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Wolfram syndrome (MIM 222300) is the association of juvenile onset diabetes mellitus and optic atrophy, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). Patients present with diabetes mellitus followed by optic atrophy in the first decade, cranial diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade. Other abnormalities include primary gonadal atrophy. Death occurs prematurely, often from respiratory failure associated with brainstem atrophy. Most patients eventually develop all complications of this progressive, neurodegenerative disorder. The pathogenesis is unknown, but the prevalence is 1 in 770000 in the UK and inheritance is autosomal recessive. A Wolfram gene has recently been mapped to chromosome 4p16.1, but there is evidence for locus heterogeneity, and it is still possible that a minority of patients may harbour a mitochondrial genome deletion. The best available diagnostic criteria are juvenile onset diabetes mellitus and optic atrophy, but there is a wide differential diagnosis which includes other causes of neurodegeneration.
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PMID:Wolfram (DIDMOAD) syndrome. 935 Aug 17

We describe a Thai family with three children, two of whom presented with Wolfram syndrome, which is a rare syndrome characterised by diabetes insipidus, diabetes mellitus, optic atrophy, deafness and urinary tract dilatation. A girl and her younger brother had insulin-dependent diabetes mellitus at 11 years old with early onset of renal impairment, proteinuria and hypertension. Urinary tract dilatation was demonstrated in both patients. Kidney biopsies were compatible with diabetic nephropathy. Both children also had bilateral sensorineural hearing loss. Optic atrophy with severe loss of vision was detected in the girl and bilateral cataract in her brother. Both patients were HLA DR2 positive. At 16 years old, her creatinine clearance was 16 ml/min/1.73 m2. Her brother's creatinine clearance was 25 ml/min/1.73 m2 at 13 years old. We conclude that renal function should be evaluated in patients with Wolfram syndrome and the cause of renal failure in these patients may be rapid and severe diabetic nephropathy.
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PMID:Renal failure in two patients with Wolfram syndrome. 946 37

Wolfram syndrome is the association of diabetes mellitus and optic atrophy, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). Incomplete characterisation has caused diagnostic confusion; we therefore undertook a nation-wide cross-sectional case finding study. We identified 45 patients with Wolfram syndrome, median age 29 years. All patients fulfilled the ascertainment criteria (juvenile onset diabetes mellitus and optic atrophy). Optic atrophy presented in 38 patients with reduced visual acuity and colour vision defect (median age 11 years), progressing to visual acuity of 6/60 or less in 35 patients (median time 8 years, range 1-25 years). Visual field examinations recorded before acuity deteriorated showed central scotomas with peripheral constriction. Blind patients had absent pupillary reflexes. Horizontal nystagmus was seen in patients with other signs of cerebellar degeneration. There was no pigmentary retinal dystrophy; only 3 patients had background diabetic retinopathy, despite a median duration of diabetes of 24 years. Electroretinography was normal in 3 patients and showed reduced amplitude in 3 patients; visual evoked responses were abnormal (10/10 patients: reduced amplitude to both flash and pattern stimulation). Magnetic resonance imaging showed generalised brain atrophy with reduced signal from the optic nerves and chiasm. A postmortem brain specimen from one patient revealed atrophy of the optic nerves, chiasm, cerebellum and brainstem. We found no evidence of mitochondrial genome defects or rearrangements. This primary neurogenerative disorder presents with diabetes mellitus and progressive optic atrophy, probably due to pathology in the optic nerve.
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PMID:Optic atrophy in Wolfram (DIDMOAD) syndrome. 953 52

We report the case of a young insulin-dependent diabetic patient in whom acute renal failure led to detection of ureterohydronephrosis secondary to neurogenic bladder. The persistence of a high daily urine volume revealed diabetes insipidus, suggesting Wolfram syndrome, which was confirmed by the diagnosis of optic atrophy. The main features of Wolfram syndrome, particularly urologic ones, and their treatment are discussed in the light of our findings in this patient.
Diabetes Metab 1998 Jun
PMID:Acute renal failure in a diabetic patient. 969 60

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.
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PMID:A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). 977 6

Wolfram syndrome (WS) is characterized by optic atrophy, insulin-dependent diabetes mellitus, vasopressin (VP)-sensitive diabetes insipidus, and neurosensory hearing loss. Here we report a disturbance in VP precursor processing in the supraoptic and paraventricular nuclei of WS patients. In these patients with diabetes insipidus we could hardly detect any cellular immunoreactivity for processed VP in the supraoptic and paraventricular nuclei. On the other hand, in the paraventricular nucleus a considerable number of cells immunoreactive for the VP precursor were present. In addition, the proprotein convertase PC2 and the molecular chaperone 7B2 were absent. As expression of PC2 and 7B2 was detected in the nearby nucleus basalis of Meynert of one WS patient and in the anterior lobe of the other WS patient, the absence of the two proteins in the paraventricular nucleus was not due to mutations in their genes. These results indicate that in WS patients with diabetes insipidus, not only does VP neuron loss occur in the supraoptic nucleus, but there is also a defect in VP precursor processing.
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PMID:The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2. 981 87

