Wfs1 Wolfram Syndrome Spectrum Disorder
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 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| WFS1 | Sequence analysis 3 | >95% 4 |
| Gene-targeted deletion/duplication analysis 5 | 3 reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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
| Feature | Common | Uncommon | ||
|---|---|---|---|---|
| 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 problems | Functional: Neurogenic bladder | ● | ||
| Structural: Upper urinary tract dilation | ||||
| Bowel dysfunction | ● | |||
| Seizures | ● | |||
| Other endocrine | Central 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:
- Cataract, described in eight individuals [Hansen et al 2005]. Cataract may be a frequent, but underdiagnosed, finding. See Genetically Related Disorders for a description of isolated autosomal dominant congenital cataract due to a pathogenic missense variant in WFS1.
- Pigmentary retinopathy rather than optic atrophy in one person [Dhalla et al 2006]
- Nystagmus
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 Mechanism | Disorder | MOI | Selected Features of This Disorder | |||
|---|---|---|---|---|---|---|
| Endocrine abnormalities | Eye findings | Hearing loss | Neurologic abnormalities | |||
| ALMS1 | Alström syndrome | AR | Insulin 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 individuals | Progressive 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 syndrome | AR | Non-insulin-dependent DM/type 2 usually evident in adolescence or adulthood; male hypogonadotropic hypogonadism | Cone-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 audiometry | Significant learning difficulties in majority of individuals; severe impairment on IQ testing in a minority |
| DMPK | Myotonic dystrophy type 1 (DM1) | AD | DM is common in mild DM1 & classic DM1 | Cataract in mild DM1 & classic DM1 | No data available | Mild myotonia (sustained muscle contraction) in mild DM1; muscle weakness/wasting & myotonia in classic DM1 |
| FXN | Friedreich ataxia | AR | 30% have DM | Optic nerve atrophy, often asymptomatic, occurs in ~25%. Progressive diminution of contrast acuity is typical w/disease progression. | SNHL in 13% of individuals | Slowly 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 deletion | Kearns-Sayre syndrome (See Mitochondrial DNA Deletion Syndromes.) | Mat | DM, hypoparathyroidism, & growth hormone deficiency | Pigmentary retinopathy & progressive external ophthalmoplegia w/onset age <20 yrs | SNHL in some individuals | Cerebellar ataxia; impaired intellect (ID &/or dementia) |
| SLC19A2 | Thiamine-responsive megaloblastic anemia syndrome | AR | DM; non-type I in nature w/age of onset from infancy to adolescence | OA (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 treatment | Significant neurologic deficit incl stroke & focal or generalized epilepsy reported in early childhood in 27% of individuals |
Ristow [2004], Barrett [2007]
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
| Gene | Disorder | MOI | Selected Features of the DIfferential Disorder | ||
|---|---|---|---|---|---|
| Eye findings | Hearing loss | Neurologic abnormalities | |||
| OPA1 | Optic atrophy type 1 | AD | Bilateral & 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. |
| PRPS1 | Charcot-Marie-Tooth neuropathy X type 5 | XL | Optic neuropathy in males; onset of visual impairment at age 7-20 yrs | Early-onset (prelingual) bilateral profound SNHL in males | Peripheral neuropathy in males w/onset age 5-12 yrs |
| TIMM8A 2 | Deafness-dystonia-optic neuronopathy syndrome | XL | Slowly progressive ↓ visual acuity from OA beginning at ~20 yrs in males | Prelingual 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/Concern | Evaluation | Comment | |
|---|---|---|---|
| Diabetes mellitus | Fasting plasma glucose & HbA1c | Diabetic ketoacidosis is rare; prolonged remission phase is common. | |
| Optic atrophy | Ophthalmologic evaluation | Assess:
| |
| Sensorineural hearing impairment | Audiologic examination | Including:
| |
| Motor disability | Neurologic examination incl brain MRI (if not performed previously) & cognitive assessment | Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). 1 Evaluate for:
| |
| Refer to neuromuscular clinic (OT/PT / rehabilitation specialist) | To assess:
| ||
| Autonomic dysfunction | Obtain history of orthostatic hypotension, anhidrosis, hypohydrosis, constipation, gastroparesis, hypothermia, hyperpyrexia. | ||
| Bulbar dysfunction | Assessment by speech & language pathologist | Assess for speech disorder (dysarthria) & swallowing disorder (dysphagia). | |
| Respiratory function | Polysomnography | Central apnea can occur secondary to brain stem dysfunction. | |
| Development (young children) | Developmental assessment | To 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/Behavioral | Neuropsychiatric evaluation | Individuals age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD | |
| Neurogenic bladder | History of spastic bladder symptoms: urgency, frequency, difficulty voiding, urinary incontinence, recurrent infections | Referral to urologist; consider urodynamic evaluation & imaging of urinary tract & kidneys for dilated ureters; assessment of renal function | |
| Bowel dysfunction | History of constipation, gastroparesis | ||
| Other endocrine | Diabetes insipidus | Assess concentrating ability of urine. | Morning paired urine & fasting plasma osmolarity & sodium concentration after nocturnal & morning euglycemia |
| Hypogonadism | History of absent of delayed puberty &/or infertility | Refer to endocrinologist to assess for primary gonadal failure &/or hypogonadotropic hypogonadism. | |
| Hypothyroidism | Thyroid function tests | To assess thyroid function | |
| Growth retardation | Plot height, weight, & head circumference on standard growth charts. | To identify growth failure &/or provide a baseline | |
| Genetic counseling | By genetics professionals 2 | To inform patients & families re nature, MOI, & implications of WFS1-WSSD in order to facilitate medical & personal decision making | |
| Family support / Resources |
| ||
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.
