Early-Onset Hearing Loss in Leber’s Hereditary Optic Neuropathy: A Case Report

Abstract

Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders that is characterized in young adults and teenagers as bilateral, painless, subacute visual failure. Extraocular manifestations include neurological and cardiac features. Sensorineural hearing loss (SNHL) has not been reported as a clinical feature of this disorder. We report a patient diagnosed with LHON having the common m.11778G>A; p. Arg340 pathogenic variant who was also diagnosed with bilateral mild-to-moderate high-frequency SNHL as a neonate through our provincial newborn screening program. Genetic workup, including a next-generation sequencing “Comprehensive Hereditary Hearing Loss Panel” for common and non-syndromic hearing loss and sequencing of the mitochondrial genome, was negative for a second pathogenic variant. The infectious workup was negative. Non-enhanced magnetic resonance imaging of the brain and internal auditory canal was normal. To our knowledge, SNHL has not been reported before as a clinical feature of patients diagnosed with LHON, and hence this rare and unusual presentation merits reporting.

Introduction

Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders that is characterized in young adults as bilateral, painless, subacute visual failure.^1,2 The typical age of onset of vision loss is between 15 and 35 years. Males are more likely to be affected by vision loss than females, with a reported ratio of 4:1 to 5:1. ² Neurologic abnormalities such as postural tremors, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported, as well as multiple sclerosis-like illnesses. The latter is more frequent in females. ¹ Cardiac arrhythmias were also reported. ²

There is a paucity of approved, effective treatments for LHON. ³ Early treatment with ubiquinone and especially idebenone can result in better visual outcomes.^3,4 Gene therapy is an exciting option; however, this is not clinically available, and a few clinical trials are ongoing. ³

LHON is caused by pathogenic variants in the mitochondrial DNA (mtDNA) and the 3 most common mtDNA pathogenic variants observed are m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6. ¹ The G11778A is the most common variant with 73% of the patients carrying this variant. ² Other mtDNA variants have been reported to be associated with LHON (www.mitomap.org/). ⁵

Yuan et al conducted a systematic review of G11778A LHON patients. They reported a subgroup of pediatric patients presenting with early ophthalmological disease onset. The mean onset age was 12.5 years, and male patients accounted for more than 80% of the cases. ²

Hearing loss is not a common presentation for LHON. Yang et al reported the co-occurrence of pathogenic variants for LHON and hearing loss genetic variants, which can account separately for the hearing loss in these cases. ⁵ Ahmad et al reported a case of an adult patient diagnosed with LHON who also presented with a history of chronic kidney disease, diabetes mellitus, sensorineural hearing loss (SNHL), and preeclampsia. However, this patient was found to have the m.13513G>A; p.D393N variant in ND5, which is reported to have a clinically heterogeneous phenotype. ⁴

In this paper, we report a patient diagnosed with LHON having the common m.11778G>A; p. Arg340 pathogenic variant who was diagnosed with bilateral mild-to-moderate high-frequency SNHL as a neonate through our provincial newborn screening program. Genetic and infectious workups were negative.

Case Report

We report a 20 month-old male, who was initially assessed in the Metabolic clinic at the Hospital for Sick Children at the age of 7 months due to a history of a maternal homoplasmic pathogenic point mutation in MT-ND4: m.11778G>A; p. Arg340 causing LHON. Targeted genetic testing confirmed the diagnosis in the proband as he carries the familial genetic change in homoplamy levels (99.9%).

This patient had an unremarkable perinatal history; however, he failed his newborn hearing screen, which has led to further diagnostic testing. He has had multiple auditory brainstem response tests, which have consistently demonstrated bilateral mild-to-moderate high-frequency SNHL. The tympanic membranes and middle ears were clear. The workup for hearing loss included a non-enhanced magnetic resonance imaging (MRI) of the brain and internal auditory canal that showed grossly normal brain and inner ear structure as well as preserved auditory nerves. His cytomegalovirus (CMV) neonatal screening (PCR for CMV on dried blood spot [DBS]) came back negative and remained negative upon repeat testing. Genetic testing done as a part of newborn screening was negative for DFNB1- and DFNB4-associated permanent hearing loss. DNA was tested using a panel of 10 common, primarily highly penetrant mutations in GJB2. And 11 common mutations in SLC26A4. The patient also underwent a next-generation sequencing Comprehensive Hereditary Hearing Loss Panel for common and non-syndromic hearing loss that included mutations in 58 genes as well as copy number variants. This revealed only a single variant of uncertain significance in WHRN: c.2510GA; p. Arg837His. This is an autosomal recessive gene that was not thought to be the etiology of his hearing loss. Sequencing of the mitochondrial genome did not lead to a second mitochondrial mutation.

His development was neurotypical; however, he was connected with speech therapy due to potential speech delay secondary to his hearing loss. His past medical history includes a heart murmur that was detected at 6 weeks old, and he was seen by a cardiologist and had an echocardiography that showed a patent foramen ovale (PFO) and a mild physiological peripheral pulmonary stenosis, but his ECG was normal. He also had a left-sided inguinal hernia repair at 18 months. His physical examination is unremarkable. The patient was fitted with hearing aids and started treatment with Coenzyme Q10 at 4 mg/kg/day.

