Wolfram Syndrome Type 1&Type 2

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This entry is adapted from the peer-reviewed paper 10.3390/ijerph18094796

Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy.

Wolfram Syndrome

1. Introduction

Wolfram syndrome (WS) is a rare neurodegenerative disorder that is sometimes referred to as Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD), and it was described for the first time by Wolfram and Wagener in 1938 ^[1]. They described four siblings who were born to consanguineous parents with diabetes mellitus (DM) and optic atrophy, which are key elements that are used to diagnose this syndrome. In 1966, Rose et al. ^[2] reviewed the literature and suggested that this syndrome could be due to homozygous mutation in the disease gene. Furthermore, in consideration of the clinical heterogeneity and wide clinical spectrum involving different organs, they hypothesized that one or more additional genes could play a role in modulating the phenotype. In 1994, more than 50 years after the syndrome was first described, Polymeropoulos et al. ^[3] described the WS locus on the short arm of chromosome 4. Four years later, Inoue et al. ^[4] described the wolframin gene (WFS1; 606201) as the WS disease gene. They reported that WFS1 encodes a transmembrane protein in beta cells and neurons, which explains the pleiotropic features of the syndrome. In 2000, El-Shanti et al. ^[5] provided evidence that there are two different subtypes of WS. They studied Jordanian siblings who were born to consanguineous parents featuring the typical WS phenotype and gastrointestinal symptoms, and they provided conclusive evidence of the existence of a second autosomal recessive form of WS, called WS type 2 (WFS2; 604928). A linkage study later showed that a second locus could be localized in 4q22-q24. In 2007, Amr et al. ^[6] showed that the WFS2 disease gene is the CISD2 gene (611507.0001), which encodes the endoplasmic reticulum (ER) intermembrane small (ERIS) protein that is located in the ER.

2. Epidemiology

WS is very rare. The first epidemiological study was a nationwide study that was conducted in the UK in 1995, and it showed a prevalence of one in 770,000 subjects ^[7]. This study showed results that were similar to data from Japan, which indicated a prevalence of one in 710,000 ^[8]. The prevalence is reported to be strikingly higher in Lebanon, where Zalloua et al. ^[9] found 22 patients with a genetically confirmed diagnosis of WFS1 out of 399 (5.5%) with juvenile onset diabetes. Other papers reported a lower prevalence of WS (<0.5%) in patients with DM from Italy ^[10]^[11] and China ^[12], and this prevalence was even lower (0.04%) in a large international multi-center pediatric diabetes registry ^[13]. No epidemiological data are available about WFS2 because patients have not been diagnosed in all countries. Only one paper distinguished between the two types, and four patients with genetically confirmed WS were reported, three with WS type 1 and one with WS type 2 ^[11].

3. Clinical Findings and Treatment

WS is a progressive neurodegenerative disorder, which should always be suspected in patients with insulin-dependent DM and optic atrophy. DM often occurs before 10 years of age. Diabetic ketoacidosis is rare, the insulin requirement is low, and the clinical course is not progressive, and it is also milder than type 1 DM ^[14]. Microvascular complications are uncommon, and they are likely related to residual insulin secretion. Unfortunately, hypoglycemia episodes may be frequent due to neurologic dysfunctions, which may lead to hypoglycemia unawareness. The treatment is based on the basal-bolus insulin regimen and the metabolic control is effective even on low doses ^[15].

Optic atrophy is progressive, and it is usually diagnosed before 15 years of age. It is characterized by a progressive decrease in visual acuity with a color vision defect, which leads to blindness. No treatment is currently available to stop the progression of eye involvement. Less frequent findings may include cataract, nystagmus, and pigmentary retinopathy ^[15].

Besides these two key elements for the diagnosis of WS, several other possible clinical findings that involve different organs may occur. The most frequent occurrence is sensorineural hearing loss, which is estimated to involve about two-thirds of these patients. The clinical spectrum may range from congenital deafness to mild impairment, which is sometimes progressive as a consequence of the central nervous system degenerative process ^[7]. It is usually diagnosed in the second decade of life. The audiogram typically shows a downward sloping progressive pattern of hearing loss ^[16]. Regular monitoring is suggested for appropriate treatment, and hearing aids and cochlear implants may be therapeutic tools for these patients ^[17].