Bürk & Sival [2018]
- 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/Concern | Treatment | Considerations / Other | |
|---|---|---|---|
| Diabetes mellitus | Routine practice for insulin-dependent DM | ||
| Optic atrophy | Correction of refractive error | Evaluate for visual aids. Community vision services through early intervention or school district. Idebenone and docoshexaenoic acid are of no benefit. | |
| Sensorineural hearing impairment | Treatment of SNHL depends on the degree of hearing impairment. 1 | Hearing loss affects high frequencies first. | |
| Mobility | Feet: 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 living | Physical therapist | Transfers (e.g., from bed to wheelchair, wheelchair to car); training on how to fall to minimize risk of injury | |
| Occupational therapist | To accomplish tasks incl mobility, washing, dressing, eating, cooking, & grooming; to assist w/household modifications to meet special needs | ||
| Dysphagia | Determine 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 | ||
| Dysarthria | Speech and language pathologist | Help maintain vocal control, improve speech, breathing techniques, & communication in general. | |
| Brain stem dysfunction | Treatment of central apnea | ||
| Development in young children | See Developmental Delay / Intellectual Disability Management Issues | ||
| Cognitive decline / Intellectual disability | |||
| Psychiatric / Behavioral | Per standard treatment by psychiatric professional (psychiatrist, psychologist, neuropsychologist) as needed | Watch for personality changes. | |
| Neurogenic bladder | Anticholinergic drugs; clean intermittent self-catheterization or indwelling catheter; treatment of recurrent urinary tract infections | ||
| Bowel dysfunction | Dietary management | Frequent small meals, ↑ dietary fiber, ↑ water intake | |
| Other endocrine | Diabetes insipidus | Per standard treatment | |
| Hypogonadism | |||
| Hypothyroidism | |||
| Growth retardation | |||
| Family/Community | Ensure 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/Concern | Evaluation | Frequency | |
|---|---|---|---|
| Diabetes mellitus | See footnote 1. | See footnote 1. | |
| Complications of diabetes mellitus | Nephropathy | Annual screening starting at age 12 yrs | |
| Retinopathy | In those w/duration of diabetes >5 yrs: annual screening | ||
| Neuropathy | Annual screening for numbness, pain, cramps, parathethesias | ||
| Dyslipidemia | See footnote 1. | ||
| Hypertension | At least annually | ||
| Optic atrophy | Eye examination (visual acuity, color vision testing, slit lamp examination for cataracts, fundoscopy, visual fields); need for low vision aids | Annually | |
| Sensorineural hearing impairment | Audiogram incl assessment of speech discrimination | Every 1-2 yrs | |
| Neurologic | Neurologic examination incl assessment of cerebellar ataxia as well as memory, personality changes | Every 1-2 yrs | |
| Activities of daily living & mobility | Physical medicine, OT/PT assessment of mobility, self-help skills | Per treating clinicians | |
| Dysphagia | Assess swallowing. | Per treating clinician | |
| Dysarthria | Speech & language pathologist | Per treating speech-language pathologist | |
| Development in young children | Monitor developmental progress & educational needs. | Annually | |
| Cognitive decline / Intellectual disability | Per treating clinician | Annually | |
| Psychiatric/Behavioral | Assess for signs of depression, suicidal behavior, changes in personal appearance, & social behavior | Per treating clinician | |
| Neurogenic bladder | Urodynamic examination & assess bladder emptying. Routine urine cultures when there is bladder dysfunction or other urinary tract abnormality | Annually | |
| Other endocrine | Diabetes insipidus | Assess concentrating ability of urine. | Per treating clinician |
| Hypogonadism | Monitor for signs of onset of puberty | Per treating clinician | |
| Hypothyroidism | Monitor linear growth in children using standard growth charts. | Per treating clinician | |
| Growth retardation | Per treating clinician | ||
| Family/Community | Ensure 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.
For details see Wolfram Syndrome Clinical Management Guidelines, pages 6-12.
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.