Condition AZ: a

In general terms there are two types of presentation in AGS. Some babies, especially those with AGS1 mutations (see ‘What are the causes?’), experience problems at or very soon after birth. Features include feeding difficulties, abnormal neurological signs, low platelets (blood cells involved in clotting), and liver abnormalities. In contrast, other children, develop normally for the first few weeks or months of life. They then experience the sudden onset of a period of intense irritability, cry a lot for hours at a time, sleep poorly, and can develop fevers without infection. During this period there is a loss of skills.

After a few months the disease process seems to ‘stop’. Many individuals with AGS are still stable in their late teens and early twenties. Typical neurological features of AGS include learning problems, stiffness of the limbs with poor body and head control, dystonia (impairment in muscle tone) of the limbs, and seizures (see entry Epilepsy). Although the neurological problems seen in AGS are often severe, a small number of children, usually those with AGS2 or AGS5-7 mutations, display good communication skills, and a few children can have completely normal intellectual development.

Seven different genes have been identified that, when damaged by a mutation, can cause Aicardi-Goutières syndrome (AGS). Only one gene is involved in any one family.

The following treatments may be used for the management of AGS:

• management of seizures (which are quite common in more severely affected children) using standard protocols
• some children need tube or gastrostomy feeding because of difficulties with feeding secondary to the associated neurological problems
• chest physiotherapy and antibiotic treatment may be needed for respiratory complications, which can occur secondary to the associated neurological problems
• in some cases, treatments may be considered for chilblains

Surveillance includes the following:

• assessment for glaucoma (seen in a small percentage of cases)
• monitoring of the spine for the development of scoliosis (which can sometimes occur because of muscle imbalance)
• monitoring for signs of insulin-dependent diabetes mellitus (IDDM) and hypothyroidism (these are rare, but treatable, associations seen in a small percentage of patients)
• in the case of SAMHD1-related disease, there may be need for monitoring of the blood vessels in the brain with special scans

Inheritance patterns
AGS is most frequently inherited as an autosomal recessive genetic disorder. This means that for a couple with one affected child there is a 1 in 4 risk of having a further affected child in any future pregnancy. However, there are rare autosomal dominant cases with specific genetic changes in AGS1 and AGS6, and the same dominant situation applies to all cases due to genetic changes in AGS7. Where the disease occurs due to a single ‘new mutation’ in the affected child, known as a sporadic mutation, the risk of recurrence is very low. Very rarely with dominantly inherited disease, a ‘carrier’ parent is at risk of having a more severely affected child.

Prenatal diagnosis
The availability of genetic testing allows for confirmation of the diagnosis of AGS in most, but not all, families. For couples where mutations have been identified in their child it may be possible to offer testing during a subsequent pregnancy.

Contact Professor Yanick Crow: [email protected]  

Group details last updated July 2018.

Learning disability is common and varies from moderate to severe. Most affected will have no expressive language and remain totally dependent on adults for their self-care. Self-injurious behaviours and aggression towards people and objects has been reported.

Associated epilepsy usually occurs by two months of age and remains difficult to control. Investigation with electroencephalogram (EEG), a recording of the brain’s electrical activity, may reveal a pattern characteristic of these spasms called hypsarrhythmia. This form of epilepsy is sometimes referred to as West syndrome. The majority of individuals with Aicardi syndrome are severely affected with persisting epilepsy. Disturbed sleep (possibly due to fitting) and waking in the night are also common problems.

The abnormalities at the back of the eye, evident only on internal examination with an ophthalmoscope, are to the structure of the choroid and retina. They appear as distinctive multiple, round ‘footprint shaped’ yellow-white lesions (marks). The level of vision depends upon the extent of these retinal lesions and the severity of any associated learning disability.

Aicardi syndrome is associated with a host of other variable symptoms. These can include abnormalities of the bony structure of the spine, spinal curvature (see entry Scoliosis) and cleft lip and palate. Life expectancy can be severely limited. There are some children with a milder structural brain abnormality who, although suffering visual impairment and learning difficulties, may have some understanding of language, some independent mobility and be responsive to their environment.

