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WFS1 Wolfram Syndrome Spectrum Disorder

, MD, PhD, , MD, PhD, and , PhD.

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Initial Posting: ; Last Update: April 9, 2020.

Estimated reading time: 28 minutes

Summary

Clinical characteristics.

WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment.

Diagnosis / testing.

The diagnosis of WFS1-WSSD is established in a proband with suggestive findings and biallelic pathogenic variants in WFS1 by molecular genetic testing.

Management.

Treatment of manifestations: Recommendations (based on detailed clinical guidelines for Wolfram syndrome) include routine management by multidisciplinary specialists for the following: insulin-dependent DM; OA; hearing impairment; mobility and activities of daily living; dysarthria; dysphagia; endocrine disorders; developmental delay/intellectual disability; neurogenic bladder; and psychiatric/behavioral issues.

Surveillance: Routine follow up evaluations to assess effectiveness of ongoing care and to identify new disease manifestations.

Genetic counseling.

WFS1-WSSD is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the WFS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) should be suspected in individuals with the following clinical findings and family history.

Clinical findings [Barrett et al 1995, Urano 2016]:

  • Diabetes mellitus (onset age <15 years)
  • Optic atrophy (onset age <15 years)
  • High-tone sensorineural hearing impairment (sometimes congenital and severe)
  • Cerebellar ataxia
  • Dementia / intellectual disability (Both may occur, but intellectual disability is rare.)
  • Psychiatric disease
  • Neurogenic bladder or bladder dyssynergia
  • Other endocrine findings:
    • Central diabetes insipidus
    • Delayed / absent puberty; hypogonadism in males
    • Non-autoimmune hypothyroidism
    • Growth retardation
  • Cardiomyopathy and structural congenital heart defects

Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of WFS1-WSSD is established in a proband with biallelic pathogenic variants in WFS1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of WFS1-WSSD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of WFS1-WSSD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of WFS1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step typically is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of WFS1-WSSD.

A deafness multigene panel that includes WFS1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene[s] are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis; however, to date such variants have not been identified as a cause of WFS1-WSS.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in WFS1 Wolfram Syndrome Spectrum Disorder

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
WFS1Sequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 53 reported 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Hardy et al [1999], Khanim et al [2001], Smith et al [2004], Chaussenot et al [2015] and data derived from subscription-based professional view Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Three intragenic deletions of one or more exons have been described [Smith et al 2004, Elli et al 2012, Chaussenot et al 2015].

Clinical Characteristics

Clinical Description

Typical autosomal recessive WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) features are childhood-onset diabetes mellitus, optic atrophy, hearing impairment/deafness, diabetes insipidus, neurologic abnormalities, and psychiatric abnormalities (see Table 2).

Note: This GeneReview focuses on Wolfram syndrome spectrum disorder caused by biallelic WFS1 pathogenic variants. Wolfram syndrome-like disorder, caused by heterozygous WFS1 pathogenic variants and associated with a clinical spectrum overlapping that of autosomal recessive WFS1-WSSD, is addressed in Genetically Related Disorders.

Table 2.

Select Features of WFS1-WSSD

FeatureCommonUncommon
Diabetes mellitus
Optic atrophy
Sensorineural hearing impairment
Cerebellar ataxia
Autonomic dysfunction
Bulbar dysfunction
Respiratory
Development delay (young children)
Intellectual disability (older children & adults)
Psychiatric disease
Urinary tract problemsFunctional: Neurogenic bladder
Structural: Upper urinary tract dilation
Bowel dysfunction
Seizures
Other endocrineCentral diabetes insipidus
Hypogonadism
Hypothyroidism
Growth retardation

A comprehensive review of WFS1 and its role in different clinical presentations is available [Tranebjærg 2008].

WFS1-WSSD is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities, and other endocrine abnormalities. Almost every organ system may be affected; however, because only a minority of published cases have had extensive clinical workup, the natural history of these multiorgan findings in WFS1-WSSD is largely unknown.

The natural history of Wolfram syndrome was described in 45 individuals in 29 families in the UK [Barrett et al 1995]. Hearing impairment was present in 64% by age 20 years. Sixty percent of all individuals studied (mean age 16 years, range 5-32 years) had one or more of the following: cerebellar ataxia, peripheral neuropathy, intellectual disability, dementia, psychiatric illness, and urinary tract atony. Life span was considerably shortened. In the families of British, Pakistani, and mixed Arab/African origin, WFS1 pathogenic variants were subsequently identified in 17 of 19 probands [Hardy et al 1999].

