Table 4.

Genes of Interest in the Differential Diagnosis of Usher Syndrome Type II

Gene(s)DisorderMOIClinical CharacteristicsComment
USH1 ARCongenital bilateral profound SNHL, vestibular areflexia, adolescent-onset RPChildren w/USH1 are usually do not walk until age 18 mos to 2 yrs due to vestibular involvement (those w/USH2 usually walk at age ~1 yr).
USH3 (OMIM 276902, 614504)ARPostlingual progressive SNHL, late-onset RP, variable impairment of vestibular functionSome persons w/USH3 may have profound HL & vestibular disturbance & thus be clinically misdiagnosed w/USH1 or USH2. 1
(13 genes) 2
Zellweger spectrum disorder (ZSD) 3Intermediate/
milder ZSD
(AD) 4
Mainly sensory deficits &/or mild developmental delay; intellect may be normal.Milder ZSD & USH2 can both have SNHL & retinal pigmentary abnormalities, but visual impairment in milder ZSD is more variable. Also, those w/milder ZSD typically develop ameliogenesis imperfecta of secondary teeth.
Severe ZSDARSevere neurologic dysfunction, craniofacial abnormalities, liver disfunction, absent peroxisomesInfants w/severe ZSD are significantly impaired & usually die during 1st yr of life, usually having made no developmental progress.
Refsum disease ARRP, HL, anosmia, polyneuropathy, ataxiaRP is nearly always 1st noticeable feature; anosmia, polyneuropathy, & then mild-to-moderate HL follow.
ABHD12 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, & cataract (PHARC) (OMIM 612674)ARPolyneuropathy, HL, ataxia, RP, cataractPersons w/PHARC typically develop polyneuropathy & ataxia in teens or early adulthood; & RP typically later in adulthood.
TIMM8A 5Deafness-dystonia-optic neuronopathy syndrome (DDON)XLMales: pre- or postlingual SNHL in early childhood; optic atrophy → slowly progressive ↓ visual acuity from age ~20 yrs; dementia from age ~40 yrs; slowly progressive dystonia or ataxia in the teens 6
Females: mild hearing impairment & focal dystonia
In DDON, appearance of the retina, night vision, & ERG are usually normal; in USH, impaired vision results from retinal dystrophy that first manifests as impaired dark adaptation. 7

AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss; MOI = mode of inheritance; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; USH = Usher syndrome; XL = X-linked


60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in PEX1, 14.5% with pathogenic variants in PEX6, and 7.6% with pathogenic variants in PEX12. In total, 13 genes are known to be associated with ZSD.


The term "Zellweger spectrum disorder" refers to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.


One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.


DDON syndrome is caused by either (1) a hemizygous TIMM8A pathogenic variant in a male proband or a heterozygous TIMM8A pathogenic variant in a female proband or (2) a contiguous gene deletion of Xp22.1 involving TIMM8A.


In DDON syndrome, hearing impairment appears to be constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs (e.g., personality change and paranoia) vary in degree of severity and rate of progression.


From: Usher Syndrome Type II

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