Wolfram syndrome, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare autosomal recessive disorder with an estimated prevalence of 1 in 770,000. The minimal criteria for diagnosis are juvenile-onset diabetes and optic atrophy, but patients may also develop diabetes insipidus, sensorineural deafness, renal tract abnormalities, and neuropsychiatric disorders. Variants exist with only partial features, and prognosis is mainly linked to the severity of the neurological symptoms. Wolfram syndrome is genetically heterogeneous: most patients carry mutations in the WFS1 gene, encoding an endoplasmic reticulum membrane embedded protein called Wolframin. A second causative gene is CISD2, which encodes a mitochondrial protein. Mutations in the WFS1 gene are also associated with the poorly defined ‘Wolfram-Like Syndrome (WS-like) disorders’ including diabetes, optic atrophy or deafness inherited in dominant or recessive fashion, and in dominantly-inherited low-frequency sensorineural hearing loss. There is no specific therapy, but screening for associated features may alleviate their consequences to some extent.
Wolfram syndrome (WS) is a rare neurodegenerative disorder characterised by childhood onset insulin dependent diabetes mellitus (DM) and progressive optic atrophy (OA). The syndrome was originally reported in 1938 by Wolfram and Wagener in four siblings. The prevalence of Wolfram syndrome in the United Kingdom was estimated to be 1 in 770 000 with a carrier frequency of 1/354 in a case-finding study from 1995 . The prevalence is higher in South Asia, the Middle East and North Africa, probably due to a higher prevalence of consanguinity. A higher carrier frequency of up to 1/100 has been suggested.
DM and OA are the minimal diagnostic criteria for diagnosis of this disease; however WS patients also present with additional complications, hence the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). The mean age of presentation of diabetes mellitus has been reported to be 5±4 years . The cause of the diabetes is selective non-autoimmune, non-HLA linked, beta-cell death .
The natural history of WS is shown in Figure 1 A&B
Reprinted with permission from Elsevier(The Lancet 1995;346:1458-1463); it shows the presentation of diabetes mellitus in the first decade of life and optic atrophy leading to blindness in the first to the second decades. Deafness, renal complications and diabetes insipidus appear often in 2nd to the 3rd decades. Neurological complications such as ataxia, autonomic nervous system dysfunction, mental retardation and brainstem atrophy occur in 3rd to 4th decade. However, very recent studies based on MRI scans of young patients and more detailed neurological examinations, showed that neurological symptoms actually occur in the first decade of life (Figure 1B) . Death is premature and may arise from intercurrent infection, or respiratory failure as a result of brain stem atrophy .
Figure A) The median age of onset of the symptoms and complications of Wolfram syndrome are presented with different curves and the intersections with the x-axis. .
Figure B) Neurological complication seem to occurs earlier in childhood than previously thought .
Wolfram syndrome has an autosomal recessive pattern of inheritance. The causative gene for this syndrome, WFS1, was identified by two different groups in 1998. These researchers cloned WFS1 and positioned it on the short arm of chromosome 4 (4p16) by linkage analysis and genetic mapping using microsatellite markers . The gene was named WFS1 by Inoue and colleagues and the protein was named Wolframin by Strom and colleagues. Figure 2 shows a schematic representation of WFS1. Its genomic structure comprises 8 exons of which exon 1 is non-coding. The majority of mutations found in WFS1 are in exon 8 as this exon covers half of the coding region of the gene (1,812 nucleotides) .
More than 90% of WS patients carry mutations that result in a loss of function of the WFS1 gene . According to the Euro-WABB mutations data base (www.euro-wabb.org), there are currently about 225 mutations (46% missense, 16%, nonsense, 22.7% frame shift, 8% deletion, 0.2% insertion 1.8% duplication and 3% others) identified in the WFS1 gene, from which the majority are loss of function mutations. WS is genetically a very heterogeneous disease, and because of its rarity it has been difficult to identify clear genotype phenotype correlations. A recent report by Chaussenot and colleagues conducted a detailed clinical study and genotype-phenotype correlation in 59 patients, so far the largest number of patients. They demonstrated a correlation between neurological manifestation and the location of the mutation within the gene . This study showed that patients with neurological complications more frequently had a mutation in the C-terminal domain, and presence of mutations in the N-terminal domain were significantly correlated with the absence of neurological symptoms.
Studies have shown that first degree relatives of WS patients have increased frequencies of diabetes mellitus and certain psychiatric disorders, suggesting that sequence variants of the WS gene predispose these individuals to these conditions. A review by Fawcett (2010) described studies which have shown that common gene variants of WS influence the susceptibility to type 2 diabetes . The first study uncovered 5 non-synonymous coding variants, encoding amino acid changes, by DNA sequencing of diabetic patients. The most important genetic variant changes the amino acid Histidine to Arginine (H611R) at position 611; this variant is thought to be protective from diabetes. A genome-wide association study showed that variations in WFS1 gene are associated with susceptibility to type 2 diabetes using 1,500 SNPs as markers for 84 beta cell candidate genes in a large number of UK Europe and Ashkenazi Jewish cases and controls. This study identified four associated SNPs with significant linkage disequilibrium (LD) in a 39 kb LD block, including the H611R variant.
In recent years, a second form of WS has been reported in Jordanian families. This gene was named WFS2 and mapped to the locus 4q24 . In addition to WS clinical features, with the exception of diabetes insipidus, these patients also suffer from bleeding tendencies and defective platelet aggregation.