Diabetes mellitus (DM). Median age of onset of DM was before age ten years (age range <1-17 years). Almost all with DM were insulin dependent. DM may present with ketoacidosis; however, overall the course is milder than that seen in isolated DM, with lower prevalence of microvascular disease [Cano et al 2007a] and microvascular retinopathy.

Optic atrophy (OA). OA occurs eventually in all known individuals with WSSD. OA is progressive: the median age of onset is before ten years; after a median of eight years visual acuity is reduced to about 6/60 in most individuals [Barrett et al 1995]. Note: Visual acuity of 6/60, signifying that the tested person sees at six meters what an average person sees at 60 meters, is the definition of "registered blind" in the UK and "legally blind" in the US.

Other ophthalmologic findings reported in WSSD but not confirmed as part of the phenotype:

Sensorineural hearing impairment, present in about 66% of individuals with WSSD, ranges from congenital deafness to a milder, sometimes progressive sensorineural hearing impairment. Median age of onset was 12.5 years [Barrett et al 1995]. Audiograms show a downsloping progressive pattern of hearing loss [Pennings et al 2004]. Among individuals with inactivating WFS1 variants, five females were significantly more hearing impaired than four males, giving rise to speculation that hormonal factors may modulate hearing loss [Pennings et al 2004]. A multicenter study confirmed the preferential involvement of high frequencies and the slowly progressive rate of hearing loss, but did not confirm any gender differences in degree of hearing loss [Plantinga et al 2008].

Deterioration in speech recognition score with increasing age is more pronounced than could be explained by age-related decline in hearing alone, suggesting that progressive central nervous system involvement may also account for difficulties with speech over time [Pennings et al 2004].

Note: Although experience is limited, abnormal vestibular function does not appear to be a prominent feature of WFS1-WSSD. Among six individuals with WFS1-WSSD who were evaluated, only one had vestibular areflexia [Pennings et al 2004]. Balance problems may be the result of neurologic movement abnormalities.

Neurologic abnormalities were present in 62% of the individuals (mean age 30 years, range 5-44 years) studied by Barrett et al [1995] before molecular confirmation of the diagnosis was possible. However, very limited data are available regarding the frequency of the types of neurologic abnormalities.

Current experience indicates the presence of neurologic findings by the fourth decade with an onset typically between the first and second decade.

Neurologic findings are progressive and result from general brain atrophy with brain stem and cranial nerve involvement [Barrett et al 1995, Pakdemirli et al 2005, Domenech et al 2006]. Abnormal cerebral MRIs found in eight of 45 individuals typically showed generalized brain atrophy most prominently of the cerebellum, medulla, and pons; and reduced signal intensity of the optic nerves and the posterior part of hypothalamus [Barrett et al 1995]. The correlation between brain atrophy on MRI and clinical findings is not always strong [Ito et al 2007].

  • Truncal or gait ataxia was found in 15 of 45 individuals studied [Barrett et al 1995].
  • Episodes of apnea, a serious manifestation, occurred in five of 45 individuals studied [Barrett et al 1995].
  • Dementia is seen as part of the wider neurodegeneration in older patients. Intellectual disability is not common.
  • A significantly increased risk of suicidal behavior and psychiatric illness requiring hospitalization has been observed [Swift et al 1998].

Other endocrine findings

  • Diabetes insipidus of central origin occurred in 72% with a median age of onset of 15.5 years. The range in age of onset is broad, possibly because of delays in establishing the correct diagnosis.
  • Hypogonadism is more prevalent in males than in females. It can be either hypogonadotropic (i.e., central) or hypergonadotropic (i.e., secondary to gonadal failure). The underlying pathology of either type is not understood. Females usually retain their ability to become pregnant; about six successful pregnancies are described in the literature. One female had absence of the uterus [Tranebjærg, personal observation].
  • Hypothyroidism. Frequency is not known.
  • Growth retardation. Most adults have normal height, but growth retardation is not infrequent. The age of onset of puberty varies.

