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WFS1-Related Disorders

Includes: DFNA6/14/38 Nonsyndromic Low-Frequency Sensorineural Hearing Loss (WFS1-Related Low-Frequency Sensory Hearing Loss), Wolfram Syndrome (DIDMOAD), Wolfram Syndrome-Like Disease

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

Author Information
, MD, PhD
Professor of Medical Genetics and Genetic Audiology, Department of Audiology
H:S Bispebjerg Hospital
University Hospital, Copenhagen
Wilhelm Johannsen Center for Functional Genomics
Institute of Cellular and Molecular Medicine
The Panum Institute
University of Copenhagen
Copenhagen, Denmark
tranebjaerg@sund.ku.dk
, MD, PhD
School of Clinical and Experimental Medicine
University of Birmingham
The Medical School
Birmingham, United Kingdom
, PhD
Wilhelm Johannsen Center for Functional Genomics
Institute of Cellular and Molecular Medicine
The Panum Institute
University of Copenhagen
Copenhagen, Denmark

Initial Posting: ; Last Update: December 19, 2013.

Summary

Disease characteristics. WFS1-related disorders range from Wolfram syndrome (WFS) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 low-frequency sensorineural hearing loss [LFSNHL]). WFS is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 16 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony), and other endocrine abnormalities. Median age at death is 30 years. WFS-like disease is characterized by sensorineural hearing loss, diabetes mellitus, psychiatric illness, and variable optic atrophy. WFS1-related LFSNHL is characterized by congenital, nonsyndromic, slowly progressive, low-frequency (<2000 Hz) sensorineural hearing loss.

Diagnosis/testing. Diagnosis of WFS and WFS-related disorder is based on clinical findings and molecular genetic testing of WFS1, the only gene in which mutations are known to cause WFS1-related disorders. WFS1-related LFSNHL is diagnosed based on audiologic findings and molecular genetic testing.

Management. Treatment of manifestations: Treatment is symptomatic for the manifestations of WFS and WFS-like disease. Depending on the degree of hearing impairment and the frequencies affected, hearing loss may be managed with hearing aids or possibly cochlear implantation.

Prevention of secondary complications: Medical complications related to long-term diabetes mellitus can be minimized or avoided through optimization of glycemic control following established guidelines.

Surveillance: Regular evaluations over time to detect the typical manifestations, including regular audiologic examination and speech discrimination testing.

Evaluation of relatives at risk:

  • WFS: Sibs of a proband warrant either molecular genetic testing (if the family-specific mutations are known) or screening for diabetes mellitus, optic atrophy, and sensorineural hearing loss in childhood to allow for early diagnosis and treatment.
  • WFS1-related LFSNHL: Molecular genetic testing (if the family-specific mutation is known) or audiologic evaluation of at-risk relatives to detect the earliest manifestations of low-tone hearing loss.

Pregnancy management: Glycemic control prior to and during pregnancy is recommended for women with diabetes mellitus to decrease the risk for birth defects in the fetus; high-resolution ultrasound, fetal echocardiogram, and consultation with a maternal-fetal medicine specialist should be considered in pregnant women with diabetes mellitus.

Genetic counseling

  • WFS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing is possible if the disease-causing mutations in the family are known.
  • WFS-like disease and WSF1-related LFSNHL are inherited in an autosomal dominant manner. Risk to offspring of an affected individual is 50%.

Prenatal testing for pregnancies at increased risk for all three phenotypes is possible if the disease-causing mutation(s) in the family are known.

Diagnosis

Clinical Diagnosis

WFS1-related disorders include a phenotypic spectrum ranging from Wolfram syndrome (WFS) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 LFSNHL).

Wolfram syndrome (WFS) is sometimes referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). The following are sensitive and specific for WFS [Barrett et al 1995]:

  • Juvenile-onset (age <16 years) diabetes mellitus
  • Juvenile-onset optic atrophy (age <16 years)
  • Autosomal recessive inheritance

Additional clinical features include the following:

  • High tone sensorineural hearing impairment (which can sometimes be 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

Wolfram syndrome-like disease, described in two families with the same mutation in exon 8, includes the following:

WFS1-related low-frequency sensory hearing loss is congenital, nonsyndromic, slowly progressive, and low frequency (<2000 Hz). Because it is mild and involves the low frequencies, this hearing loss is often not diagnosed until after language is acquired. Note: This disorder has also been identified by mapping studies as DFNA6/14/38 nonsyndromic LFSNHL.

