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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.
Diabetes Res Clin Pract 1994 Jan
PMID:Analysis of the contribution of the HLA system to the inheritance in the Wolfram syndrome. 820 Feb 99

The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues.
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PMID:Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300). 838 98

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.
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PMID:Successful pregnancy in two sisters with Wolfram syndrome. 844 96

Wolfram syndrome was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. Other neurological features subsequently emerged, and "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) became a commonly accepted acronym. Here, we describe 4 further cases from 2 families, in whom there occurred previously unrecognized neurological features, central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure (fatal in 1 case), startle myoclonus (in 2 unrelated cases), axial rigidity, and Parinaud's syndrome. Magnetic resonance images revealed striking brainstem atrophy affecting, in particular, the pons and midbrain. The mitochondrial DNA from 3 cases (and relatives) showed no evidence of any of the previously reported abnormalities. These neurological and neuroradiological features, in conjunction with (1) analyses showing the neurodegenerative origin of optic atrophy, deafness, diabetes insipidus, and incontinence, (2) other previously reported neurological complications (including anosmia, ataxia, epilepsy, and neuropsychiatric and cognitive abnormalities), and (3) the very small number of published postmortem studies, indicate that Wolfram syndrome should be reemphasized as a unique hereditary neurodegenerative disorder with prominent optic atrophy and diabetes mellitus.
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PMID:Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. 860 54

Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and approximately 5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level.
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PMID:Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion. 865 Dec 80

Hereditary diabetes insipidus can occur in two forms: the first, referred to as central diabetes insipidus, is responsive to vasopressin whereas the second, termed nephrogenic diabetes insipidus, is resistant to treatment. Recent advances in molecular genetics have contributed to elucidate the pathogenesis of these affections. Familial central diabetes insipidus depicts two unsimilar illnesses. The first, characterized by an autosomal dominant transmission, is of delayed onset and worsens progressively all through life. It is related to a heterozygous mutation of the vasopressin precursor gene mainly involving either the sequence encoding for the signal peptide or the one encoding for neurophysin II, the hormone carrier protein. Mutations described to date are responsible for impairment of vasopressin precursor transportation and processing. Therefore mutant protein accumulates in the posterior pituitary which is involved in the persistant bright spot seen on magnetic resonance imaging. The second illness or Wolfram syndrome, autosomal recessive, associates obligatory features: insulin-dependant diabetes, bilateral optic atrophy and more inconstantly: diabetes insipidus, deafness, genito-urinary and neuropsychiatric disturbances. The cause of this syndrome, still unknown, may involve mitochondrial ADN mutations. Familial nephrogenic diabetes insipidus, of neonatal onset, are mainly X-linked and associated to mutations in the V2 receptor gene. About 60 mutations have been described until now. Some rare cases, transmission of which is autosomal recessive, result from homozygous mutations of aquaporin 2 gene, a water channel involved in the water reabsorption in the renal collecting duct. Other mutations will be probably discovered in future. In conclusion, familial diabetes insipidus constitutes an interesting pathogenic model because it may be explained by impairment of vasopressin gene precursor as well as by abnormalities of renal receptor or post receptor mechanisms of the hormone.
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PMID:[Congenital diabetes insipidus. Recent advances in molecular genetics]. 868 70

A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy with neuropathological examination was performed in one case. Molecular studies focused on the short arm of chromosome 6, including the HLA DR2 locus associated with narcolepsy and the (CAG)n repeat at the spinocerebellar ataxia type 1 (SCA1) locus. Biochemical investigation of muscle biopsy of one case indicated mitochondrial dysfunction with selective decrease in ATP production for substrates that normally give the highest rates. The activity of glutamate dehydrogenase was reduced, indicating a low mitochondrial density. We postulate an autosomal dominant genetic factor responsible for this syndrome. Linkage was excluded to HLA DR2, and a normal sized SCA1 repeat was observed. We conclude that a locus predisposing to ataxia, deafness and narcolepsy exists outside this region of chromosome 6.
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PMID:Autosomal dominant cerebellar ataxia deafness and narcolepsy. 874 54

The association of insipidus diabetes, diabetes mellitus, optic atrophy and deafness is known as the Wolfram syndrome. This paper contributes two case reports with significant urological sings and symptoms associated (ureterohydronephrosis, neurogenic bladder) both studied from a radiological and urodynamic point of view, with comments on the probable origin of the urological alternatives as well as their evolution, which was favourable after treatment with antibiotics and intermittent vesical catheterism.
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PMID:[Urologic manifestations in Wolfram's syndrome]. 876 8

Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the region. Haplotype inspection of the remaining 11 families, which appear linked to chromosome 4p and had typical phenotypes, revealed crossover events during meiosis, which also placed the gene in the interval D4S432 and D4S431. In these families no recombinants were detected with the marker D4S3023, which maps within the same interval.
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PMID:Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity. 880 1

Wolfram or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, which has long been known as an autosomal-recessive disorder, has recently been proposed to be a mitochondrial-mediated disease with either a nuclear or a mitochondrial genetic background. The phenotypic characteristics of the syndrome resemble those found in other mitochondrial (mt)DNA mediated disorders such as Leber's hereditary optic neuropathy (LHON) or maternally inherited diabetes and deafness (MIDD). Therefore, we looked for respective mtDNA alterations in blood samples from 7 patients with DIDMOAD syndrome using SSCP-analysis of PCR-amplified fragments, encompassing all mitochondrial ND and tRNA genes, followed by direct sequencing. Subsequently, we compared mtDNA variants identified in this disease group with those detected in a group of LHON patients (n = 17) and in a group of 69 healthy controls. We found that 4/7 (57%) DIDMOAD patients harbored a specific set of point mutations in tRNA and ND genes including the so-called class II or secondary LHON mutations at nucleotide positions (nps) 4216 and 4917 (haplogroup B). In contrast, LHON-patients were frequently (10/17, 59%) found in association with another cluster of mtDNA variants including the secondary LHON mutations at nps 4216 and 13708 and further mtDNA polymorphisms in ND genes (haplogroup A), overlapping with haplogroup B only by variants at nps 4216 and 11251. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. We propose that haplogroup B represents a susceptibility factor for DIDMOAD which, by interaction with further exogeneous or genetic factors, might increase the risk for disease.
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PMID:Analysis of the mitochondrial DNA from patients with Wolfram (DIDMOAD) syndrome. 930 89


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