Urinary tract. Dilated renal outflow tracts (hydroureter), urinary incontinence, and recurrent infections are common signs of neurogenic bladder. Fifty-five percent of 29 index patients had such signs with median age of onset of 22 years (age range: 10-44 years) [Barrett et al 1995]. Urodynamic examinations showed incomplete bladder emptying or complete bladder atony.

Gastrointestinal dysmotility and celiac disease. Constipation, chronic diarrhea, and other bowel dysfunction is reported in 25% of individuals with WFS1-WSSD, sometimes the result of gluten intolerance, which is 20 times more frequent in those who have had diabetes mellitus for several years [Barera et al 2002, Skovbjerg et al 2005, Liu et al 2006] (see Celiac Disease).

Cardiomyopathy. No data on frequency are available.

Causes of death. Ten of the 45 individuals reported in the study of Barrett et al [1995] had died. The median age at death was 30 years. Reports suggest 65% mortality by age 35 years. It must be kept in mind, however, that a bias toward reporting the most severe cases of WSSD in the literature may skew these figures. The causes of death were hypoglycemic coma, status epilepticus, end-stage renal disease from recurrent urinary tract infection, and suicide. Three individuals died from central respiratory failure associated with brain stem atrophy.

Neuropathology. Currently the only published reports are of clinically diagnosed individuals; neuropathology of molecularly confirmed cases has not yet been published. In two cases the findings included atrophy of the olfactory bulbs, optic nerves, pontine nuclei, inferior olive, and dentate nuclei of the cerebellum; loss of cochlear ganglion cells; and mild loss of neurons in the spinal cord [Genís et al 1997, Shannon et al 1999].

Genotype-Phenotype Correlations

The clinical course of WFS1-WSSD is highly variable, even within a family, and is not predictable from the type or location of the pathogenic variant.

Cano et al [2007a] found that two WFS1 alleles, both with inactivating pathogenic variants, predisposed to an earlier age of onset of both diabetes mellitus and optic atrophy. Moreover, the clinical expression of WSSD was more complete and occurred earlier in individuals with no missense variant.

Nomenclature

Wolfram syndrome has sometimes been referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).

Prevalence

More than 90 individuals from more than 60 families have been described worldwide [Khanim et al 2001, Tessa et al 2001, Domènech et al 2002, Colosimo et al 2003, Cryns et al 2003, Simsek et al 2003, van den Ouweland et al 2003, Smith et al 2004, Giuliano et al 2005, Hansen et al 2005, Cano et al 2007b].

A study from the UK estimated a prevalence of WSS of 1:550,000 children in the UK [Barrett et al 1995].

Differential Diagnosis

Wolfram syndrome type 2 (WS2) (OMIM 604928) is an autosomal recessive disorder caused by biallelic pathogenic variants in CISD2. Like WFS1-WSSD, WS2 presents as a continuum of clinical features; however, the full clinical spectrum of WS2 abnormalities has not yet been fully established because so few affected individuals have been described. To date, the following clinical features have been reported in individuals with WS2:

  • Juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding in four Jordanian families described by El-Shanti et al [2000], al-Sheyyab et al [2001], and Amr et al [2007]; abnormal facial features were described in one family [Amr et al 2007].
  • Diabetes insipidus, psychiatric abnormalities, and variable degrees of optic atrophy in individuals from Italy and Morocco [Mozzillo et al 2014, Rondinelli et al 2015, Rouzier et al 2017]. Peptic ulcers, mucocutaneous bleeding, and defective platelet aggregation were also described in a subset of these individuals.

Note: A novel CISD2 pathogenic variant (c.215A>G; p.Asn72Ser) was identified in an affected individual who met all the diagnostic criteria for Wolfram syndrome spectrum but did not have WFS1 pathogenic variants [Rouzier et al 2017].

Hearing impairment. See Hereditary Hearing Loss and Deafness Overview.

Neurodegenerative disorders with diabetes mellitus (DM). See Table 5.

Table 5.

