Harding Disease

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Article initiated by:

Rohini Kaur Chahal, Amna Ali, Bohan Kim, Sanjana Jaiswal, Elizabeth Arogundade, Andrew Go Lee, MD

All contributors:

Rohini Kaur Chahal, Amna Ali, Bohan Kim, Nagham Al-Zubidi, MD, Sanjana Jaiswal

Assigned editor:

Osama Al Deyabat, MBBS

Review:

Assigned status Update Pending

 by Osama Al Deyabat, MBBS on January 27, 2025.

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Disease

Harding’s disease describes the coexistence of multiple sclerosis (MS) and Leber’s hereditary optic neuropathy (LHON). LHON is a mitochondrial-inherited disease often characterized by bilateral, painless vision loss which can lead to severe optic atrophy. It can be associated with other conditions like movement disorders, epilepsy, cardiac arrhythmias, and multiple sclerosis. Multiple sclerosis is a neurological inflammatory condition that attacks heavily myelinated regions of the nervous system including the optic nerve, spinal cord, and cerebellum. It can present with optic neuritis, involving unilateral vision loss with pain on eye movement. When these two diseases coexist, the condition is termed Harding’s disease.

Etiology

Harding’s disease is a maternally inherited disorder caused by mutations in mitochondrial DNA (commonly m.11778G>A, m.3460G>A, and m.14484T>C). A total of 88 cases of Harding’s disease have been reported in the literature thus far. Various hypotheses regarding the distinct phenotype of Harding Disease have been proposed. First, it is possible that mtDNA mutations modify the phenotype of MS, causing an atypical optic neuritis that presents painlessly, more severe, and irreversibly. Second, it is possible that genetic and environmental factors that predispose to MS in women precipitate acute LHON in mtDNA mutation carriers who would have otherwise remained asymptomatic. Third, a patient with the LHON mtDNA mutation would lead to a coincidental inflammatory response that affects the anterior visual pathway in individuals susceptible to developing MS.

Risk Factors

Environmental factors such as smoking and alcohol intake have been implicated in influencing disease expression in LHON, suggesting that these risk factors may affect patients with Harding’s disease.

Pathophysiology

Neurological sequelae vary from mild disturbances to a course resembling relapsing-remitting MS. Visual changes initially begin unilaterally with painless blurring, progressing to severe loss of visual acuity.

Compared to LHON, Harding’s disease presents with similar age of onset, bilateral sequential visual involvement, and lack of visual recovery. However, Harding’s disease demonstrates a predominance of affected women (2.38:1), a large proportion of patients with greater than 2 visual events or persisting unilateral visual loss, and the long time interval before both eyes are affected. This is unlike LHON, as those patients are predominantly men (3:1), only have 2 visual events, and both eyes are largely invariably affected within a shorter period of time.

Compared to MS, Harding’s disease presents with similar age of onset and predominance in women. However, Harding’s disease has a higher proportion of patients with visual involvement, absence of ocular pain and absence of visual recovery. This is unlike MS, as fewer patients are expected to have visual involvement throughout the course of their illness, optic neuritis accompanied with ocular pain, and the majority will recover significant visual acuity.

Thus, Harding’s disease has significant similarities and differences between both MS and LHON, indicating interaction between both disorders.

Diagnosis

One study conducted by Pfeffer et al. defined patients with Harding’s disease as those who met diagnostic criteria for MS while also possessing a primary LHON mutation. It is important to consider the diagnosis of Harding’s disease in MS patients who are “higher risk,” such as those with severe or bilateral visual field loss or a matrilineal family history. In patients with seronegative neuromyelitis optica spectrum disorder (NMOSD), a clinical phenotype that may prompt testing for Harding’s disease is extensive dorsal column myelopathy, with or without visual field loss. In female patients, earlier consideration of a Harding’s disease diagnosis may allow for genetic counseling which would help to determine the risk of passing down the mutation to future offspring.

History

A thorough patient history is essential for establishing a timeline of symptom onset and diagnosing Harding’s disease. The condition typically begins with painless blurring of vision, which progressively worsens, leading to severe loss of visual acuity and central scotoma. Harding’s disease usually affects both eyes, with the second eye becoming involved within six to eight weeks. The pattern and severity of vision loss, along with the lack of recovery, closely resemble those seen in LHON. However, Harding’s disease is distinguished by a longer interval before the second eye is affected. Additionally, unlike LHON, Harding’s disease causes multiple episodes of visual loss. Patients with Harding’s disease are also less likely to report eye pain as compared to patients with MS.

Physical examination

Visual acuity is severely reduced, and visual field testing reveals dense central or centrocecal scotomas. Fundoscopic examination may show disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity. Optic disc atrophy may be observed in the chronic phase.

Extraocular findings include neurologic abnormalities such as postural tremor, peripheral neuropathy, movement disorders, and multiple sclerosis-like illness. Some patients may also have cardiac arrhythmias, muscle weakness and myopathy.

Laboratory test

MRI findings resemble those in MS, showing demyelinating white matter lesions. Interestingly, female Harding’s disease patients were found to have MRI imaging that was more consistent with MS as compared to male patients with Harding’s disease. Of note, one report by Kuer et al found features that distinguish Harding’s disease from MS, including reduced brightness and indistinct margins of T2 lesions and a lack of hyperintensity on T1 lesions on MRIs.

Diagnosis of Harding’s disease can also be confirmed through mitochondrial DNA (mtDNA) analysis, multigene panels, or complete mtDNA sequencing to identify one of three pathogenic variants: m.3460G>A, m.11778G>A, and m.14484T>C. In cases where mtDNA mutations are not identified, exome sequencing can be used to detect mutations in nuclear genes such as DNAJC30, which have been associated with atypical LHON-Plus presentations.

Management

Diagnosing Harding’s disease is especially important in females who can transmit the mutation to offspring, and early genetic counseling is advised. Patients should be advised to stop smoking and moderate alcohol intake. An ECG should be performed to exclude cardiac preexcitation syndromes. Due to the dual nature of the disease, treatment is complex and requires a multidisciplinary approach. Idebenone shows promise in potentially halting progression in early-stage LHON patients with discordant visual acuity. However, its efficacy in long-term disability remains uncertain. Mitoxantrone has been considered for severe MS cases but is fraught with serious side effects, prompting caution. However, a case study by Buhmann et al demonstrated visual recovery in a patient with an LHON mutation and concurrent MS-like disease after treatment with mitoxantrone. Another option, 4-aminopyridine, has shown potential in improving visual evoked potentials in MS, suggesting it could be relevant for Harding’s disease patients with severe visual prognosis. Treatment decisions should thus be individualized, pending further prospective research into effective therapies and biomarker development for Harding’s Disease.