Middle-aged man presents with weakness, progressively worsening vision
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A 48-year-old Hispanic man presented to the University of New Mexico Eye Clinic with progressively worsening vision in both eyes over many years. He denied diplopia, painful eye movements, flashes, floaters, nausea or recent weight loss.
Medical history was notable for benign prostate hyperplasia, fecal incontinence, gout, dyslipidemia, hypertension, and 20 years of heavy alcohol and tobacco use (sober since age 40). He was seen regularly by the neurology service for peripheral neuropathy and ataxia, which began at age 39 and slowly progressed until he was unable to ambulate without a walker. After extensive neurological workup (Table 1), his paresthesia and ataxia were attributed to alcohol abuse and a remote history of low vitamin B12 levels. Recent MRI of the brain and spine, blood counts, serum chemistries and vitamin panels were unremarkable. Around the time that he developed difficulty ambulating, he was noted to have temporal optic nerve pallor bilaterally and diagnosed with toxic optic neuropathy. Ocular history was otherwise notable for congenital color blindness and dry eyes.
Medications included allopurinol, amitriptyline, baclofen, chlorthalidone, gabapentin, lisinopril, meloxicam, metoprolol, omeprazole and tamsulosin. He had no history of head or ocular trauma. Family history was notable for alcoholism, diabetes and hypertension, and he believed his father had issues with ataxia as an adult. There was no known family history of eye disease.
Examination
Visual acuity was 20/50 with no pinhole improvement in the right eye and 20/70 with pinhole improvement to 20/60 in the left eye. Pupils were equal in size and had a sluggish reaction to light bilaterally; however, there was no relative afferent pupillary defect. IOP was 10 mm Hg in the right eye and 11 mm Hg in the left eye. The patient identified 2.5/10 Ishihara color plates in the right eye and 2/10 in the left eye.
There was a mild symmetric reduction in all versions and ductions in both eyes, most notably seen in upgaze. Ptosis was noted bilaterally with a margin to reflex distance of 1 mm in both eyes. The anterior segment examination was normal. The dilated fundus examination was notable only for severe temporal pallor of both optic nerves without optic nerve swelling or hemorrhage. The dilated examination was otherwise unremarkable. Cranial nerve testing demonstrated symmetric weakness in the orbicularis muscles and bilateral decreased hearing. The patient was able to transfer from his wheelchair to the exam chair without assistance but was unable to stand without support.
What is your diagnosis?
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Worsening vision
Prolonged vitamin B12 deficiency is known to cause peripheral paresthesia, gait abnormalities and toxic optic neuropathy, but the progressive nature of our patient’s presentation along with his ptosis and ophthalmoplegia raised concerns for an alternate etiology.
Bilateral optic atrophy with temporal pallor and decreased visual acuity in the context of normal head imaging suggests an acquired condition affecting mitochondrial function, such as nutritional or toxic optic neuropathy or an inherited condition such as Leber hereditary optic neuropathy or autosomal dominant optic atrophy. The bilateral ptosis and ophthalmoplegia raised our concern for a mitochondrial disease such as chronic progressive external ophthalmoplegia and its variants. Other differentials considered included pigmented retinopathies such as Kearns-Sayre syndrome, neuropathy, ataxia and retinitis pigmentosa (NARP), and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
Workup and management
In the ophthalmology clinic, OCT demonstrated bilateral thinning of the retinal nerve fiber layer temporally (Figure 1 on page 33). Humphrey visual field testing showed a superior arcuate defect in the right eye and diffuse depression with a central defect and inferior arcuate in the left eye (Figure 2).
Source: Gavin Gorrell, MD, and Kevin Sitko, MD
The possibility of a mitochondrial process as a basis of our patient’s ocular and nervous system disease was discussed with the neurology service, which agreed that a genetic disorder better explained the progression in our patient’s symptoms despite several years of sobriety and normal vitamin B12 levels. Whole exome sequencing of the mitochondrial and nuclear genome was ordered in our patient, but this testing was denied by his insurance carrier, and he could not afford the several thousand dollar out-of-pocket cost.
We began our workup for mitochondrial disease by sequencing the mitochondrial genome for duplications and deletions and by testing the nuclear DNA for dominant optic atrophy, the most common inherited optic neuropathy. Mitochondrial genome sequencing was unremarkable, and no mutations in the dominant optic atrophy genes OPA1 and OPA3 were identified. Next, the possibility of a nuclear mutation leading to mitochondrial dysfunction was considered, and a genetic panel evaluating the 202 nuclear mutations associated with mitochondrial disease was obtained. This panel revealed two pathologic mutations in the SPG7 gene on chromosome 16, yielding the diagnosis of hereditary spastic paraplegia type 7 (SPG7), an inherited mitochondrial disease associated with vision changes, ataxia and sensory neuropathies.
