A rare, likely pathogenic variant causing Leber's hereditary optic neuropathy in three-generation females of an African-American family.

Purpose: We report a rare, likely pathogenic variant gene causing Leber's hereditary optic neuropathy (LHON) in three-generation female members of an African-American family. Observations: The granddaughter and mother presented with a subacute, painless visual loss in both eyes at age 10 and 42 years to legal blindness. The maternal grandmother presented with a gradual onset of moderate visual loss at age 60. The mother and grandmother reported a history of bariatric surgery and subsequent vitamin deficiencies. All three patients shared similar Optical Coherent Tomography (OCT) findings of profound thinning of ganglion cell complex (GCC) and relatively preserved peripapillary retinal nerve fiber layer thickness (pRNFL). Nuclear and mitochondrial DNA sequencing identified a 14596A > T likely pathogenic variant, p.(Ile26Met), in the MT-ND6 gene, with 100% homoplasmy in the granddaughter and mother and 65% heteroplasmy in the grandmother. The mother and grandmother were treated with idebenone in addition to vitamin supplements, with a slight improvement in their vision. Conclusions and Importance: Our patients' presentation stresses the importance of including LHON in the differential diagnosis in females presenting with unexplained bilateral, painless, severe visual loss. The OCT finding of profound GCC thinning with relatively preserved pRNFL thickness can be a red flag for LHON. A collaboration with genetic specialists to utilize expanded gene sequencing may greatly enhance our ability to identify rare pathogenic variants.

Ocular evaluation and genetic test for an early Alström Syndrome diagnosis.

PURPOSE: We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease. OBSERVATIONS: The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants. CONCLUSIONS AND IMPORTANCE: ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.