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On guard for Wolfram syndrome

Discussion

For a child presenting with the symptoms outlined in the case report, the common expected cause is diabetes mellitus (DM) type 1, an autoimmune disorder that results in the destruction of beta cells in the pancreas. Estimates of new cases of DM type 1 in the paediatric population in Ireland under the age of 15 are approximately 15 per 100,000 children per year (Roche, et al. 2005), although recent studies have recorded approximately 215 paediatric patients per year attending paediatric DM type 1 centres in Ireland (Hawkes and Murphy, 2014).

In addition to ‘common’ DM type 1, there are, collectively, a number of rare inherited forms of diabetes such as Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome, which result in glucose intolerance and multi-system disease involvement.

Wolfram, Alström, and Bardet-Biedl syndromes are all rare conditions (called the WABB syndromes) that affect the human body on a cellular level and carry with them multi-system complications. The constellation of symptoms includes glucose intolerance, neurological dysfunction and visual impairment and may include hearing loss. Alström syndrome often results in sensorineural hearing loss, cognitive delay and retinal dystrophy. In Bardet-Biedl syndrome, patients tend to present with obesity, retinitis pigmentosa and hypogonadism (Ayme et al, 2014).

Wolfram syndrome

Wolfram syndrome is a rare neurodegenerative condition with an estimated prevalence of 1/777,000 individuals in the UK. There are two types of Wolfram syndrome; Wolfram syndrome type 1 (WS1) and Wolfram syndrome type 2 (WS2) (Lopez De Heredia and Nunes Martinez 2014), with type 1 being more common. WS1 results in diabetes insipidus, DM, optic atrophy and deafness, a combination from which it derives its acronym, DIDMOAD.

The full DIDMOAD phenotype is seen in approximately 65 per cent of cases of WS1 (Lopez De Heredia and Nunes Martinez, 2014). WS2 shares many of these features, although diabetes insipidus is not seen in WS2 and patients with this variant have a greater tendency to develop coagulation disorders (Cassandra and McKusick, 2014).

The genetic basis for WS1 lies in the WSF1 gene, located on the short arm of chromosome 4. This gene is responsible for the coding of a protein known as wolframin, located in the membrane of the endoplasmic reticulum, which aids in the formation of new protein by controlling the levels of calcium in the cell. Without functional wolframin in the cell, the endoplasmic reticulum falters and programmed cell death is triggered.

This occurs in an array of tissues such as the pancreas, the optic nerve and the inner ear, resulting in the features of Wolfram syndrome (WSF1, 2012). WS2 is caused similarly by cell death within specific organs. This is due to dysfunctional mitochondria, coded for by mutations of the CISD2 gene, which is located on the long arm of chromosome 4 (Lopez De Heredia and Nunes Martinez, 2014).

As WS1 and WS2 are autosomal recessive conditions, two defective copies of the gene are required in each cell for the full expression of the syndrome.

There are approximately 200 different mutations known in the WFS1 gene that result in WS1. Carriers of WS1 (ie, parents and other first-degree relatives of affected children) have intermediate levels of functional wolframin protein and have been recognised to be at an increased risk of diabetes and deafness. With the risk to carriers, WSF1 may play a greater role in diabetes than previously suspected (WSF1, 2012).

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Figure 1: Research – ‘What is Wolfram syndrome?’ 2012 http://thesnowfoundation.org/research/

Diagnosis

The symptoms of Wolfram syndrome usually present themselves within the first 10 years of life. Generally, patients develop DM initially. A gradual decline in vision is often reported thereafter. Diabetes insipidus usually follows along with an array of other symptoms.

Neurological difficulties are a large component of Wolfram symptomatology. These include ataxia, epilepsy and cognitive disability (Ayme et al, 2014). Psychiatric disorders are also commonly seen in Wolfram syndrome; reported incidences of mental health illness and behavioural problems lie at 60 per cent (Hamosh and McKusick, 2013).

Renal tract complications, gastrointestinal disorders, hypogonadism and other ocular complications have also been reported in Wolfram syndrome. Beyond that, life-threatening outcomes can also arise; central apnoea due to bulbar dysfunction is frequent and may lead to aspiration pneumonia (Wolfram Syndrome, 2012).