Molecular Genetic Testing

Gene. WFS1 is the only gene in which mutations are known to cause WFS1-related disorders [Inoue et al 1998].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in WFS1-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method and Phenotype 3
WFSWFS-likeDFNA6/14/38
WFS1Sequence analysis Sequence variants 490% 5Two families 6100% 7
Deletion/duplication analysis 8Partial- and whole-gene deletion/duplicationUnknown 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Khanim et al [2001] report identification of at least one WFS1 mutation in 90% of individuals meeting specific WFS diagnostic criteria. Individuals with typical WFS with only one apparent de novo WFS1 missense mutation [Hansen et al 2005] remain unexplained.

6. Only two families with WFS-like disease caused by a heterozygous WFS1 (p.Glu864Lys) mutation have been reported [Eiberg et al 2006, Valéro et al [2008].

7. Smith et al [2004]

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Berg et al [2007]

Testing Strategy

To confirm/establish the diagnosis in a proband

Carrier testing for relatives at risk for autosomal recessive WFS requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for the autosomal recessive disorder WFS and are not at risk of developing WFS.

Predictive testing for:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

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

Wolfram Syndrome

Wolfram syndrome (WFS) 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, only a minority of published cases have had extensive clinical work-up; thus, the natural history of these multi-organ findings in WFS is largely unknown.

The natural history of WFS was described in 45 individuals from 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 Arab/African origin, WFS1 mutations were subsequently identified in 17 of 19 probands [Hardy et al 1999].

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

Optic atrophy (OA). Optic atrophy (OA) occurs eventually in all known individuals with WFS. OA is progressive: the median age of onset is before age 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 WFS but not confirmed as part of the phenotype include:

Sensorineural hearing impairment, present in about 66% of individuals with WFS, 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 mutations, 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].

It is unknown why hearing loss is high frequency in WFS and low frequency in WFS1-related LFSNHL.

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-related disorders. Among six individuals with WFS 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 prominent 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].
  • 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.

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 hypogonodatrophic (i.e., central) or hypergonadotrophic (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, unpublished].
  • 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.

Gastrointestinal dysmotility and celiac disease. Constipation, chronic diarrhea, and other bowel dysfunction is reported in 25% of individuals with WFS, 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 WFS in the literature may skew these figures. The causes of death were hypoglycemic coma, status epilepticus, end-stage renal disease (ESRD) 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, the optic nerves, pontine nuclei, inferior olives, 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].

Wolfram Syndrome-Like Disease

In the family reported by Valéro et al [2008], the 60-year-old male proband had non-insulin-dependent diabetes mellitus and congenital moderate hearing impairment (50-60 dB HL over all frequencies) that had required use of a hearing aid since childhood. His 81-year-old mother had non-insulin-dependent diabetes mellitus, mild hearing impairment (no hearing aid needed), and bilateral optic atrophy since age 60 years (i.e., WFS). No other signs of WFS were present in mother and son [Valéro et al 2008].

In the family reported by Eiberg et al [2006], autosomal dominant optic atrophy, hearing impairment, and impaired glucose regulation were observed. One individual had undiagnosed diabetes mellitus, one had impaired glucose tolerance by oral glucose tolerance test (OGTT), and others had poor pancreatic b-cell function as demonstrated by the insulinogenic index (calculated as: the 30-minute post-OGTT serum insulin concentration minus the fasting serum insulin concentration, divided by the 30-minute post-OGTT plasma glucose concentration).

The occurrence of (milder) optic atrophy in patients/families with dominantly inherited WFS-like disease [Eiberg et al 2006] suggests that diabetes mellitus and congenital moderate hearing impairment in the absence of optic atrophy may be an under-recognized presentation of heterozygosity for WFS1 mutations, behaving in a dominant fashion.