Neurodegenerative Disorders with DM in the Differential Diagnosis of WFS1-WSSD

Gene(s) / Genetic MechanismDisorderMOISelected Features of This Disorder
Endocrine abnormalitiesEye findingsHearing lossNeurologic abnormalities
ALMS1Alström syndromeARInsulin resistance / type 2 DM often presents in teen yrs / 2nd decade. Other endocrine abnormalities incl hypogonadotropic hypogonadism in boys, polycystic ovaries in girls, & hypothyroidism.Cone-rod dystrophy presents as progressive visual impairment, photophobia, & nystagmus starting between birth & age 15 mos; no light perception by age 20 yrs in many individualsProgressive SNHL begins in 1st decade in ~70% of individuals. Hearing loss may become moderate to severe (40-70 dB) by end of 1st-2nd decade.Detrusor-urethral dyssynergia in females in their late teens
BBS1
BBS2
BBS4
BBS7
BBS9
BBS10
BBS12
MKKS
MKS1
TTC8 1
Bardet-Biedl syndromeARNon-insulin-dependent DM/type 2 usually evident in adolescence or adulthood; male hypogonadotropic hypogonadismCone-rod dystrophy; night blindness usually evident by age 7-8 yrs; mean age of legal blindness is 15.5 yrs.~50% of adults develop a subclinical SNHL that is only detectable by audiometrySignificant learning difficulties in majority of individuals; severe impairment on IQ testing in a minority
DMPKMyotonic dystrophy type 1 (DM1)ADDM is common in mild DM1 & classic DM1Cataract in mild DM1 & classic DM1No data availableMild myotonia (sustained muscle contraction) in mild DM1; muscle weakness/wasting & myotonia in classic DM1
FXNFriedreich ataxiaAR30% have DMOptic nerve atrophy, often asymptomatic, occurs in ~25%. Progressive diminution of contrast acuity is typical w/disease progression.SNHL in 13% of individualsSlowly progressive ataxia w/mean onset age 10-15 yrs (usually <25 yrs); dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, & loss of position & vibration sense
mtDNA deletionKearns-Sayre syndrome (See Mitochondrial DNA Deletion Syndromes.)MatDM, hypoparathyroidism, & growth hormone deficiencyPigmentary retinopathy & progressive external ophthalmoplegia w/onset age <20 yrsSNHL in some individualsCerebellar ataxia; impaired intellect (ID &/or dementia)
SLC19A2Thiamine-responsive megaloblastic anemia syndromeARDM; non-type I in nature w/age of onset from infancy to adolescenceOA (when commented on in case reports) appears common.Progressive SNHL w/generally early onset; can be detected in toddlers. SNHL is irreversible & not prevented by thiamine treatmentSignificant neurologic deficit incl stroke & focal or generalized epilepsy reported in early childhood in 27% of individuals

AD = autosomal dominant; AR = autosomal recessive; DM = diabetes mellitus; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OA = optic atrophy; SNHL = sensorineural hearing loss

1.

Listed genes represent the most commonly associated genes; at least 19 genes are associated with Bardet-Biedl syndrome (see Bardet-Biedl Syndrome).

Optic atrophy associated with hearing impairment. See Table 6.

Table 6.

Disorders with Optic Atrophy Associated with Hearing Impairment in the Differential Diagnosis of WFS1-WSSD

GeneDisorderMOISelected Features of the DIfferential Disorder
Eye findingsHearing lossNeurologic abnormalities
OPA1Optic atrophy type 1ADBilateral & symmetric optic nerve pallor assoc w/insidious ↓ in visual acuity usually age 4-6 yrs; visual field defects; color vision defects. Visual impairment is usually moderate (6/10-2/10), but ranges from mild or even insignificant to severe (legal blindness w/acuity <1/20)Auditory neuropathy → SNHL ranging from severe & congenital to subclinical 1~20% have assoc additional clinical features, especially neurologic signs.
PRPS1Charcot-Marie-Tooth neuropathy X type 5XLOptic neuropathy in males; onset of visual impairment at age 7-20 yrsEarly-onset (prelingual) bilateral profound SNHL in malesPeripheral neuropathy in males w/onset age 5-12 yrs
TIMM8A 2Deafness-dystonia-optic neuronopathy syndromeXLSlowly progressive ↓ visual acuity from OA beginning at ~20 yrs in malesPrelingual or postlingual SNHL in early childhood in males; females may have mild hearing impairment.Slowly progressive dystonia or ataxia in the teens; dementia beginning at age ~40 yrs; psychiatric symptoms (e.g., personality change, paranoia) may appear in childhood & progress. Females may have focal dystonia.