Diagnosis may not be made until the affected girl develops seizures and investigations such as a magnetic resonance imaging (MRI) scan to assess the corpus callosum and a special eye examination are carried out.

There is no cure for Aicardi syndrome. Treatment is only supportive aiming to alleviate the symptoms experienced by an individual. Choice of antiepileptic medication can be difficult as seizures are often resistant to it. Depending on the type of seizures present, drugs which may be effective include vigabatrin (Sabril) or a course of corticosteroids.

Inheritance patterns
The condition is transmitted in an X-linked dominant manner with lethality (death during development of the baby) in males. Reoccurrence within a family appears to be extremely uncommon.

Prenatal diagnosis
Although structural brain abnormalities may sometimes be evident on prenatal ultrasound scan, this is not the case in the majority of cases of Aicardi syndrome. There is no prenatal diagnosis available.

Support for Aicardi syndrome is available from CORPAL (see entry Agenesis of the Corpus Callosum).

The symptoms of ACC are best described under two headings: syndromic (those that are associated with a known syndrome), and nonsyndromic, agenesis of the corpus callosum that is not part of a known syndrome.

Non-syndromic ACC is common and affected patients usually have a large head, seizures and developmental delay. Hypertelorism (widely spaced eyes) also occur in many people with the condition. Seizures may be difficult to control. Hydrocephalus  can also occur.

Many neurological syndromes also include ACC. All of these have additional brain malformations and affected individuals are usually severely affected often displaying typical facial features and global developmental delay. This is often associated with other midline cerebral and cranial abnormalities such as septo-optic dysplasia. ACC is sometimes associated with abnormal development of the pituitary gland. Because of this, fits are sometimes due to hypoglycaemia (low levels of growth hormone and cortisol) as well as due to structural brain abnormality.

ACC may be, and often is, associated with other developmental brain abnormalities and it is often these, rather than the callosal agenesis itself, which is the cause of subsequent difficulties with the neurological system.

Inheritance patterns
In nonsyndromic ACC, genetic inheritance is rare. Genetic advice to affected individuals and their families can be helpful. More frequently, the non-syndromic form of callosal agenesis is an abnormality of brain development that is determined once a baby is conceived. In the syndromic form of ACC, referral for precise neurological diagnosis is required. The majority of these syndromes do occur sporadically but there are occasional groups reported with the condition occurring in families.

Prenatal diagnosis
ACC is undetectable through routine prenatal tests, however, it may be detected with a scan at 18 weeks.

CORPAL

Email: [email protected]
Website: corpal.org.uk

The Group is a Registered Charity in England and Wales No. 1086019. It provides information and support for children and adults with Agenesis of the Corpus Callosum or Aicardi Syndrome and their parents, families and carers. 

Group details last updated December 2014.

There are several forms of ALD. Not every person who carriers the genetic fault will develop any symptoms and even within families people may develop different forms of the disease.

Childhood cerebral form – boys usually develop normally until they reach between four to ten years of age when behavioural changes, such as loss of memory and emotional instability may be experienced often appearing first as school difficulties. The condition progresses with vision, hearing and movement problems. The adrenal glands may fail (see entry Addison’s disease). There is continuous progressive deterioration of the nervous system in the cerebral form of ALD. The rate of deterioration varies in each child.

Adolescent/adult cerebral form – similar difficulties occur in a smaller number of teenagers and adults and may be mistaken initially as psychiatric problems

Adrenomyeloneuropathy/myeloneuropathy (AMN) – a different form of ALD may occur in men or women during late adolescence, or early adult life. It causes difficulty with walking and bladder function and may be misdiagnosed as multiple sclerosis. Adrenal function is often affected, although not in women.

Neonatal ALD – despite the similar name, has a completely separate genetic cause and has more severe problems with brain development, vision, hearing and epilepsy.

ALD is caused by a fault (mutation) in the ABCD1 gene, which is responsible for transporting special types of fat in a particular part of the body’s cells.

