DIDMOAD syndrome (Wolfram syndrome) in four male siblings.
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Adolescent↗
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A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.
Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.
Adult↗
[Positional cloning of the gene(WFS1) for Wolfram syndrome].
Wolfram syndrome(DIDMOAD syndrome) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset, insulin-requiring diabetes mellitus and optic atrophy. Other symptoms including diabetes insipidus, neurosensory deafness, urinary tract and neurological abnormalities are often accompanied. In patients, beta-cells are selectively lost from their pancreatic islets of Langerhans. The gene was previously mapped to 4p16.1. By haplotype analysis and recombination mapping in 5 families, we localized the gene within a region less than 250 kb on chromosome 6p. In the region, we identified a novel gene(WFS1) encoding a putative transmembrane protein. Mutations were identified in all affected members of the families and these mutations were associated with disease phenotype. This finding was further confirmed by other investigators and to date, more than 50 mutations were identified in the WFS1 gene from the patients with Wolfram syndrome. The WFS1 gene encodes a protein of 100.3 kDa with 9 to 10 putative transmembrane domains. The protein appears to be important in the survival and maintenance of normal pancreatic beta-cells and neurons. Physiological function of the WFS1 protein and mechanisms by which defective WFS1 lead to the development of Wolfram syndrome need to be clarified.
Cell Survival↗
Evidence of widespread axonal pathology in Wolfram syndrome.
Wolfram syndrome, characterised by diabetes insipidus, diabetes mellitus, optic atrophy sensorineural deafness and acquired urinary tract abnormalities, is an hereditary neurodegenerative syndrome, the pathogenesis of which is unknown. We report the post-mortem findings on a patient with well-documented Wolfram syndrome. The brain showed severe degeneration of the optic nerves, chiasm and tracts as well as severe loss of neurons from the lateral geniculate nuclei, basis pontis, and the hypothalamic paraventricular and supraoptic nuclei. In addition, there was a widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices and the deep cerebral white matter. This widespread axonal pathology parallels the pattern of neurodegeneration and in many areas is more striking than neuronal loss.
Adult↗
Imaging characteristics of familial Wolfram syndrome.
Wolfram syndrome is a rare diffuse neurodegenerative disorder also known as DIDMOAD due to its characteristics of diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness. It is also associated with a wide variety of abnormalities of the central nervous system, urinary tract and endocrine glands. It may be familial or sporadic. Imaging findings include absence of the short T1 nature of the pituitary posterior lobe, atrophy of the optic nerve, chiasma, and tracts. Atrophy of the brain stem and cerebellum has also been reported. We describe a 15-year-old boy and an 11-year-old girl with Wolfram syndrome who were siblings from a diabetes mellitus family. They received regular insulin control at our hospital and had symptoms of frequent urinary tract infection and diabetes insipidus. Magnetic resonance imaging revealed marked pons and cerebellar atrophy. Optic nerve and chiasma atrophy was also noted.
Adolescent↗
[From gene to disease; mutations in the WFS1-gene as the cause of juvenile type I diabetes mellitus with optic atrophy (Wolfram syndrome)].
Wolfram syndrome patients are mainly characterised by juvenile onset diabetes mellitus and optic atrophy. A synonym is the acronym DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness. Diabetes insipidus and sensorineural high-frequency hearing impairment are important additional features. This rare autosomal recessively inherited neurodegenerative syndrome is caused by mainly inactivating mutations in the WFS1 gene. It is located at chromosome 4p16 and encodes wolframin, a transmembrane protein. No function has yet been ascribed to this protein.
Chromosomes, Human, Pair 4↗
Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome.
Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.
Adrenocorticotropic Hormone↗
A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).
Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.
Adult↗
Molecular characterization of WFS1 in patients with Wolfram syndrome.
Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for Wolfram syndrome (WFS1) has been identified on the short arm of chromosome 4 and subsequently mutations in WFS1 have been described. We have screened 12 patients with Wolfram syndrome from nine Dutch families for mutations in the WFS1-coding region by single-strand conformation polymorphism analysis and direct sequencing. Furthermore, we analyzed the mitochondrial genome for gross abnormalities and the A3243G point mutation in the leucyl-tRNA gene, because Wolfram syndrome shows phenotypic similarities with mitochondrial disease. Seven mutations in WFS1 were identified in six of nine families: two missense mutations, one frameshift mutation, one splice donor site mutation, and three deletions. In addition, a splice variant near the 5'UTR of WFS1 was identified, present in patient as well as control RNA samples in various percentages, alternating the translation initiation consensus sequence. Whether this WFS1 splice variant displays impaired translation efficiency remains to be determined. No MtDNA lesions were identified in any of the Wolfram patients. Our results demonstrate the usefulness of molecular analysis of WFS1 in the refinement of clinical diagnostic criteria for Wolfram syndrome that helps to dissect the clinically overlapping syndromes sharing diabetes mellitus and optic atrophy.
Adolescent↗
Successful pregnancy in two sisters with Wolfram syndrome.
Wolfram's Syndrome is a rare disorder comprising diabetes insipidus, diabetes mellitus, optic atrophy and high tone sensineural deafness. Successful pregnancy is extremely rare and has not previously been reported in siblings with this disorder. We report on two Irish sisters suffering from Wolfram's syndrome who have given birth to three healthy male infants.
Adolescent↗
Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family.
Wolfram syndrome (MIM 222300) is characterized by juvenile-onset diabetes mellitus and optic atrophy. Previous linkage analyses in the United States and UK families have indicated that the gene for Wolfram syndrome (WFS) is localized on the short arm of chromosome 4. We herein confirm the linkage of the WFS locus to D4S3023 on 4p with a two-point LOD score of 3.42 in a large Japanese family with Wolfram syndrome. Multipoint linkage analysis revealed the maximum LOD score of 4.82 between D4S3023 and D4S394. We also evaluated putative health risks in carriers by multiple logistic analysis with independent variables, age, gender, and numbers of affected haplotypes and with dependent variables, such as hearing loss, diabetes mellitus, polyuria, incontinence, psychological illness, and visual acuity. The results showed that the putative disease haplotype increased a risk of hearing loss (odds ratio =35.68, 95% confidence interval =4.12-308.95) and diabetes mellitus (odds ratio =7.57, 95% confidence interval =2.03-28.23) independently. This is the first report of an increased health risk of illness in carriers, other than for psychiatric disease.
Adolescent↗
[A novel mutation of WFS1 gene in Chinese patients with Wolfram syndrome].
OBJECTIVE: Wolfram syndrome is an autosomal recessive disorder characterized by early-onset diabetes mellitus, diabetes insipidus, optic atrophy and deafness. The aim of this study was to scan the WFS1 gene mutations in a Chinese Wolfram syndrome pedigree. METHODS: Eight exons and flanking introns of WFS1 gene were screened using PCR-DNA direct sequencing. Effects of the mutation on the structure and function of the WFS1 gene product, Wolframin, were evaluated by bioinformatics. RESULTS: A novel mutation, F417del, in the WFS1 gene was identified. The patient was homozygous of this mutation and the consanguineous parents were heterozygous. The mutation causes the lose of a non-polar amino acid, which was located in the transmembrane domain of the protein product. Bioinformatics predicted that the mutation altered the secondary structure of the transmembrane domain and decreased the hydrophobicity of F417del protein. CONCLUSIONS: This study identified a novel mutation of WFS1 gene and represented the first cause of molecular characterization of Chinese Wolfram syndrome patients.
Adult↗
Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees.
Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease mainly characterized by familial diabetes mellitus and optic atrophy. WS patients frequently present with other clinical features such as diabetes insipidus, renal abnormalities, psychiatric disorders, and a variety of neurologic symptoms: deafness, ataxia, peripheral neuropathy. A gene responsible for Wolfram Syndrome (WFS1) has been recently identified on chromosome 4p16.1. Twenty-two Wolfram patients from 16 Spanish families were screened for mutations in the WFS1 coding region by SSCP analysis and direct sequencing. Since WS has been considered a mitochondrial disorder for some time, mitochondrial DNA (mtDNA) in these families was also examined. WFS1 mutations were detected in 75% of families (12 of 16). One of these mutations, an insertion of 16 base pairs in exon 4, turned out to be notably frequent in Spanish pedigrees. As many as 50% of pedigrees with WFS1 mutations harbored this insertion, either in one (33% of cases) or in two chromosomes (67%). Ten other mutations were identified: 7 missense changes, 2 deletions, and 1 nonsense mutation. Only 3 of these changes had been previously described in non-Spanish pedigrees. Large mtDNA rearrangements and LHON point mutations were detected in four and six families, respectively. No correlation could be established between WFS1 gene mutations and specific point mutations or rearrangements in mtDNA. We would suggest first screening for the 16-bp insertion in exon 4 when a new Spanish WS case is reported.