AD = autosomal dominant; Mat = maternal; MOI = mode of inheritance; OA = optic atrophy; SNHL = sensorineural hearing loss; XL = X-linked

1.

Identified by specific audiologic testing only.

2.

The diagnosis of deafness-dystonia-optic neuronopathy syndrome is established in either a male proband who has a hemizygous TIMM8A pathogenic variant, or a female proband who has a heterozygous TIMM8A pathogenic variant or a contiguous gene deletion of Xp22.1 involving TIMM8A.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD), the evaluations summarized in Table 7 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

See also Wolfram Syndrome Clinical Management Guidelines, page 5 for recommended baseline investigations.

Table 7.

Recommended Evaluations Following Initial Diagnosis in Individuals with WFS1-WSSD

System/ConcernEvaluationComment
Diabetes mellitusFasting plasma glucose & HbA1cDiabetic ketoacidosis is rare; prolonged remission phase is common.
Optic atrophyOphthalmologic evaluationAssess:
  • Extraocular movement, best corrected visual acuity, color vision testing, visual field testing, visual evoked potentials, OCT, fundus examination
  • Need for visual aids
Sensorineural hearing impairmentAudiologic examinationIncluding:
  • ABRs to confirm pathology & provide baseline
  • Evoked otoacoustic emissions to identify type of hearing impairment
  • Speech discrimination tests
Motor disabilityNeurologic examination incl brain MRI (if not performed previously) & cognitive assessmentUse standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). 1 Evaluate for:
  • Peripheral neuropathy
  • Anosmia or hyposmia
  • Decreased ability to taste
  • Possible seizures
  • Hypersomnolence
  • Headaches
Mental health assessment as warranted
Refer to neuromuscular clinic (OT/PT / rehabilitation specialist)To assess:
  • Gross motor & fine motor skills
  • Mobility, activities of daily living, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Autonomic dysfunctionObtain history of orthostatic hypotension, anhidrosis, hypohydrosis, constipation, gastroparesis, hypothermia, hyperpyrexia.
Bulbar dysfunctionAssessment by speech & language pathologistAssess for speech disorder (dysarthria) & swallowing disorder (dysphagia).
Respiratory functionPolysomnographyCentral apnea can occur secondary to brain stem dysfunction.
Development (young children)Developmental assessmentTo incl motor, adaptive, cognitive, & speech/language evaluation & evaluation for early intervention / special education
Cognitive impairment (older children & adults)To incl: motor & speech/language evaluation; general cognitive skills
Psychiatric/BehavioralNeuropsychiatric evaluationIndividuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD
Neurogenic bladderHistory of spastic bladder symptoms: urgency, frequency, difficulty voiding, urinary incontinence, recurrent infectionsReferral to urologist; consider urodynamic evaluation & imaging of urinary tract & kidneys for dilated ureters; assessment of renal function
Bowel dysfunctionHistory of constipation, gastroparesis
Other endocrineDiabetes insipidusAssess concentrating ability of urine.Morning paired urine & fasting plasma osmolarity & sodium concentration after nocturnal & morning euglycemia
HypogonadismHistory of absent of delayed puberty &/or infertilityRefer to endocrinologist to assess for primary gonadal failure &/or hypogonadotropic hypogonadism.
HypothyroidismThyroid function testsTo assess thyroid function
Growth retardationPlot height, weight, & head circumference on standard growth charts.To identify growth failure &/or provide a baseline
Genetic counselingBy genetics professionals 2To inform patients & families re nature, MOI, & implications of WFS1-WSSD in order to facilitate medical & personal decision making
Family support / Resources
  • Contact w/a patient advocacy organization may provide additional benefit.
  • Assess need for social work involvement for caregiver support.
  • Need for help coordinating multidisciplinary care
  • Use of community resources & support/advocacy organizations (e.g., Parent to Parent)

ABRs = auditory brain stem responses; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia

1.
2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12 for management recommendations.

Table 8.