In males measurement of very long chain fatty acids (VLCFAs) in a blood sample shows elevation of particular types of fat. The diagnosis can be confirmed by genetic testing. VLCFA measurement is unreliable in women and gene testing should be carried out if myeloneuropathy is suspected or to confirm carrier status (somebody who carries the ABCD1 mutation, but doesn’t have symptoms of the condition) in an unaffected female relative if requested.

If the adrenal glands are failing treatment with replacement hormones is very important.

Asymptomatic boys (those that display no symptoms of the condition) are carefully monitored and if the brain disease appears a bone marrow transplant may be offered, which can be cure the condition.

Successful early trials of genetic manipulation of patients’ own cells have occurred for boys for whom there was no appropriate bone marrow donor.

Lorenzo’s oil and a low fat diet may have a role for boys who are asymptomatic aiming to reduce the risk of developing cerebral ALD.

There is no cure for symptomatic ALD and supportive treatment, to give the best quality of life to affected boys, is very important.

Inheritance patterns
X-linked inheritance.

Prenatal diagnosis
Prenatal diagnosis is usually by genetic analysis of a sample of foetal cells collected by chorionic villus sampling (CVS). Preimplantation genetic diagnosis has been successfully performed for this condition.

Alex, The Leukodystrophy Charity (formerly ALD Life)

Tel: 020 7701 4388
Email: [email protected]
Website: www.alextlc.org

Alex, the Leukodystrophy Charity,  is a Registered Charity in England and Wales No. 1106008. It provides practical support, advice and information to patients and families with Adrenoleukodystrophy (ALD) and other Leukodystrophies. Services include financial support, and bringing families together to share experiences.

Group details last updated July 2019.

There is often an infection that occurs before the diagnosis of ADEM, or even an immunisation, the interval varying between several days up to one month, the average being one to two weeks. In a minority of cases there is no clear preceding illness. At the beginning, symptoms can be non-specific but nonetheless worrying, such as fever, headache, stiff neck, a loss of appetite and vomiting. This is usually followed by or accompanied with a decreased conscious level such that the child may seem confused, lethargic or drowsy and does not respond in their normal way. For a diagnosis of ADEM to be made, a child’s level of consciousness must be affected and this is referred to as ‘acute encephalopathy’. At times the child can even slip into coma.

Other symptoms include:

• difficulties standing or walking
• hemiparesis (weakness down one side of the body)
• balance problems or ataxia (unsteadiness)
• cranial nerve palsies (paralysis of the nerves that emerge directly from the brain)
• visual impairment or visual loss due to inflammation of the optic nerve (eg optic neuritis) often involving both eyes
• epileptic seizures (these are more common in the younger child – five years old or younger).

Why ADEM occurs remains poorly understood. The risk of developing ADEM seems to be dependent on an interaction between different factors: an individual’s genetic predisposition, exposure to infectious agents or to immunisation and the individual’s immune response to the latter.

As ADEM is generally preceded by an infection, this suggests an immune/inflammatory process is important. Whilst many different bacteria, viruses and other infections have been related to ADEM, this condition does not appear to be caused by any one specific infectious agent.

A special committee, the International Pediatric Multiple Sclerosis Study Group (IPMSSG*) was brought together to define ADEM, given variations in its definition until then, and also because there are no diagnostic tests for this condition. The group established criteria for the definition of ADEM in 2007, which were recently reviewed and amended in 2013 and are now largely accepted as a definition to aid a working diagnosis of ADEM.

In the early stages of the illness, a child may be thought to have meningitis or encephalitis. The diagnosis of ADEM is made based upon i) the clinical history and its evolution, ii) brain imaging  and iii) other tests.

Magnetic resonance imaging (MRI) scans of the head are done and often show changes as described by the IPMSSG* criteria. Other tests include a lumbar puncture, where a small amount of fluid called cerebrospinal fluid (CSF) is removed from the spine with a needle inserted in the lower back. This fluid is analysed and in ADEM it is often abnormal with an increase in white cells and protein. An electroencephalogram (EEG), which records the surface brain activity, is also done and often found to be abnormal.

In the initial stages, antibiotics and antiviral drugs are given in the veins (intravenously). When ADEM is diagnosed, high-dose steroid (methylprednisolone) given intravenously (through a vein) for a few days is the main form of treatment. Most children recover significantly, if not completely, and overall the prognosis is very good.