Discussion
Hereditary spastic paraparesis (HSP) is a group of inherited neurologic diseases characterized by spasticity of the lower limbs. More than 70 genetic mutations leading to HSP have been identified, and inheritance has been described in an autosomal dominant, autosomal recessive or X-linked pattern. HSP is categorized as “pure” if symptoms are limited to spastic lower extremity paresis or “complex” if there are additional central nervous system or phenotypic abnormalities. SPG7 is a complex HSP caused by a mutation in paraplegin, a metalloproteinase in the mitochondrial membrane.
Mutation of the paraplegin protein SPG7 is often transmitted in an autosomal recessive manner and presents in the third to fourth decade with progressive weakness and spasticity of the lower extremities, often resulting in ataxia and dependence on mobility devices. This disease is also associated with optic neuropathy, ptosis, ophthalmoplegia, hearing difficulties, sphincter dysfunction and pes cavus, all of which were present in our patient. Treatment for HSP is mainly supportive with a focus on spasticity with medications such as baclofen and botulinum toxin in addition to physical therapy to maintain mobility. Genetic counseling is helpful for family planning and to identify family members at risk for inheriting this disease.
Mitochondrial diseases often have ocular involvement with characteristic manifestations such as ptosis and impairment of ocular motility. Once a pattern of mitochondrial disease is recognized, the next challenge lies in determining what genetic testing to obtain. Mitochondrial function relies on both the mitochondrial genome and proteins encoded on nuclear DNA; therefore, testing for mitochondrial disease often requires investigation of both genomes, and some experts recommend whole exome sequencing of the mitochondrial and nuclear genome as the first step in patients with suspected mitochondrial disease. Whole exome sequencing is a nonspecific modality that can identify every mutation present in the mitochondrial and chromosomal genome, regardless of its relation to the disease in question. A gene panel is a more targeted approach that evaluates specific genes that are known to be related to a diagnosis or a phenotype. In our patient, a mitochondrial disease panel was ordered that sequenced the mitochondrial genome for pathologic variants and tested for mutations in the 202 nuclear genes that have been linked to mitochondrial disease. There are a multitude of genetic panels available from a variety of vendors, and providers can order tests from a menu categorized by symptoms, findings and diagnosis. Improvements in sequencing technology have decreased the cost and turnaround time of genetic testing. At the time of this writing, pricing ranges from $1,400 for small panels to $2,500 for whole exome sequencing, and results are typically available in 4 to 8 weeks.
In addition to genetic testing, mitochondrial disease can be detected with muscle biopsy and histochemical stains. Striated muscle cells contain large amounts of mitochondria, which contain specific proteins involved in production of adenosine triphosphate through oxidative phosphorylation. In mitochondrial disease, affected muscle fibers do not have the energy production necessary for normal function and appear “ragged” in comparison to neighboring muscle fibers. These fibers will show minimal histochemical staining of cytochrome oxidase, the final enzyme of the mitochondrial respiratory chain.
For the ophthalmologist, it is unlikely that a rare disease such as the SPG7 variant of HSP will come into the clinic. However, this case highlights the importance of recognizing findings suggestive of mitochondrial disease, such as ptosis with ocular dysmotility, optic neuropathy and pigmented retinopathies, and understanding the testing options available to evaluate for mitochondrial diseases.
- References:
- Casari G, et al. Spastic paraplegia 7. https://www.ncbi.nlm.nih.gov/books/NBK1107/. Updated Oct. 25, 2018.
- Combined mito genome plus mito focused nuclear gene panel. https://www.genedx.com/tests/detail/combined-mito-genome-plus-mito-focused-nuclear-gene-panel-736.
- Gorman GS, et al. Saudi J Ophthalmol. 2011;doi:10.1016/j.sjopt.2011.02.002.
- Lallemant-Dudek P, et al. Rev Neurol (Paris). 2021;doi:10.1016/j.neurol.2020.07.001.
- Panels. https://blueprintgenetics.com/tests/panels/. Updated May 14, 2021.
- Pricing. https://blueprintgenetics.com/pricing/. Updated May 12, 2021.
- Schrier SA, et al. Curr Opin Ophthalmol. 2011;doi:10.1097/ICU.0b013e328349419d.
- Spastic paraplegia 7. https://rarediseases.info.nih.gov/diseases/4927/spastic-paraplegia-7. Accessed Dec. 11, 2021.
- Theunissen TEJ, et al. Front Genet. 2018;doi:10.3389/fgene.2018.00400.
- For more information:
- Gavin Gorrell, MD, and Kevin Sitko, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Allison V. Coombs, DO, MS, and Nisha S. Dhawlikar, MD, MPH. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.