1	WOLFRAM SYNDROME IN 2 SIBLINGS D.S.Casper, MD Edward Harkness Eye Institute
2	Patient History A 21 yo Hispanic male (Pt A) and his 19 yo sister (Pt B) were seen for complaints of poor vision.
3	Past Medical History The two patients have known diabetes mellitus (DM), diabetes insipidus (DI), optic atrophy (OA), and the boy shows some mild deafness. They arrived in this country from the Dominican Republic in late 1994. They were both diagnosed with DM Type 1 prior to the age of 4 and are both on insulin.
4	PMH – Patient A Within days of their arrival here, Pt A. was admitted to the hospital with a diagnosis of Diabetic Ketoacidosis and dehydration; his blood glucose was 665. During the hospitalizations Optic Nerve atrophy was first noted in Pt A at age 12; and diabetes insipidus was noted at age 18. No other pathologies were noted
5	PMH – Patient B Pt B. was admitted within weeks of her arrival with recurrent hypoglycemia. Pt B. was admitted again at the same hospital at age 14 for poorly controlled DM with worsening polyuria and polydipsia. In view of her brother’s diagnoses, she was evaluated at that time by our service, and found to have optic atrophy as well. Studies to determine whether she had DI were inconclusive, although it was felt that she probably had some minimal DI at that time. Pt. B. was also found to have peripheral neuropathy, for which she was started on gabapentin.
6	Clinical / Ocular Examination Patient A Visual acuity of CF @ 6 OD and HM at 1 foot OS with poor projection. Pupils were large, and only barely reactive APD was not appreciated. The remainder of the examination was notable for bilateral optic atrophy (see Fig 1 in the next slide) without evidence of diabetic retinal changes. MRI in the year 2000 confirmed the finding of bilateral optic hypoplasia with thinned optic chiasm. A repeat scan this year showed no interval change.
7	Figure 1
8	Patient B Visual acuity was found to be 20/150 bilaterally. Pupils were also large, but were round and reactive OU without APD. Funduscopic examination revealed bilateral optic atrophy without diabetic changes. (see fig 2 in the next slide) MRI study in the year 2000 showed bilateral small optic nerves.
9	Figure 2
10	DISCUSSION This progressive neurodegenerative disorder, also known as DIDMOAD (DI = Diabetes Insipidus; DM = Diabetes Mellitus; OA = Optic Atrophy; D = Deafness) It is named after the physician who first described 4 siblings with juvenile diabetes mellitus and optic atrophy in 1938. Wolfram1s Syndrome is the inherited association of juvenile-onset insulin-dependent diabetes with progressive optic atrophy. The estimated prevalence in North America is approximately 1/100,000. Pathogenesis: unknown.
11	"A nuclear gene," A nuclear gene, WFS1/woframin, has been identified, as has autosomal recessive inheritance. A high frequency of the HLA-DR2 antigen has been noted in these patients. Mutation analysis of the WFS1 gene (mapped to chromosome 4p16.1) in Wolfram patients has shown mutations in 90% of patients. A second locus (WFS2) has been implicated at 4q, and it has been suggested that a minority of patients may harbor a mitochondrial genome deletion.
12	Clinical Characteristics Ocular manifestation typically present in the first decade of life with diabetes mellitus followed by optic atrophy Visual evoked potentials usually show reduced amplitude to both flash and pattern stimulation. Diabetes insipidus and sensorineural deafness in the second decade Dilated renal outflow tracts early in the third decade Multiple neurologic abnormalities develop early in the fourth decade.
13	Cont’ Most patients eventually develop all major aspects of the disease. In addition, short stature, hypogonadism, psychiatric disorders (depression, psychosis, aggression and dementia) Grand mal seizures are associated with the more well-known pathologic features of this syndrome. Death typically occurs prematurely (median age at death ~ 30 yrs), usually from respiratory failure secondary to brainstem atrophy.