Treatment of Manifestations in Individuals with WFS1-WSSD

Manifestation/ConcernTreatmentConsiderations / Other
Diabetes mellitusRoutine practice for insulin-dependent DM
Optic atrophyCorrection of refractive errorEvaluate for visual aids. Community vision services through early intervention or school district. Idebenone and docoshexaenoic acid are of no benefit.
Sensorineural hearing impairmentTreatment of SNHL depends on the degree of hearing impairment. 1Hearing loss affects high frequencies first.
MobilityFeet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores. Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
Activities of daily livingPhysical therapistTransfers (e.g., from bed to wheelchair, wheelchair to car); training on how to fall to minimize risk of injury
Occupational therapistTo accomplish tasks incl mobility, washing, dressing, eating, cooking, & grooming; to assist w/household modifications to meet special needs
DysphagiaDetermine the exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. Attention to oral hygiene & dental care as dysphagia may lead to impaired clearance of organisms & pathogenic colonization
DysarthriaSpeech and language pathologistHelp maintain vocal control, improve speech, breathing techniques, & communication in general.
Brain stem dysfunctionTreatment of central apnea
Development in young childrenSee Developmental Delay / Intellectual Disability Management Issues
Cognitive decline / Intellectual disability
Psychiatric / BehavioralPer standard treatment by psychiatric professional (psychiatrist, psychologist, neuropsychologist) as neededWatch for personality changes.
Neurogenic bladderAnticholinergic drugs; clean intermittent self-catheterization or indwelling catheter; treatment of recurrent urinary tract infections
Bowel dysfunctionDietary managementFrequent small meals, ↑ dietary fiber, ↑ water intake
Other endocrineDiabetes insipidusPer standard treatment
Hypogonadism
Hypothyroidism
Growth retardation
Family/CommunityEnsure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.Consider involvement in adaptive sports or Special Olympics.

DM = diabetes mellitus; SNHL = sensorineural hearing loss

1.

See Hereditary Hearing Loss and Deafness Overview for details about treatment options.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12 for surveillance recommendations.

Table 9.

Recommended Surveillance for Individuals with WFS1-WSSD

System/ConcernEvaluationFrequency
Diabetes mellitusSee footnote 1.See footnote 1.
Complications of diabetes mellitusNephropathyAnnual screening starting at age 12 yrs
RetinopathyIn those w/duration of diabetes >5 yrs: annual screening
NeuropathyAnnual screening for numbness, pain, cramps, parathethesias
DyslipidemiaSee footnote 1.
HypertensionAt least annually
Optic atrophyEye examination (visual acuity, color vision testing, slit lamp examination for cataracts, fundoscopy, visual fields); need for low vision aidsAnnually
Sensorineural hearing impairmentAudiogram incl assessment of speech discriminationEvery 1-2 yrs
NeurologicNeurologic examination incl assessment of cerebellar ataxia as well as memory, personality changesEvery 1-2 yrs
Activities of daily living & mobilityPhysical medicine, OT/PT assessment of mobility, self-help skillsPer treating clinicians
DysphagiaAssess swallowing.Per treating clinician
DysarthriaSpeech & language pathologistPer treating speech-language pathologist
Development in young childrenMonitor developmental progress & educational needs.Annually
Cognitive decline / Intellectual disabilityPer treating clinicianAnnually
Psychiatric/BehavioralAssess for signs of depression, suicidal behavior, changes in personal appearance, & social behaviorPer treating clinician
Neurogenic bladderUrodynamic examination & assess bladder emptying. Routine urine cultures when there is bladder dysfunction or other urinary tract abnormalityAnnually
Other endocrineDiabetes insipidusAssess concentrating ability of urine.Per treating clinician
HypogonadismMonitor for signs of onset of pubertyPer treating clinician
HypothyroidismMonitor linear growth in children using standard growth charts.Per treating clinician
Growth retardationPer treating clinician
Family/CommunityEnsure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.

OT = occupational therapy; PT = physical therapy

1.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of WFS1-WSSD: diabetes mellitus, optic atrophy, and sensorineural hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with insulin-dependent diabetes mellitus have a two- to eightfold higher risk than pregnant women without diabetes of having a child with a birth defect or a pattern of birth defects (diabetic embryopathy). These defects can involve the craniofacial, cardiovascular, gastrointestinal, urogenital, musculoskeletal, and central nervous systems. Optimizing glucose control before and during pregnancy can reduce but does not eliminate the risk for diabetic embryopathy. High-resolution fetal ultrasonography and fetal echocardiogram are recommended to screen for congenital anomalies during pregnancy. Consultation with a maternal fetal medicine specialist during pregnancy should also be considered.