DFNA6/14/38 Nonsyndromic Low-Frequency Sensorineural Hearing Loss (WFS1-Related LFSNHL)

Families with LFSNHL are primarily diagnosed because of low-frequency slowly progressive hearing loss [Bille et al 2001, Pennings et al 2003, Tóth et al 2006]; however, some intrafamilial variation in the audiogram is observed [Tranebjærg et al 2004, Tranebjærg 2008]. No validated data are available on the age of onset; furthermore, the diagnosis of LFSNHL tends to be delayed because the hearing loss in the low-frequency range may not affect language comprehension. Often, hearing loss is not recognized at all until age-related high-frequency hearing impairment also becomes manifest [Author, personal observation].

Speech audiometry, self-recording audiometry, and auditory brain stem responses are consistent with cochlear deafness without retrocochlear dysfunction [Noguchi et al 2005]. In contrast to WFS, the decline in speech recognition scores in WFS1-related LFSNHL correlates to the level of hearing impairment. Nonetheless, data relying on a systematic clinical analysis are not available.

In LFSNHL vestibular function tends to be normal [Bille et al 2001, Pennings et al 2003, Tóth et al 2006]. In one family with WFS1-related LFSNHL, vestibular evoked myogenic potential (VEMP) and electrocochleography (EcochG) were reported to be normal [Bramhall et al 2008]. Noguchi et al [2005] found normal EcochGs and, hence, no evidence of retrocochlear abnormality in Japanese families with WFS1-related LFSNHL.

Genotype-Phenotype Correlations

Wolfram syndrome. The clinical course of WFS is highly variable, even within a family, and is not predictable from the type or location of the mutation.

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

Wolfram-like syndrome. Two families have been identified with WS-like features that are inherited in an autosomal dominant manner (i.e., only one WFS1 mutation segregating in the family) [Eiberg et al 2006]; in another family the same missense mutation was associated with co-segregation of hearing impairment and diabetes mellitus, but no optic atrophy [Valéro et al 2008].

Prevalence

Wolfram syndrome. 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, Den Ouweland et al 2003, Simsek 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 WFS of 1:550,000 children in the UK [Barrett et al 1995]. No valid estimate of prevalence is possible if atypical presentations (e.g., autosomal dominant WS-like disease, autosomal dominant LFSNHL caused by WFS1 mutations) are included.

DFNA6/14/38 (WFS1-related LFSNHL)

Differential Diagnosis

Wolfram syndrome type 2 (WFS2) (OMIM 604928), diagnosed in four Jordanian families and caused by mutations in ZCD2 on 4q22, is characterized by juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding, but not diabetes insipidus [El-Shanti et al 2000, Al-Sheyyab et al 2001, Amr et al 2007]. In one family the facial features were abnormal [Amr et al 2007]. The disorder is apparently very rare and may be confined to a certain ethnic background. Of note, molecular genetic testing of 377 hearing impaired probands did not reveal additional individuals with ZCD2 mutations, indicating that mutation of ZCD2 does not explain a substantial fraction of nonsyndromic hearing impairment.

Hearing impairment. (See Deafness and Hereditary Hearing Loss Overview.)

Approximately 20% of genetic hearing impairment is inherited in an autosomal dominant manner, a small fraction of which is LFSNHL.

LFSNHL is heterogeneous [Tranebjærg et al 2004]. In addition to DFNA6/14/38, the following loci have been identified:

Neurodegenerative disorders with diabetes mellitus, reviewed by Ristow [2004] and Barrett [2007], include the following:

  • Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. Wide clinical variability is observed among affected individuals, even within the same family. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus starting between birth and age 15 months. Many individuals have no light perception by age 20 years. Children usually have normal birth weight but develop generalized obesity during their first year. Progressive sensorineural hearing loss begins in the first decade in as many as 70% of individuals. Hearing loss may become moderate to severe (40-70 db) by the end of the first to second decade. Insulin resistance/type 2 diabetes mellitus often presents in the teenage years/second decade of life. Other endocrine abnormalities can include hypogonadotropic hypogonadism in boys, polycystic ovaries in girls, and hypothyroidism. Over 60% of individuals with Alström syndrome develop cardiac failure as a result of dilated or restrictive cardiomyopathy at some stage of their lives. Approximately 50% of individuals have delay in early developmental milestones; intelligence is normal. Urologic disorders of varying severity, characterized by detrusor-urethral dyssynergia, appear in females in their late teens. Liver involvement includes elevation of transaminases, steatosis, hepatosplenomegaly, and steatohepatitis. Portal hypertension and cirrhosis can lead to hepatic encephalopathy and life-threatening esophageal varices. Renal disease is common, slowly progressive, and highly variable, and may be unrelated to diabetes; it manifests as tubulo-interstitial disease resulting from interstitial fibrosis. Initial signs of mildly elevated serum concentrations of creatinine and blood urea nitrogen (BUN) may be followed by polyuria and polydipsia resulting from a concentrating defect. Onset can be in mid-childhood through adulthood. End-stage renal disease (ESRD) can occur as early as the mid- to late teens. Mutations in ALMS1 are causative. Inheritance is autosomal recessive.
  • Bardet-Biedl syndrome (BBS) is characterized by cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year. Non-insulin-dependent diabetes mellitus (NIDDM)/type 2 tends to become evident in adolescence or adulthood. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality. Mutations in fourteen genes are known to be causative. Inheritance is autosomal recessive.
  • Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean age of onset between ten and 15 years and usually before age 25 years. FRDA is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. About two thirds of individuals with FRDA have cardiomyopathy, 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes. Mutations in FXN are causative. Inheritance is autosomal recessive.
  • Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic and thiamine supplements may become less effective after puberty. The anemia can recur when thiamine is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers, is irreversible, and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Mutations in SLC19A2 are causative. Inheritance is autosomal recessive.
  • Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital. Mild DM1 is characterized by cataract, mild myotonia (sustained muscle contraction), and often diabetes mellitus; life span is normal. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities and diabetes mellitus; adults may become physically disabled and may have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common. DM1 is caused by expansion of a CTG trinucleotide repeat in DMPK. Inheritance is autosomal dominant.
  • Kearns-Sayre syndrome (see Mitochondrial DNA Deletion Syndromes). Mitochondrial DNA (mtDNA) deletion syndromes comprise three overlapping phenotypes that may be observed in different members of the same family or may evolve in a given individual over time: Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). Individuals with KSS have the onset of pigmentary retinopathy and PEO before age 20 years and at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Other frequent but not invariable clinical manifestations include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency. Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1-10 kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle. When inherited, mtDNA deletion syndromes are transmitted by maternal inheritance.

Optic atrophy associated with hearing impairment has been described in the following disorders:

  • Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity usually between ages four and six years, visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only). Mutations in OPA1 are causative. Inheritance is autosomal dominant [Payne et al 2004, Amati-Bonneau et al 2005].
  • Deafness-dystonia-optic neuronopathy syndrome (DDON, or Mohr-Tranebjærg syndrome). Males with DDON have a progressive auditory neuropathy with prelingual or postlingual sensorineural hearing impairment, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at about age 20 years, and dementia beginning at about age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia. DDON syndrome occurs as either a single-gene disorder resulting from mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia caused by disruption of BTK, located telomeric to TIMM8A. Inheritance is X-linked.
  • Charcot-Marie-Tooth Neuropathy X Type 5 (CMTX5) is characterized by peripheral neuropathy, early-onset (prelingual) bilateral profound sensorineural hearing loss, and optic neuropathy. The onset of peripheral neuropathy is between ages five and 12 years; the onset of visual impairment is between ages seven and 20 years. Intellect and life span are normal. Females who inherit the mutation will be carriers and typically will not be affected. Mutations in PRPS1 are causative. Inheritance is X linked.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a WFS1-related disorder, the following evaluations are recommended:

Wolfram syndrome and Wolfram-like syndrome

  • Glucose tolerance test (if not already performed)
  • Eye examination, including visual acuity, color vision, and visual fields
  • Audiologic examination, including auditory brain stem responses (ABRs) and evoked otoacoustic emissions
  • Neurologic examination
  • Neuroimaging with MRI
  • Developmental assessment in young children and assessment of cognitive abilities in older children and adolescents
  • Baseline psychologic assessment
  • Urologic consultation with imaging studies of the urinary tract and kidneys
  • Test of the concentrating ability of urine to evaluate for diabetes insipidus
  • Medical genetics consultation

Low-frequency sensorineural hearing loss (LFSNHL)

  • Audiologic examination

Treatment of Manifestations

Diabetes mellitus. Treatment follows routine practices for insulin-dependent diabetes mellitus.