WFS1 protein Wolframin
WFS1 encodes a 100 KDa protein called Wolframin which is primarily located to the membrane of the Endoplasmic Reticulum (ER). This is an integral glyco-protein containing 9 trans-membrane domains and 890 amino acids. The domains are embedded in the ER membrane with the amino terminus in the cytosol and the carboxyl-terminus in the ER lumen.
The pathophysiology of Wolfram syndrome suggests that Wolframin is involved in the survival pathways of neurons and pancreatic beta cells. Furthermore, studies have demonstrated crucial functions of Wolframin in the regulation of ER stress, ER stress induced apoptotic pathways, insulin biosynthesis, acidification of the secretory granules and regulation of ER calcium homeostasis .
A large body of evidence is suggesting that WFS1 is involved in ER stress pathways and is associated with the three ER stress sensors. A study by Fonseca and colleagues showed that WFS1 is a component of IRE1 and PERK signalling pathway and its expression is regulated by these two proteins. These authors demonstrated attenuation of ER stress by induction of WFS1 expression in IRE1α-/- and PERK-/- cells. This study suggests that WFS1 protects the cells against ER stress . Similarly, another study by Fonseca and colleagues in 2010 demonstrated that WFS1 plays a key role in the negative regulation of a feedback loop in the ER stress signalling network through the ubiquitin proteasome pathway. The authors suggested that WFS1 prevents secretory cells from death caused by dysregulation of this signalling pathway . This study showed that HRD1 (ER-resident E3 ligase) forms a complex with ATF6a and WFS1 and that WFS1 plays a role in the stabilisation of HRD1. The authors imply that under non-stress condition, the WFS1-HRD1 complex causes suppression of UPR by recruiting ATF6 to the proteasome and enhancing its ubiquitination and proteasome-mediated degradation. In the presence of ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress.
Diagnosis of Wolfram syndrome
The diagnostic criteria for Wolfram syndrome are shown in the box:
|Major criteria||Minor criteria||Minimum required||Other variable suggestive evidence:|
|*Diabetes mellitus <16 yrs, *Optic atrophy <16 yrs||*Diabetes insipidus, *Diabetes mellitus > 16 yrs, *Optic atrophy >16 yrs, *sensorineural deafness, *Neurological signs (ataxia, epilepsy, neuropathy, cognitive impairment), *Renal tract abnormalities, *1 loss of function mutation in _WFS1/CISD2_ AND/OR family history of Wolfram syndrome||*2 major OR *1 major plus 2 minor criteria||*Hypogonadism (males), *Absence of type 1 diabetes auto-antibodies, *Bilateral cataracts, *Psychiatric disorder, *Gastrointestinal disorders|
Note: The diagnosis is established in individuals of all ages in whom two pathological WFS1 or CISD2 mutations are identified. The differential diagnosis includes :
Differential diagnosis includes:
- Mitochondrial disorders: Maternally Inherited Diabetes mellitus and Deafness, Leber Hereditary Optic Neuropathy
- Thiamine-responsive megaloblastic anemia, diabetes and deafness
- Autosomal Dominant Optic Atrophy
- X-linked Charcot-Marie-Tooth disease type 5
- Deafness, Dystonia, Optic Neuronopathy syndrome
- Friedreich ataxia
- Bardet-Biedl syndrome
- Alstrom syndrome
Clinical management of Wolfram syndrome
Currently there is no specific treatment for WS. Clinical management consists of genetic counselling, screening for complications and their management. The following are helpful baseline screening investigations:
Diabetes mellitus: Fasting plasma glucose and HbA1c. Type 1 diabetes associated auto-antibodies most often absent: mainly glutamate decarboxylase (GAD), (IA-2) and insulin antibodies. Low insulin reserve is expected and best assessed by basal and/or post standard meal stimulated C- Peptide measurements. Note that Wolfram patients present rarely with diabetic ketoacidosis.
Diabetes insipidus: Morning paired urine and fasting plasma for osmolarity and sodium concentration after nocturnal and morning euglycaemia.
Hypogonadism: Testosterone, oestrodiaol, FSH and LH, inhibin B
Optic atrophy: Visual acuity, fundus examination, visual field, OCT scan, visual evoked potentials, colour vision testing
Sensorineural deafness: Audiogram, auditory evoked potentials
Neurodegeneration: Neurological examination with brain MRI and cognitive assessment Other specific investigations according to the results of clinical examination. Mental health assessment. Consider test of olfaction
Neuropathic bladder: Questionnaire regarding urinary symptoms with voiding diary, Assessment of renal function (blood electrolytes, urea, creatinine, GFR), ultrasound renal tract and urodynamic testing.
The following annual review screening is recommended:
Nephropathy: Yearly screening, starting at 12 years of age, in patients with duration of diabetes >5 years
- First morning or random urine albumin to creatinine ratio, and microalbuminuria demonstrated.
- Introduce renoprotection with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as soon as microalbuminuria is confirmed.
Diabetes mellitus: Yearly screening in patients with duration of diabetes more than 5 years
- Fundoscopy, OCT scan and fluorescein angiography if signs of diabetic retinopathy are present
Neurological complications: Yearly neurological exam to look for numbness, pain, cramps and paresthesia
- Nerve conduction studies and dysautonomia assessment in presence of clinical signs or symptoms
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