Because women with WFS1-WSSD may develop diabetes insipidus during pregnancy [Rugolo et al 2002], monitoring for diabetes insipidus during pregnancy is warranted.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Groups exploring novel potential treatment strategies for WFS1-WSSD include Abreu & Urano [2019] and Pallotta et al [2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Wolfram syndrome spectrum disorder caused by biallelic WFS1 pathogenic variants (WFS1-WSSD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If each parent is known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are not at increased risk for hearing impairment [Pennings et al 2004], but it is as yet unknown whether they could be at higher risk for diabetes mellitus, psychiatric disorders, and/or congenital cataracts [Swift et al 1998].

Offspring of a proband. The offspring of an individual with WFS1-WSSD are obligate heterozygotes (carriers) for a pathogenic variant in WFS1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WFS1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the WFS1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the WFS1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for WFS1-WSS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Syndrome de Wolfram
    Mdm Nolwen Le Floch
    résidence Gauguin
    Grand-Champ 56390
    France
    Phone: 09 63 07 32 22
  • National Library of Medicine Genetics Home Reference
  • Wolfram Syndrome UK
    WS Support UK
    9 Church Way
    Worthing West Sussex BN13 1HD
    United Kingdom
    Phone: 01903 211358
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Diabetes Association (ADA)
    Phone: 1-800-DIABETES (800-342-2383)
    Email: AskADA@diabetes.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Diabetes UK
    United Kingdom
    Phone: 0345 123 2399
    Fax: 020 7424 1001
    Email: info@diabetes.org.uk
  • International Foundation for Optic Nerve Disease (IFOND)
    PO Box 777
    Cornwall NY 12518
    Phone: 845-534-7250
    Fax: 845-534-7250
    Email: ifond@aol.com
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • EURO-WABB Project Registry
    EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome (see Farmer et al [2013])
  • Wolfram Syndrome International Registry and Clinical Study
    Phone: 314-362-8683
    Email: urano@wustl.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

WFS1 Wolfram Syndrome Spectrum Disorder: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for WFS1 Wolfram Syndrome Spectrum Disorder (View All in OMIM)

222300WOLFRAM SYNDROME 1; WFS1
600965DEAFNESS, AUTOSOMAL DOMINANT 6; DFNA6
606201WOLFRAMIN ER TRANSMEMBRANE GLYCOPROTEIN; WFS1

Molecular Pathogenesis

WFS1 Wolfram syndrome spectrum (WFS1-WSS) is considered a prototype of endoplasmic reticulum (ER) disease. WFS1 encodes wolframin 1, an endoglycosidase H-sensitive ER transmembrane glycoprotein [Yamamoto et al 2006]. Wolframin is widely expressed, including in retinal ganglion cells and optic nerve glia in monkeys [Yamamoto et al 2006, Luuk et al 2008]. The WFS1 protein lacks homology to other known proteins.

The precise function of wolframin 1 has not been established, but deficiency is thought to lead to ER stress, impair cell cycle progression, and affect calcium homeostasis [Zatyka et al 2008, Urano 2016, Abreu & Urano 2019]. There is no interaction between wolframin 1 and ER intermembrane small protein encoded by CISD2, the gene in which pathogenic variants cause WFS2 [Amr et al 2007] (see Figure 1).

Figure 1. A.

Figure 1

A. Schematic representation of WFS1, which comprises eight exons; exon 1 is noncoding. B. Hypothetic structure of wolframin protein. The location of the transmembrane regions is predicted from the SMART database (smart.embl-heidelberg.de).

Mechanism of disease causation. Pathogenic variants in WFS1 result in loss of wolframin 1 function.

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Chapter Notes

Acknowledgments

The Audiogenetic Research Group, headed by Lisbeth Tranebjærg, receives financial support from Widex AS and other research grants.

Revision History

  • 9 April 2020 (bp) Comprehensive update posted live
  • 19 December 2013 (me) Comprehensive update posted live
  • 2 June 2009 (cd) Revision: Deletion/duplication analysis available clinically
  • 24 February 2009 (me) Review posted live
  • 12 August 2008 (lt) Original submission
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