse. Individuals with FA often have abnormal eye movements (called nystagmus) and some may develop hearing and visual loss.

Various forms of heart disease can accompany FA, particularly thickening of the heart muscle (hypertrophic cardiomyopathy) which can cause problems with the pumping power of the heart and irregularities of heart rhythm (arrhythmias). Diabetes may also develop (see entry Diabetes Mellitus).

What are the causes?

The genetic change (mutation) in the majority of individuals (97 per cent plus) is an abnormally long repetition of a DNA fragment (called a GAA repeat) in the Friedreich’s ataxia gene on chromosome 9. As this is a recessive condition, you have to have a double dose of mutated genes, in both chromosomes 9, to develop the condition.

How is it diagnosed?

This requires clinical assessment, including a medical history and thorough physical examination. Genetic testing (by blood test) provides a conclusive diagnosis.

How is it treated?

Many of the symptoms of FA can be treated to help individuals maintain a good quality of life. Doctors can prescribe treatments for diabetes and heart problems, if present. Problems such as foot deformities and scoliosis can be corrected with braces or surgery. Physical therapy may prolong use of the arms and legs. There is currently no cure for FA or treatment that slows the degenerative process.

Advances in understanding the genetics of FA are leading to breakthroughs in treatment. Clinical trials of several proposed treatments have already occurred and further trials are currently underway.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
FA is inherited in an autosomal recessive manner.

Prenatal diagnosis
Prenatal diagnosis is also possible via chorionic villus sampling for families where the mutation causing the condition is known. It is also possible to test unaffected individuals in affected families to see if they carry the mutation that causes the condition. Affected families should be referred to a genetics centre for information and advice.

Is there support?

Ataxia UK

Helpline: 0845 644 0606
Email: helpline@ataxia.org.uk
Website: ataxia.org.uk

The Organisation is a Registered Charity in England and Wales No. 1102391, established in 1964. It supports people affected by Friedreich’s, cerebellar and other ataxias, their carers, families and friends, to live with the condition. The Organisation provides information, a helpline, a network of local branches and self-help groups, contact with other affected families and welfare grants. It also supports medical and scientific research into causes and potential treatments.

Group details last confirmed June 2018.

Also known as: Distal Arthrogryposis Type 2A; Whistling Face syndrome

Background

Freeman Sheldon syndrome was first described in 1938 by Freeman and Sheldon. It is a rare genetic condition that mainly affects the face, hands and feet.

Credits

Medical text written December 2012 by Dr Adam Shaw, Consultant in Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK.

What are the symptoms?

Children with Freeman Sheldon syndrome may have:

  • Distinctive facial appearance, including:

– microstomia (a small mouth) with pursed lips – giving the appearance of a ‘whistling face’
– prominent forehead and brow ridges
– mid-face hypoplasia (a sunken appearance of the middle of
the face)
– a short nose, and a long philtrum (area between the nose
and mouth)
– hypoglossia (unusually small tongue)
– micrognathia (small jaw)
– a high arch in the roof of the mouth (high-arched palate).

  • Eye problems, including:

– hypertelorism (widely spaced eyes)
– deep set eyes
– down-slanting palpebral fissures (outside corners of the eyes that point downward)
– blepharophimosis (a narrowing of the eye opening)
– ptosis (droopy eyelids)
– strabismus (a squint, ie eyes that do not look in the same direction).

  • Joint problems and bone problems, including:

– joint contractures (deformities) that restrict movement such as distal arthrogryposis  (multiple contractures in the hands and feet at birth)
– camptodactyly (permanently bent fingers and toes) due to contractures
– ulnar deviation  (a hand deformity in which all of the fingers are angled outward)
– clubfoot (inward- and downward-turning feet)
– curvature of the spine (scoliosis).

  • Affected children may also experience:

– a failure to gain weight and grow at the expected rate (failure to thrive)
– speech problems
– hearing loss.

Children affected by Freeman-Sheldon syndrome may also have an increased risk of developing a severe reaction to certain drugs used during surgery and other invasive procedures. This reaction is called malignant hyperthermia.

Intelligence is unaffected in most people with Freeman-Sheldon syndrome, but around one-third have some degree of learning disability.

What are the causes?

Freeman-Sheldon syndrome may be caused by mutations in the MYH3 gene. The MYH3 gene provides instructions for making a protein called embryonic skeletal muscle myosin heavy chain 3. This protein belongs to a group of proteins called myosins, which are important for muscle development and function.

How is it diagnosed?

Freeman-Sheldon syndrome is usually diagnosed on the combination of problems, such as the contraction of the joints and the appearance of the face. Genetic testing for the MYH3 gene may help if the diagnosis is uncertain.

How is it treated?