Other treatments used are: intravenous immunoglobulin (IVIG).  Throughout the illness the child has to be monitored closely. At times this can mean intensive care with the child placed on a ventilator, especially if the child’s breathing or swallowing is affected.

Steroids and IVIG are treatments that can change the body’s immune response, which is known as immunomodulation. There is often a dramatic improvement after this type of treatment.

Some research studies of children that had ADEM have reported a small group of patients who then went on to develop multiple sclerosis. There is a lot of research that is ongoing in this area.

Inheritance patterns
It is thought that an individual’s genetic make-up can make some people more likely to develop ADEM in the context of some infectious triggers, this is known as ‘genetic susceptibility’. However this is difficult to prove. ADEM is not thought to be a ‘genetic or inherited’ condition as such.

Prenatal diagnosis
Not applicable.

Information and support in the UK for acute disseminated encephalomyelitis is provided by the Encephalitis Society (see entry Encephalitis).

Symptoms are due to the low number of normal blood cells. Reduced red blood cells (anaemia) causes pallor (a pale colour to the skin) and tiredness, reduced platelets (a condition known as thrombocytopaenia) results in bruising and, less often, bleeding because of a failure of blood to clot, and low white blood cells may result in fevers due to infections.

Almost all cases of aAA in children are due to the body’s immune system incorrectly attacking early bone marrow cells (stem cells). This attack may be triggered by a viral infection, including hepatitis. Most of the time, no cause is found.

Diagnosis requires taking two bone marrow samples called an ‘aspirate’ and a ‘trephine’, which allows doctors to measure whether the bone marrow is producing the correct amount of cells. Other tests are used to try and find the cause of the aAA, and to include those to identify other illnesses that may affect the bone marrow.

It is rare for the bone marrow to recover without treatment, which may either be by drugs that suppress the immune system, or by a stem cell transplant to replace those cells damaged in the bone marrow and to provide a new immune system which does not attack the bone marrow. Both treatments are very effective, but stem cell transplantation is often the treatment of first choice when a tissue matched donor is available. This is usually a brother or sister of the child with aAA. Identifying a donor requires blood samples to be taken from the immediate family. Over recent years it has become possible to find a stem cell donor who is unrelated to the patient, and this greatly increases the availability of donors. In some children with aAA, an unrelated stem cell transplant will be recommended when there is no family member who is suitable.

The immune suppressive drugs used when a stem cell transplant is not the chosen treatment are called antilymphocyte globulin (ALG) and ciclosporin. Both work by reducing the number and activity of immune system cells called T lymphocytes, which are responsible for attacking the bone marrow. A third drug, prednisolone, is given with the ALG to reduce allergic side effects of the ALG drug.

Inheritance patterns
None.

Prenatal diagnosis
None.

Aplastic Anaemia Trust

Tel: 0870 487 0099
Email: [email protected]
Website: www.theaat.org.uk

The Trust is a Registered Charity in England and Wales No. 1107539. It provides information and support to anyone in the UK who is affected by aplastic anaemia.

Group details last updated January 2016.

There is no support group for acne in the UK. Families can use Contact’s freephone helpline for advice and information. Chat to other families online in our closed Facebook group.

People with achondroplasia have a range of characteristics, including:

• a near normal trunk length with shorter arms and legs
• a large head with prominent forehead and flattened bridge of the nose
• an increased curvature of the lower spine (lumbar lordosis)
• bowing of the lower legs
• crowded teeth, in some cases
• short, broad feet and hands with separation between middle and ring fingers (known as the ‘trident’ hand)
• flexible joints.

Babies with achondroplasia may develop their motor skills (the ability to use and co-ordinate the muscles in their body) and mobility more slowly than normal because of the combination of a heavier head and shorter arms and legs, but ultimately their development should be within the expected normal range.

Achondroplasia is due to a change, called a mutation, in the gene that codes for fibroblast growth factor receptor 3 (FGFR3), an important component of bone development. This leads to FGFR3 being activated resulting in restricted bone growth. In almost all cases, the change in the DNA which makes up the gene occurs at exactly the same point each time making it relatively straightforward to detect.

