Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (452 page)

   Sequencing of mtDNA.

Suggested Readings

Petersen MB, Willems PJ. Non-syndromic, autosomal-recessive deafness.
Clin Genet.
2006;69:371–392.

Schimmenti LA, et al. Infant hearing loss and connexin testing in a diverse population.
Genet Med.
2008;10:517–524.

LEBER OPTIC ATROPHY (LEBER HEREDITARY OPTIC NEUROPATHY; LHON)

MIM #535000

   Definition

Leber optic atrophy (LHON) is caused by mutations in multiple genes in complex I, III, and IV polypeptides encoded by the mitochondrial genome (mtDNA), suggesting that LHON results from a defect in the respiratory chain. The vulnerability of retinal ganglion cells to mitochondrial dysfunction leads to midlife, acute or subacute, painless, central vision loss (scotoma). Depending on the mutation, final visual acuity can range from 20/50 to no light perception. The maternal transmission is due to mtDNA mutations, but the incomplete penetrance and male bias remain puzzling. Three primary mutations at base pairs 11,778, 3,460, and 14,484 are present in at least 90% of families. However, a significant percentage of individuals with an LHON mutation do not develop the disorder. More than 50% of males and more than 85% of females with a mutation never experience vision loss due to LHON.

   Relevant Tests and Diagnostic Value

Complete and targeted sequence of the mitochondrial genome.

Suggested Readings

Kirkman MA, et al. Gene-environment interactions in Leber hereditary optic neuropathy.
Brain.
2009;132:2317–2326.

Yu-Wai-Man P, et al. Inherited mitochondrial optic neuropathies.
J Med Genet.
2009;46:145–158. Note: Erratum:
J Med Genet
. 2011;48:284 only.

NONSYNDROMIC SENSORINEURAL DEAFNESS, MITOCHONDRIAL

MIM #500008

   Definition

Mitochondrial nonsyndromic sensorineural deafness has a wide range of penetrance manifested by broad variability in severity, age-at-onset, and audiometric abnormalities of hearing impairment. Mitochondrially inherited NSHL can result from mutations in any of several mitochondrial genes (mtDNA), frequently involving the 12S rRNA and tRNA genes. The mtDNA mutations account for only about 2% of NSHL and show dominant maternal inheritance.

   Relevant Tests and Diagnostic Value

Sequence analysis of the complete mitochondrial genome.

Suggested Reading

Chaig MR, et al. A mutation in mitochondrial 12S rRNA, A827G, in Argentinean family with hearing loss after aminoglycoside treatment.
Biochem Biophys Res Commun.
2008;368:631–636.

USHER SYNDROME TYPE 1A (USH1)

MIM #276900

   Definition

Usher syndrome is the most common type of autosomal recessive syndromic hearing loss and the most common genetic cause of combined deafness and blindness. The variably progressive deafness is accompanied by a variable age of onset and progression of night blindness and loss of peripheral vision through progressive degeneration of the retina (retinitis pigmentosa, RP).

   Who Should Be Suspected?

Usher syndrome type I, the most severe form, is characterized by congenital, severe sensorineural hearing loss, vestibular dysfunction, and the onset of RP by the age 10 years. Type I is further subdivided into five types, where the pathogenic variants in the
MYO7A
(the most common),
USH1C, CDH23, PCDH15, and USH1G
(
SANS
) genes cause type 1B, type 1C, type 1D, type 1F, and type 1G, respectively. Additional Usher presentations result from mutations in the
USH2A
,
GPR98
,
DFNB31
, and
CLRN1
genes.

   Relevant Tests and Diagnostic Value

   Next-generation sequencing of the coding regions and splice sites for detection of mutations in genes associated with Usher syndrome

   Microarray targeted mutation analysis of genes associated with Usher syndrome