Clinical Characteristics
Ocular Features
The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa. Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent. Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age. Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife. The retinal disease is progressive and blindness may be the final result.
Systemic Features
Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa. Vestibular areflexia is virtually complete and constitutes a defining feature. Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age. Sitting alone may also be delayed. Sperm motility is abnormal which is likely the basis for reduced fertility in male patients. An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings. MRI imaging has found a significant decrease in intracranial volume and brain size. About 1 in 4 children have behavioral problems or psychosocial difficulties.
Genetics
Inheritance
Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease. These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943). Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'
A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).
Clinical differences have led to the categorization of three types of Usher syndrome: type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.
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.