Alleles↗
Wolfram syndrome.
The Wolfram syndrome is a rare dysmorphogenetic disease of autosomic recessive hereditary nature. The pathogenesis of the disease is still not well known. It is characterised by the presence of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Other anomalies, such as renal outflow tracts and multiple neurological disorders may develop later. In our case report the diabetes mellitus appeared at the age of 4; the hearing loss and renal disturbances at the age of 11; the optic atrophy at the age of 16. No signs of ataxia, diabetes insipidus and neurologic anomalies were found. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus asssociated with optic atrophy. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and the retinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. Other signs such as the progressive sensorineural hearing loss, the presence of nystagmus and of urodynamic disturbances and renal complications makes the diagnosis of this syndrome easier.
Adolescent↗
Psychiatric disorders in Wolfram syndrome heterozygotes.
Wolfram syndrome is an autosomal recessive disorder caused by a gene on the short arm of chromosome 4 and characterized by a range of neurological, psychiatric and behavioural abnormalities. Recent research suggests that heterozygous carriers of the disease gene are at increased risk of psychiatric hospitalization.
Chromosome Mapping↗
Analysis of the contribution of the HLA system to the inheritance in the Wolfram syndrome.
The Wolfram syndrome (WS) is an autosomal recessive disorder beginning in childhood that consists of four clinical features: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Its pathogenesis remains unknown, although the tendency to develop this syndrome has been related to some class II antigens of the HLA system. We report six new cases in four families. A review of published data from the genetic features of this syndrome is performed, establishing the high frequency of the HLA-DR2 antigen in the WS (44.4%) compared with a control group (21.9%; relative risk, 2.8) and to patients with Type 1 insulin-dependent diabetes mellitus (Type 1 diabetes) (6.77%; relative risk, 9.7). We also comment the high frequency of the HLA-DQw1 antigen (85.5%) in this syndrome, without statistical significance. A familial segregation study of the HLA haplotypes has been carried out without finding correlation between the autosomal recessive pattern attributed to the WS, and the major histocompatibility complex. In conclusion, whereas HLA may increase susceptibility to the WS, as shown by the existence of an HLA-DR2 association, the major genetic influence on the inheritance of the WS must be at another locus.
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Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families.
Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy. Patients with WS frequently develop deafness, diabetes insipidus, renal tract abnormalities, and diverse psychiatric illnesses, among others. A gene responsible for WS was identified on 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein present in a wide spectrum of tissues. A new locus for WS has been located on 4q22-24, providing evidence for the genetic heterogeneity of this syndrome. Six Spanish families with a total of seven WS patients were screened for mutations in the WFS1-coding region by direct sequencing. We found three previously undescribed mutations c.873C > A, c.1949_50delAT, and c.2206G > C, as well as the duplication c.409_424dup16, formerly published as 425ins16. Several groups had detected deletions in the mitochondrial DNA (mtDNA) of WS patients. For this reason, we also studied the presence of mtDNA rearrangements as well as Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and A1555G point mutations in the WS families. No mtDNA abnormalities were detected.
Alleles↗
MRI of Wolfram syndrome (DIDMOAD).
Wolfram syndrome (DIDMOAD) is a rare diffuse neurodegenerative disorder characterised by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and a wide variety of abnormalities of the central nervous system, urinary tract and endocrine glands. It may be familial or sporadic. Reported features on MRI of the brain are absence of the physiological high signal of the posterior lobe of the pituitary, shrinkage of optic nerves, chiasm and tracts, atrophy of the hypothalamic region, brain stem, cerebellum, and cerebral cortex. We report a 12-year-old girl with a 5-year history without brain stem, cerebellar or cerebral atrophy. MRI showed an unusual feature: a focus of high signal on PD- and T2-weighted images in the right substantia nigra. This is consistent with previously reported neuropathological post-mortem studies, but has never been reported in vivo.
Atrophy↗