OMIM ID:
Wolfram Syndrome 2
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
As in Wolfram syndrome 1, only insulin dependent diabetes mellitus and optic atrophy are essential to the diagnosis. The optic atrophy is progressive over a period of years and can be the presenting sign. Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life. The majority (77%) of patients are legally blind within a decade of onset. The visual field may show paracentral scotomas and peripheral constriction. Both VEPs and ERGs can be abnormal. Diabetic retinopathy is uncommon and usually mild.
Systemic Features
The clinical features of this disorder are many and highly variable. Sensorineural hearing loss, anemia, seizures, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years. A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported. The diabetes mellitus is insulin dependent with childhood onset. Hydroureter is often present.
Diabetes insipidus may be present in patients with Wolfram syndrome 1 (222300) but has not been reported in patients reported with Wolfram syndrome 2. Upper GI ulceration and bleeding were present in several individuals.
Genetics
Inheritance
This is an autosomal recessive disorder similar to Wolfram syndrome 1 (WFS1; 222300) but caused by mutations in the CISD2 gene (4q22-q24). The gene codes for a small protein (ERIS) localized to the endoplasmic reticulum. It seems to occur less commonly than WFS1.
Some patients have mutations in mitochondrial DNA as the basis for their disease (598500). Combined with evidence that point mutations at the 4p16.1 locus predisposes deletions in mtDNA, this suggests that at least some patients with Wolfram syndrome have a recessive disease caused by mutations in both nuclear and mitochondrial genes.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.