How is it diagnosed?

Diagnosis will be based on the presence of typical clinical features. X-rays may be needed to demonstrate changes in the skeleton that confirm the presence of the condition. Molecular testing (testing DNA) of those affected can confirm if the mutation in FGFR3, and therefore the condition, is present.

There is no cure for achondroplasia, but many of the problems associated with the condition can be detected and addressed through regular health checks involving a multidisciplinary team of health professionals including the general practitioner (GP). Growth charts designed specifically for children with achondroplasia should be used to monitor weight, length and head growth.

Children should see a paediatrician regularly who will be able to keep an eye on development and advise on lifestyle changes, such as a good diet and regular exercise. Surgery may be required to aid with spinal curvature and leg bowing. Regular assessment by a community dentist may be required to assess any dental problems.

Most people with achondroplasia are born to average size parents where the change in the FGFR3 gene has occurred for the first time prior to conception (sporadic mutation). For parents with achondroplasia the inheritance pattern is autosomal dominant.

Ultrasound scans may detect disproportionately short limbs at around 25 weeks of pregnancy. For couples where one or both already has the condition, a chorionic villus sampling test or amniocentesis may be available to look for the change in the FGFR3 ge

Information and support in the UK for achondroplasia is provided by the Restricted Growth Association (see entry Restricted Growth).

Exomphalos

The size of the exomphalos depends on the number of organs exposed. This is usually the bowel but may include the liver and other organs. The sac containing the exposed organs is usually covered in a protective membrane. Sometimes exomphalos occurs in conjunction with other problems such as chromosomal (gene) or heart defects.

Gastroschisis

In gastroschisis some of the bowel has escaped through a hole in the abdominal wall and develops outside of the baby’s abdomen. The bowel floats around in the amniotic fluid – this is a liquid that surrounds the unborn baby (fetus) – in the mother’s womb for most of the pregnancy and sometimes the fluid irritates the bowel and makes it inflamed and thick, so that it does not work properly. Sometimes the bowel becomes twisted as it floats in the fluid and the blood supply is restricted. When the baby is born, the bowel is exposed to the air which sometimes causes further inflammation to occur.

Exomphalos can, in some circumstances, be associated with genetic abnormalities. It occurs across all maternal (mothers) ages.

Gastroschisis is associated with young maternal age, with mothers under 20 years being twelve times more likely to have infants with gastroschisis. It is usually not associated with other abnormalities outside of the intestine.

Most babies with abdominal wall defects will be identified during pregnancy by fetal ultrasound.

The parts exposed out of the baby’s abdomen are usually wrapped in surgical cling film, which helps prevent infection. Once the baby is stable, surgery can be performed. If there is only a small amount of bowel outside the abdomen, it will be returned to the baby’s abdomen and the wound closed. This is called a primary repair.

Sometimes if the gastroschisis/exomphalos is large or if the abdominal cavity is small, a surgeon will construct a pouch in which the gastroschisis/exomphalos is placed. The pouch is then suspended from the ceiling of the incubator and gravity along with a reduction of the size of the pouch will help the gastroschisis/exomphalos to slip back inside the abdomen. This can usually be done in a week for gastroschisis, but may take considerably longer for exomphalos.

Some genetic syndromes are associated with exomphalos (eg Beckwith-Wiedemann syndrome). Gastroschisis is virtually always an isolated abnormality with no pattern of inheritance.

Pre-natal diagnosis
Diagnosis can be made by ultrasound scan during pregnancy.

Families can use Contact’s freephone helpline for advice, information and, where possible, links to other families.

Aarskog Foundation UK

Tel: 0800 001 6623
Email: [email protected]
Website: aarskogsyndromefoundation.co.uk

The Aarskog Foundation UK is a Registered Charity in Scotland no. SCO48708. They aim to provide support to all those affected by Aarskog Syndrome, their friends, families and carers. They provide information, raise awareness of the condition and aim to bring families together.They also have different Facebook Groups to support families and professionals.

Group details updated March 2020.