Although rare, a diagnosis of Wolfram syndrome should always be considered in a patient with juvenile-onset DM and optic atrophy. However, the presence of DM type 1 alone is a very poor indicator of Wolfram syndrome.

A study conducted in diabetic patients under the age of 18 years found that only 0.12 per cent had Wolfram syndrome (Zmyslowska et al, 2014).

For a clinical diagnosis of Wolfram syndrome to be made, two major criteria, or at least two minor criteria and one major criterion, must be reached. Only two major criteria exist: the presence of DM and the presence of optic atrophy, both before the age of 16 years. Minor criteria consist of the presence of either major criterion after the age of 16 years, the presence of diabetes insipidus, sensorineural deafness, renal tract abnormalities and the presence of neurological symptoms. Diagnosis may also be made based solely on genetic testing (Ayme et al, 2014).

At 28 years of age, the patient in the case report is now legally blind and relies heavily on the use of hearing aids as a means of communication with the world around her. She has obvious gait abnormalities and occasionally suffers from seizures.

Diabetic control is also a huge part of her daily routine. She is currently on subcutaneous insulin injections three times a day and is unable to use an insulin pump due to her visual impairment. Her diet has to be tightly controlled to maintain adequate blood glucose readings. This is of great importance in her management, as studies have shown that better diabetic control slows neurodegeneration in Wolfram syndrome (Rohayem et al, 2011).

This patient currently lives at home with her parents and although she has a certain level of independence, she relies heavily on them on a day-to-day basis.

Awareness

Physicians and the public are well informed about ‘common’ DM type 1 and its management. However, access to information about rare causes of diabetes with other systems involvement has been limited in the past.

The care of a patient with any form of rare diabetes hosts a series of challenges. By virtue of their rarity, services for these disorders have historically been either non-existent or poorly resourced. There is currently no cure for Wolfram syndrome or similar conditions; treatment aims at managing the symptoms and complications that occur from having such a condition.

Orphanet is the leading rare diseases information portal in Europe. It provides information on 4,500 rare diseases, including information about management centres, testing centres, new treatments, patient registries, active research projects and clinical guidelines. Orphanet Ireland is accessible at www.orpha.net/national/IE-EN/index/homepage/.

The EURO-WABB is a project funded by the EC Public Health Programme and is a rare diseases registry (accessible via the Orphanet link), which provides information about Wolfram, Alström and Bardet-Biedl syndromes and other rare diabetes syndromes. The website of this project — www.euro-wabb.org/en/ — is a very useful, applied resource, aimed at both patients and professionals. The website contains, among other things, very clear and concise care pathways that can be downloaded and implemented in the care of these patients. This is especially helpful for healthcare professionals who may not be entirely familiar with the disease process and its management, as patients suffering from rare diabetic disorders will need a series of tests (including complex genetic testing), interventions and multidisciplinary team care at different stages of their lives, in addition to guidance on transition between paediatric and adult services.

Conclusion

Wolfram syndrome, along with Alström and Bardet-Biedl syndromes, reaches far beyond its title of ‘rare diabetes’.

These conditions result in multi-system dysfunction, disability and reduced life span. They are the cause of much distress and burden for the patient involved and their families, compounded by the fact that many of these families, in times past, have been isolated by virtue of the rarity of the disease.

With recent developments in the EURO-WABB and similar projects, the under-resourced, poorly informed services for patients with rare diabetes will improve and be replaced by a cohesive European healthcare delivery system, whereby patients can access the information and care plans that they need and deserve, from all healthcare professionals involved in their care.

Case report

A young girl was three-years-old when she first presented to her GP with polydipsia and polyuria. Her mother noted she had lost weight and was becoming tired easily. Urine dipstick analysis showed high levels of glucose and she was referred for further testing and a diagnosis of diabetes mellitus (DM) type 1 was reached.

The patient was commenced on insulin and was adjusting well to her new diagnosis. However, at five years of age, subtle hearing difficulties were picked up after concerns were voiced by her parents. No connection was made between the patient’s diabetes and hearing loss. At 11 years of age, she developed new-onset nocturnal enuresis and polydipsia, and she was diagnosed with diabetes insipidus. By this time, it had also been noted that the patient’s visual acuity was reduced. She then began to experience seizures and to display some gait abnormalities. The combination of symptoms and diagnoses she had experienced since early childhood finally led to a diagnosis of Wolfram syndrome, made by her paediatrician.

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