Optic atrophy. Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids).

Hearing impairment

  • WFS. Hearing loss is managed with either hearing aids or cochlear implant depending on the degree of hearing impairment and the frequencies affected.
  • Low-frequency sensorineural hearing loss (LFSNHL). Hearing aids should be tried early on, but may not be necessary until later in the disease course when a broader range of frequencies is involved. Hearing should be assessed throughout childhood in order to provide hearing aids when clinically indicated.

Developmental delay/cognitive impairment. Treatment follows routine practices.

Psychiatric difficulties. Treatment follows routine practices.

Neurogenic bladder. Treatment follows routine practices. Patients with recurrent urinary infections, urodynamic abnormalities, and incomplete bladder emptying must be treated according to established protocols for these abnormalities, like clean intermittent self-catheterizations or indwelling catheter, and frequent surveillance of presence of urinary infections.

Other

  • Treatment of central diabetes insipidus follows routine practices.
  • Treatment of gastroparesis and celiac disease follows routine practices. (See Celiac Disease.)

Prevention of Secondary Complications

Prevention of diabetes mellitus related complications is through optimization of glycemic control following established guidelines.

Surveillance

Wolfram syndrome. Regular evaluations including the following to detect manifestations that can occur with time:

  • Diabetes mellitus: tests of glucose tolerance
  • Optic atrophy: ophthalmologic examination
  • Sensorineural hearing loss: audiologic examination including speech discrimination testing
  • Neurologic deficits: neurologic examination including assessment of memory, personality changes
  • Psychiatric abnormalities: assessment for signs including depression, suicidal behavior, and changes in personal appearance and social behavior
  • Urologic abnormalities: urodynamic examination and assessment of ability to empty the bladder. Regular urine cultures when bladder dysfunction or other renal tract abnormality is present.
  • Diabetes insipidus: assessment of concentrating ability of the urine
  • Growth delay: monitoring of linear growth in children using standard growth charts
  • Hypogonadism
  • Puberty: monitoring for signs of onset of puberty

Once diabetes mellitus is present, regular follow-up for complications that can occur with time, including evaluations for:

  • Diabetic retinopathy
  • Microalbuminuria

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

Low-frequency sensorineural hearing loss (LFSNHL). Regular audiologic examination including speech discrimination testing is appropriate.

Evaluation of Relatives at Risk

Wolfram syndrome. Sibs of a proband warrant either molecular genetic testing (if the family-specific mutations are known) or screening for the earliest manifestations of WFS (i.e., diabetes mellitus, optic atrophy, and sensorineural hearing loss) to allow for early diagnosis and treatment.

Low-frequency sensorineural hearing loss (LFSNHL). At-risk relatives should be encouraged to seek either molecular genetic testing (if the family-specific mutation is known) or audiologic evaluation because the earliest manifestations of low-tone hearing loss may not be appreciated clinically.

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.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 is inherited in an autosomal recessive manner. Individuals with typical Wolfram syndrome (WFS) who have apparently only one, and in some cases, de novo mutations have been reported [Hansen et al 2005].

Wolfram syndrome-like disease is inherited in an autosomal dominant manner.

DFNA6/14/38 nonsyndromic low-frequency sensorineural hearing loss (WSF1-related LFSNHL) is inherited in an autosomal dominant manner.

Risk to Family Members –Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic although conflicting reports exist on the possibility of an increased risk of psychiatric symptoms [Pennings et al 2004].