Treatment for the condition consists of reducing the affects of the symptoms, therefore improving quality of life. Babies often need help with feeding in infancy and nutritional support. Growth should be monitored by a paediatrician through childhood. Physiotherapy should be used to alleviate the joint contractures and occupational therapy is often helpful. Many people require orthopaedic surgery to relieve joint contractures and improve function and mobility.

Glue ear can be a problem and is treated with grommets by an ear, nose and throat (ENT) specialist. A squint should be treated in the same way as in other children.

There may be malocclusion (misalignment) of the teeth and orthodontic treatment of this may be required. Opening the mouth fully for dental treatment may be difficult.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
Freeman Sheldon syndrome is usually inherited as an autosomal dominant trait, although often a child is the first member of the family to be affected. Affected families should be referred to a genetics centre for information and support

Prenatal diagnosis
Prenatal diagnosis would be available if the genetic alteration in the family is known.

Background

Fragile X syndrome is the most common identifiable cause of inherited intellectual disability and autism spectrum conditions. It arises from changes on the X chromosome in a specific gene that normally makes a protein necessary for brain development. Boys are usually more severely affected than girls as they have only one X chromosome. Girls have a second X chromosome, which can compensate for problems with the faulty one.  However some girls can be quite severely affected while some boys are only mildly affected.

Credits

Medical text written April 2016 by Professor J Turk. Last updated March 2018 by Professor J Turk,  Professor of Developmental Psychiatry, Institute of Psychiatry, University of London and Consultant Child and Adolescent Psychiatrist, Child and Adolescent Mental Health Neurodevelopmental Services, South London and Maudsley NHS Foundation Trust, London, UK.

Although great care has been taken in the compilation and preparation of all entries to ensure accuracy, we cannot accept responsibility for any errors or omissions. Any medical information is provided for education/information purposes and is not designed to replace medical advice by a qualified medical professional.

What are the symptoms?

The main feature is intellectual disability. This can range from very minor, so that the person has a normal IQ and shows no signs of fragile X syndrome though may experience difficulties with specific areas such as mathematics and social abilities, to severe intellectual difficulties. How badly someone is affected depends to a degree on the amount of genetic change on their X chromosome.

Other problems include delayed and distorted speech and language development. There can be difficulties with the social use of language and speech. There may also be repetitive behaviour, attention deficits and overactivity. In some individuals there may be evidence of autistic-like features (see entry Autism Spectrum conditions), such as repetitive speech, poor eye contact, hand flapping, social anxiety, abnormal shyness and an insistence on routine.

Associated physical features include a relatively large head, a long face with prominent ears, largish jaw and double-jointedness. However, these features are rarely obvious. Additionally, thirty per cent of people with fragile X syndrome develop epilepsy.

What are the causes?

The cause is an abnormal DNA expansion just above the tip of the X chromosome’s long arm. The expansion consists of small repeats of a DNA sequence, which are unstable and can get larger across generations. This means that a child can be more affected than the parent from which they inherited the changed X chromosome.

How is it diagnosed?

Diagnosis is by blood test, using DNA analysis to test for the change in the gene.

How is it treated?

There is no cure for fragile X syndrome. Psychological and educational support for children and their families are vital to help them reach their best potential and to maximise their quality of life.

For children with delayed speech and language development, specialised help from a speech and language therapist is important. Sensory issues and coordination difficulties may be helped by an occupational therapist. Hyperactivity and impulsivity may be alleviated by behavioural therapy and in some cases medication. Behavioural therapy can help children who have problems developing relationships, need assistance in developing social skills and need help coping with stressful situations.

Some children can be educated in mainstream schools, with support. However, some with more severe intellectual disability, or complicating factors like ASD or ADHD may need special schooling.

Adults with fragile X syndrome may require support with daily living tasks and may benefit from assisted living arrangements. This is dependent on the degree of intellectual disability.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
Fragile X syndrome is inherited in an autosomal recessive manner. Some people are carriers of the condition meaning that they carry an affected X chromosome but do not experience adverse consequences. However, the genetics is more complicated as some people only have a small change, called a permutation, in the gene. They too can experience developmental and psychological challenges but these are usually less marked than when there is a ‘full mutation’ of the gene. A premutation makes the gene unstable and at risk of developing into a full mutation when passed onto the next generation.

Prenatal diagnosis
Prenatal diagnosis is possible by chorionic villus sampling where a small piece of tissue from the placenta is analysed genetically. Fetal blood sampling is also possible.

Is there support?

Fragile X Society

Tel: 01371 875 100
Email: info@fragilex.org.uk
Website: fragilex.org.uk

The Society is a Registered Charity in England and Wales No. 1127861. It provides information and support to families affected by fragile X. The Society creates a network of families through an online community and support groups, and provides information in multiple languages, including Gujarati, Hindi and Urdu.

Group details last reviewed March 2018.