Family history includes non-consanguineous parents. The patient’s mother is reported to be visually intact but was diagnosed with a prolonged QT (the time between the start of the Q wave and the end of the T wave on an electrocardiogram) interval. She had no subjective complaints of hearing loss; however, she underwent a Puretone audiometric assessment (250 Hz-8 kHz), which revealed normal hearing thresholds bilaterally. The maternal first cousin had vision loss and was diagnosed with LHON. The maternal grandmother, uncle, and sister were also diagnosed with LHON.

The 5-year-old female sister presented with an unremarkable perinatal history and was initially assessed in the Metabolic Clinic at the Hospital for Sick Children at the age of 20 months due to the familial history. Targeted genetic testing confirmed the diagnosis as she carries the familial genetic change MT-ND4: m.11778G>A; p. Arg340His, in homoplamy levels (99.9%). On her initial assessment, she did not have any developmental concerns or any significant past medical history. However, she presented with a hearing impairment at 3 years of age. She had a reported history of multiple episodes of acute otitis medias. Baseline audiology testing done at 4 years of age indicated normal otoscopy bilaterally. Tympanometry results were abnormal bilaterally. Play audiometry was done using inserted earphones with good reliability. Results revealed borderline normal to slight hearing loss bilaterally, conductive in nature. Audiology was repeated 6 months later. Tympanometry results revealed normalization of the middle ear pressure in the left ear while abnormal middle ear function in the right remained. Play audiometry was done using insert earphones with good reliability and revealed normal hearing in the left ear and normal hearing in the right ear, gradually sloping to borderline normal hearing levels at 3 to 6 K and moderate hearing loss at 8 K in the right ear. Distortion Product Otoacoustic Emissions (DPOAEs), an objective test of inner ear function, were present between 2 and 8 K in the left ear and absent between 2 and 8 K in the right ear. Present DPOAEs are consistent with normal cochlear function and normal hearing in the left ear. Absent DPOAEs in the right could not be interpreted, given abnormal middle ear function in the right ear. Further audiometric evaluation (250 Hz-4 kHz) revealed normalization of the Puretone thresholds bilaterally. Overall, his sister was not considered to have SNHL. She is also treated with Coenzyme Q.

Discussion

LHON is a painless, sequential loss of vision that typically has its onset during the teenage or young adult years. The disease is well known to be triggered by environmental factors, including smoking and excessive use of alcohol. ¹ Patients could present with other systemic presentations, including cardiac arrhythmias and neurological manifestations.^1,2

The co-occurrence of pathogenic variants for LHON and hearing loss has been reported in more than 200 individuals based on a database of more than 26,000 whole mitochondrial genomes. ⁵ Wei et al reported a male patient who presented with both LHON and mild hearing impairment. Genetic testing noted a homoplasmic LHON-associated ND6 T14484C mutation and a second 12S rRNA A1555 variant which is associated with deafness. ⁶

To our knowledge, SNHL has not been reported as a clinical feature of patients diagnosed with LHON as a result of m.11778G>A; p. Arg340 without a concurrence with a second variant related to hearing loss. A workup to diagnose a second cause of asymptomatic hearing loss in a normally developed child included reviewing the neonatal CMV screening on the DBS, as well as retesting of the sample all came back negative. A hereditary hearing loss genetic panel Next Generation Sequencing (NGS) for 58 genes related to common and non-syndromic hearing loss did not identify a better explanation for the hearing loss. Sequencing of the mtDNA was completed and was normal; a second variant that could explain his presentation with SNHL was not identified.

Despite the well-established association between mitochondrial dysfunction and SNHL in several mitochondrial disorders, auditory involvement is typically rare in LHON. Although it is not fully described in the literature, several explanations can be proposed to account for this tissue specificity. One hypothesis is that retinal ganglion cells, which are primarily affected in LHON, have high energy demands and limited mitochondrial reserve, rendering them more susceptible to energy failure compared to auditory neurons. ⁷ The second hypothesis involves tissue-specific threshold effects, whereby the optic nerve appears to have a lower tolerance for mitochondrial dysfunction than the auditory system, resulting in selective vulnerability. ⁸ A third possible explanation is the variability in mtDNA heteroplasmy across tissues; a lower proportion of mutant mtDNA in cochlear structures may contribute to the preservation of auditory function and thus mitigate the risk of hearing impairment. ⁹

Conclusion

LHON features typically manifest in the second and third decades of life with predominantly subacute, painless visual failure. We reported a patient diagnosed with both early-onset SNHL and LHON. Genetic workup and infectious workup for a second diagnosis to explain the neurosensory hearing loss came back negative. A non-enhanced MRI of the brain and internal auditory canal showed grossly normal brain, inner ear structure, and preserved auditory nerves. We recognize that there might be other possible rare medical explanations for this child having both the diagnosis of LHON and congenital SNHL; however, we wanted to highlight this rare and unusual presentation.