DM is not the only endocrine disease in WS. Diabetes insipidus is frequent, and it occurs mostly in the second decade of life. It is characterized by the loss of ability to concentrate urine, leading to low osmolality urine with polyuria. It can be also partial, making this diagnosis more difficult, and thus, it is often delayed. Most of the patients respond well to treatment with desmopressin ^[18]. Male patients may present hypogonadism more frequently than female patients, secondary to hypothalamus–pituitary axis impairment or gonadal failure. Hypothyroidism and growth retardation have also been reported, and some pregnant patients have been described ^[15].

Neurologic abnormalities occur later, usually in the third and fourth decade of life in about 60% of the patients. A more detailed evaluation may show subclinical neurological abnormalities even in earlier stages of the disease (late puberty), and thus, the mean age at onset of these abnormalities is currently considered to be more precocious than in the past. They are progressive, leading to general brain atrophy, which is more prominent in the cerebellum, pons, and medulla, and there is brain stem and cranial nerve involvement ^[7]^[19]^[20]. There is no evident correlation between neurological imaging and clinical findings ^[21]. Other uncommon findings may be truncal or gait ataxia, central apnea, dementia, and intellectual disability. A significant increase in suicidal behavior and psychiatric illness has been reported ^[22]. Neurological abnormalities may also involve the urinary tract, causing neurogenic bladder with hydroureter, urinary incontinence, and recurrent infections. Incomplete bladder emptying or complete bladder atony may be detected by a urodynamic examination, which is required in patients with these symptoms.

De Heredia et al., analyzed clinical and genetic data from 412 patients with WS who were reported in the literature in the previous 15 years ^[23]. They showed that 98.2% of the patients had DM, 82.1% had optic atrophy, 48.2% had deafness, and 37.8% had diabetes insipidus. Urological manifestations and neurological symptoms were described in 19.4% and 17.1% of patients, respectively. However, the phenotype depends on the age of the patient, and thus, less frequent clinical findings may become more frequent in older patients. Death occurred at a median age of 30 years, with two frequency peaks around 24 and 45 years.

Life expectancy is shortened. About 65% of WFS1 patients die before 30–40 years and the average age of death is 30 (range 25–49) years ^[24].

The clinical picture that is reported above is the typical WS phenotype that is described in the literature. Over the past two decades, upper intestinal ulcers and defective platelet aggregation have been reported in some patients. These clinical findings are absent in WFS1 and are pathognomonic of WFS2 ^[25]^[26] and, thus, they represent important points for a differential diagnosis, which leads to analysis of the CISD2 rather than the WFS1 sequence. They have been observed in up to 90% of patients with WFS2 ^[27].

As in WFS1, optic atrophy is progressive and associated with the loss of ganglion cells, even if the eye impairment in WFS2 is milder and even if there is less progression ^[5]. Mozzillo et al., discussed eye involvement and provided data suggesting that involvement of the optic nerve is compatible with a diagnosis of optic neuropathy rather than that of optic atrophy ^[26].

Differences in the phenotype between WFS1 and WFS2 are related to a difference in tissue expression of WFS1 and CISD2. Table 1 summarizes the typical clinical findings in both types.

Table 1. Clinical features of Wolfram syndrome type 1 and type 2 and age at onset. Major clinical findings are reported in order of age at onset in the clinical history. Adapted from Pallotta et al. ^[28].

Major Clinical Findings	Other Clinical Findings
Diabetes mellitus (a) Age at diagnosis: 6–10 years	Urinary tract problems and renal dysfunction (neurogenic bladder, bladder incontinence, urinary tract infection) Age of diagnosis: second decade of life
Optic atrophy (a) Age at diagnosis: 10–15 years	Psychiatric symptoms (depression, psychosis, panic attacks, sleep abnormalities, mood swings)
Diabetes insipidus Age at diagnosis: 14–20 years	Neurological manifestation/autonomic dysfunction (central apnea, dysphagia, areflexia, epilepsy, decreased ability to taste and detect odors, headache, orthostatic hypotension, hypothermia, hyperpyrexia, gastroparesis, constipation)
Sensorineural hearing loss Age at diagnosis: 16–20 years	Endocrine disorders (hypogonadism, growth hormone deficiency, corticotropin deficiency, delayed menarche)
Ataxia Age at diagnosis: 15–25 years	Dominant disease with or without diabetes mellitus and recessive Wolfram-like disease without diabetes mellitus
Upper intestinal ulcers and platelet aggregation defect (b)

Treatment Perspective

Each disorder that is associated with WS can be properly treated, but the main goal of a specific treatment for WS would be to stop disease progression in all the involved tissues ^[29]. Possible specific drugs should aim to prevent cellular aging and the degenerative process, by the maintenance of ER, calcium homeostasis, protein folding, and redox regulation ^[29]^[30]^[31]. Current ongoing projects in regenerative medicine and gene therapy are great challenges for the treatment of WS and all neurodegenerative disorders ^[28], but the clinical application seems to remain unchanged. To date, there are no pharmacological therapies for WS.