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.
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PMID:Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family. 985 92

The optic disc and retinal neovascularization are less prominent and less frequent in myopic eyes in patients suffering from diabetes mellitus. The exact mechanisms of this phenomenon are not well known, but there is some evidence that there is a reduced blood flow in myopic eyes which is associated with less damaged microcirculation in eyes of patients with diabetes mellitus. The aim of our study was to evaluate the correlation between myopic refractive error and degree of diabetic retinopathy. We conducted a retrospective study in a group of randomized patients, divided into the following groups according to their refractive error: emmetropia (30 eyes), myopia simplex (30 eyes) and high myopia, over -6.5 dsph (21 eyes). Among patients with high myopia, seven had monocular myopia. All patients suffered from non insulin dependent diabetes mellitus for more than ten years, and their average age was 52.37-3.48 years. We did not observe patients with rubeosis iridis and neovascular glaucoma or patients with myopia less than -2.0 dsph. Our results indicated that there was no significant difference in the appearance of fundus between the studied groups. In all patients the incidence rate of non proliferative and proliferative diabetic retinopathy was the same as well as the absence of retinopathy (Fisher's test). The only exception were the patients with monocular myopia over -13.o dsph who had no signs of diabetic retinopathy in myopic eye, while the other, emmetropic eye, showed various stages of retinopathy, from severe non proliferative to proliferative. Some of the risk factors which influence the incidence rate of ocular complications in diabetic patients are well known, as are duration of diabetes mellitus, blood sugar level, blood pressure, ocular pressure and eye perfusion. On the other hand, it is also known that amblyopia, optic atrophy, low blood pressure in central retinal artery and retinitis pigmentosa are ocular conditions which are not associated with proliferative diabetic retinopathy. It was also noticed that complications of diabetes in high myopic eyes are less prominent than in emmetropic eyes. This finding is in harmony with our results. Sultanov et al. observed diabetic changes in the retina in 40.9% of myopic refraction patients, 65.2% of emmetropia cases and 70.4% of hypermetropia cases. The severity of involvement was less in myopia than in other types of refraction. In medium severe myopia, no proliferative diabetic retinopathy was observed, and in high myopia (10 eyes) no diabetic involvement of the fundus oculi was found. In anisometropia diabetic symptoms on the myopic side were either absent or poorly manifest. The possible cause of such findings could be the changes in retinal perfusion in myopic eyes and eyes in patients with diabetes mellitus. In 1973 a lower blood flow was detected in the retina and the choroid, proportionally to the degree of myopia. In 1982, Perkins indicated that the circulation time and pulsation rate in the central retinal artery in myopic eyes were reduced proportionally to the degree of myopia. In cases with early diabetic retinopathy Coscas detected a lesser blood flow in retinal veins. On the other hand, it has been found that high blood pressure increases the risk of diabetic retinopathy. These data suggest that the reduced blood flow in high myopia is a protective factor regarding the occurrence of complications in diabetes. Anisometropia and amblyopia in cases with monocular myopia, which presents a particular group in our study, could be factors which also prevent the occurrence of proliferative diabetic retinopathy. Instead of conclusion, we would like to point out that pathophysiologic mechanisms of these phenomena are not discussed enough. It is, nevertheless, important to appropriately examine the fundus in patients with high myopia and diabetes mellitus, because if the complications appear, they may be disastrous and must be treated immediately.
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PMID:[Occurrence of changes in the eye in diabetic retinopathy with significant myopia]. 992 Oct 19

Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.
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PMID:Mitochondrial disorders: clinical and genetic features. 1007 67

Recent advances in genetics tend to center on the discoveries of molecular biology. A disease is first linked to a region on a chromosome, a gene is later cloned, or a candidate gene identified, point mutations described, phenotype-genotype correlations made, and rationales for treatment proposed. Several neuro-ophthalmological diseases have recently been studied in this way; including Leber's hereditary optic neuropathy and other mitochondrial diseases, autosomal dominant (Kjer) optic atrophy, Wolfram syndrome, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), Usher syndrome, neurofibromatosis types I and II, and two disorders of the paired box genes: aniridia and Waardenburg's syndrome. Apart from molecular biology there are still some new disease entities being described and new inheritance patterns identified for some syndromes, such as periodic alternating nystagmus.
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PMID:Recent advances in hereditary disease and neuro-ophthalmology. 1016 Apr 19


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