Offspring of a proband. The offspring of an individual with WFS are obligate heterozygotes (carriers) for a disease-causing mutation in WFS1.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with WFS-like disease or DFNA6/14/38 have an affected parent.
  • A proband with WFS-like disease or DFNA6/14/38 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been documented it remains a possibility, as there are reports of apparently de novo mutations in individuals with WFS.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include hearing evaluation, physical examination, and molecular genetic testing of WFS1 if the mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with WFS-like disease or DFNA6/14/38 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and neither has a WFS1 mutation, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with WFS-like disease or DFNA6/14/38 has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

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 carrier 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

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)
    ATTN: Center for Information
    1701 North Beauregard Street
    Alexandria VA 22311
    Phone: 800-342-2383 (toll-free information/support); 703-549-1500
    Email: AskADA@diabetes.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #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 Insipidus Foundation, Inc
    1232 24th Street
    Ames IA 50010
    Phone: 706-323-7576
    Email: ndi-support@diabetesinsipidus.org
  • Diabetes UK
    Macleod House
    10 Parkway
    London NW1 7AA
    United Kingdom
    Phone: 020 7424 1000
    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 Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • National Library of Medicine Genetics Home Reference
  • EURO-WABB Project Registry
    An EU Rare Diseases Registry for Wolfram syndrome, Alström syndrome, Bardet-Biedl syndrome and other rare diabetes syndromes.

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-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for WFS1-Related Disorders (View All in OMIM)

222300WOLFRAM SYNDROME 1; WFS1
600965DEAFNESS, AUTOSOMAL DOMINANT 6; DFNA6
606201WFS1 GENE; WFS1

Normal allelic variants. WFS1 has a transcript of 3640 nucleotides of which 2673 bp are coding. WFS1 consists of eight exons with the first exon being non-coding. The largest exon is exon 8, where the coding part is 1812 bp long. Numerous normal sequence variants, mainly in exon 8 of WFS1, have been reported. WFS1 extends over 33.4 kb of genomic DNA.

Pathogenic allelic variants. More than 71 different missense, nonsense, and splice mutations, 37 different deletions, and 14 different insertions have been identified as causal for WFS. Most mutations predict premature protein truncation; a minority of mutations are non-truncating missense mutations. The mutations are mainly found in exon 8, although mutations in exon 3, 4, 5, and 6 have also been reported (see Table A). Most of the WFS1 mutations are unique to an individual or a few individuals, and therefore the entire coding region of WFS1 must be analyzed to make a molecular diagnosis [Cryns et al 2003].

At least 38 different missense mutations (mostly in exon 8) that segregate with autosomal dominant isolated (i.e., nonsyndromic) LFSNHL have been identified (see Table A).

Table 2. Selected WFS1 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.2590G>Ap.Glu864LysNM_006005​.2
NP_005996​.1

Normal gene product. Wolframin 1, comprising 890 amino acids, is predicted to have nine putative transmembrane domains. Wolframin 1 is an integral, endoglycosidase H-sensitive membrane glycoprotein that localizes to the endoplasmic reticulum (ER) [Yamamoto et al 2006]. Antibody studies indicate that the N terminus localizes in the cytoplasm, whereas the C terminus is in the ER lumen [Hofmann et al 2003]. Wolframin is widely ubiquitously expressed, and also expressed in retinal ganglion cells and optic nerve glia in monkeys [Yamamoto et al 2006, Luuk et al 2008]. The highest levels of expression are in brain, pancreas, heart, and insulinoma b-cell lines [Hofmann et al 2003]. 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]. A recent study has shown that the C-terminal domain (amino acids 652-890) and the transmembrane region (amino acids 322-652) interact with sodium-potassium ATPase b1 subunit [Zatyka et al 2008].

There is no interaction between wolframin 1 and endoplasmic reticulum intermembrane small protein (ERIS) encoded by WFS2, the gene in which mutation causes WFS2 [Amr et al 2007] (see Figure 1).

Figure 1
A

Figure

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

Abnormal gene product. Only a few WFS1 abnormal allelic variants have been tested in expression systems where effect on expression level, stability, degradation, and the intracellular fate of wolframin have been investigated. All mutations generated mutant proteins that were highly unstable and degraded, implying that these WFS1 mutations cause loss of function by cellular depletion of wolframin [Hofmann et al 2003, Hofmann & Bauer 2006].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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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

  • 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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