The most suitable treatment strategy seems to be based on chemical chaperones, which play a role in protein folding in the ER. Two chemical chaperones, 4-phenylbutyricacid (PBA) and tauroursodeoxycholic acid (TUDCA), are under investigation. They preserve beta cell function by reducing stress and cell death. Furthermore, they slow down the neurodegeneration process ^[32]. Another approach is based on the prevention of calcium-mediated ER stress, and in turn, prevention of cell death, by modulating intracellular calcium levels. Dantrolene, which is used for some neurological disorders, suppresses the efflux of calcium from the ER to the cytosol, which preserves the integrity of beta and neural cells ^[33]. A similar effect could be exerted by drugs that bind to the sarco/ER Ca²⁺-ATPase, which is a substrate of Wolframin, or that target the calcium channel receptor that is activated by inositol triphosphate ^[34]. Finally, valproate acid is also being investigated as a novel drug treatment for neurodegeneration and diabetes in WS. Valproate acid is neuroprotective, and recently, a phase 2 clinical trial in patients with WS has been started.

Besides these experimental trials, different hypoglycemic agents, which are already licensed for DM, have been shown to improve glycemic control in these patients with limited and controversial effects on the generation process ^[28]. However, their use seems to be effective only on blood glucose homeostasis and not on the pathogenesis of WS.

4. Genetic Analysis of Wolfram Syndrome

According to the literature that was examined in this review, WS is caused by WFS1 and CISD2 mutations. Therefore, if WFS1 is suspected, it is appropriate to proceed to the sequencing of all eight of the exons and their flanking intronic regions. Similarly, if WFS2 is suspected, it is useful to sequence the three CISD2 exons and their flanking intronic regions.

Additionally, WS could be caused by point mutations and, in some cases, by the deletion of an entire exon. Thus, it is recommended to perform an exhaustive molecular analysis that is aimed to identify any type of genetic alteration including quantitative imbalance such as “copy number variation” (CNV) as well as the possible presence of UPD.

5. Conclusions

WS is a rare and severe neurodegenerative disorder that involves different organs. To consider the pleiotropic manifestations, a multidisciplinary, team approach to the different clinical problems should be used for these patients. This diagnosis should be considered in all the patients with DM and optic atrophy and with an overall absence of type 1 DM autoantibodies. We recommend that this diagnosis should also be suspected in patients with non-autoimmune DM who present less frequent clinical findings that are suggestive of WS, such as sensorineural hearing loss or bowel disease. We recommend particular attention is given to patients with likely WS and bowel disorders or a wild-type wolframin gene sequence because WFS2 is not as well-known and, thus, it is investigated less frequently. Furthermore, CISD2 gene sequencing is not performed in all the laboratories, and thus, WFS2 could be underdiagnosed.

From a basic science point of view, WS is an interesting model to investigate drugs and molecules that are involved with ER homeostasis and cellular senescence. Inflammatory pathologies, DM, atherosclerosis, neurodegenerative diseases, and even cancer are related to ER dysfunction. More insights into these mechanisms could be interesting for translational research.

An early diagnosis allows proper genetic counseling and proper follow-up to occur, which prompts clinicians to search for possible associated disorders. Unfortunately, the genotype does not predict the phenotype, and determining a prognosis for these patients is difficult.

Finally, we would like to comment about the possibility of diagnosing WS at pre-clinical or paucisymptomatic stage. Increasing knowledge about the genetic mechanisms of monogenic DM allows exome sequencing for a molecular diagnosis, which allows the diagnosis of many monogenic subtypes including WS. Besides the great advantages of this technique, more attention should be paid in the diagnosis of an untreatable neurodegenerative disorder, such as WS. What could be the backlash of a neurodegenerative disorder in a patient with DM? What is the advantage of diagnosing WS in a patient with non-autoimmune diabetes without eye involvement? Shall we tell a patient: “You have diabetes but it is very likely you will become blind; we do not know when, and we cannot do anything to prevent it”? This review highlights that the genetic variant will not strictly predict the clinical findings and, thus, we are not able to provide a reliable prognos.

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