Nerve-Wracking Eye Puzzle: A Rare Case of Alpers-Huttenlocher Syndrome

Alpers-Huttenlocher syndrome (AHS) is a rare progressive mitochondrial disease that manifests in the first decade of life. It is associated with a constellation of symptoms resulting in significant motor disability, refractory seizures, and liver dysfunction and is ultimately fatal.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Nerve-Wracking Eye Puzzle: A Rare Case of AlpersHuttenlocher Syndrome Ashwini Kini T, MD, Zabeen Mahuwala, MD, Flavius Raslau, MD, Padmaja Sudhakar, MD A lpers-Huttenlocher syndrome (AHS) is a rare progressive mitochondrial disease that manifests in the first decade of life. It is associated with a constellation of symptoms resulting in significant motor disability, refractory seizures, and liver dysfunction and is ultimately fatal. Ocular muscles may be involved, such as other mitochondrial disorders, resulting in progressive external ophthalmoplegia. We describe a young male patient with a positive family history of AHS who was diagnosed with this condition after genetic testing. An 18-year-old, previously healthy, Caucasian man was referred to the neuromuscular clinic for weakness. He was performing well in high school, with no concerns for cognitive difficulties. He reported considerable back pain and poor co-ordination that began several months ago. He had been evaluated for scoliosis previously. He reported difficulty tying shoelaces and buttoning his clothes as he felt “clumsy.” He had difficulty with walking due to poor balance and falls. His nonidentical twin brother had died at the age of 6 from a genetic disease. On examination, he had hammer toes with high arches. He was alert with intact cognitive and language functions. He had limited extraocular motility in all directions of gaze, but the rest of the cranial nerves were unremarkable. He had diffuse motor weakness, predominantly affecting proximal muscles with normal bulk and tone. On sensory examination, he had diffuse patchy sensory loss to light touch and pain in all extremities, loss of vibration at both ankle and toes, and loss of proprioception at the toes. His deep tendon reflexes were depressed throughout. He had agraphesthesia in the hands and feet bilaterally. He had finger-to-nose ataxia, breakdown of rapid alternating movements, and imprecise, slow, poor amplitude with finger tapping bilaterally. His gait was broad-based and stiff with inability to do tandem walking and walk on his toes and heels. Rest of his physical examination was unremarkable. On ophthalmic examination, his best-corrected visual acuity with myopic correction was 20/25 in the right eye and 20/30 in the left eye, with no afferent pupillary defect and intact color vision on Ishihara color plates. There was bilateral moderate ptosis with poor levator action and marked limitation of ocular motility in all direction of gaze, more pronounced in up-gaze (Fig. 1). Anterior segment examination was unremarkable with normal intraocular pressure. Fundus examination showed a cup-to-disc ratio of 0.6 bilaterally. Visual fields showed a cecocentral scotoma with nasal depression in both eyes with a mean deviation of 26.01 dB in the right eye and 27.10 dB in the left eye. Retinal nerve fiber layer analysis by optical coherence tomography showed reduced thickness with polar thinning bilaterally and no loss of ganglion cell layer. Preliminary laboratory findings were normal except for an elevated creatinine kinase. Electromyography and nerve conduction studies showed severe axonal and demyelinating FIG. 1. Extraocular motility shown with limitation of extraocular movements in all directions of gaze but more prominent in upgaze. Departments of Neurology (AK, ZM, PS), Ophthalmology (PS), and Radiology (FR), University of Kentucky, Lexington, Kentucky. The authors report no conflicts of interest. Address correspondence to Padmaja Sudhakar, MD, 740, S Limestone, Lexington, KY 40536; E-mail: [e-mail] e6 Kini T et al: J Neuro-Ophthalmol 2023; 43: e6-e8 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. MRI orbits in coronal (top row) and axial section (bottom row) in Short Tau inversion recovery (A), T1 (B), and postcontrast T1 fat suppressed (C). Arrows point out the atrophied extraocular muscles. polyneuropathy, predominantly sensory. Contrast enhanced MRI head showed an incidental left frontal lobe developmental venous anomaly, and MRI orbits showed significant atrophy of all extraocular muscles (Fig. 2). Visual evoked potential showed delay in latency and reduced amplitude on pattern reversal. Multifocal electroretinogram was consistent with cone dysfunction. Although his initial presentation was concerning for a hereditary peripheral neuropathy, the presence of motor weakness with external ophthalmoplegia raised concerns for mitochondrial disease. He had worsening weakness in his extremities over next 2–3 years associated with pain that was worse on activity. He eventually used a wheelchair. He developed myoclonus and generalized tonic-clonic seizures. He received several different pain medications and levetir- acetam for his seizures. Electroencephalogram showed excessive slowing of the posterior background, with intermittent moderate bihemispheric slowing but no interictal epileptiform discharges. Cardiac echocardiogram showed global hypokinesis. A muscle biopsy of his vastus lateralis revealed ragged red fibers. His family revealed that his twin brother had died at a young age from a mitochondrial disease, AHS. He was sent to genetic testing that revealed POLG mutation (heterozygous on chromosome 15 hg 19 g.p Gly 11 asp, p ala 467 thr, p arg 852 cys) establishing the diagnosis of AHS. Our patient died because of refractory status epilepticus at age 27. POLG-related disorders comprise a spectrum of phenotypes with significant overlaps, with AHS being most severe. TABLE 1. Diagnostic Criteria for Alpers Huttenlochers syndrome 1. Clinical triad of refractory seizures, psychomotor regression, and hepatopathy. 2. In the absence of either hepatopathy (Table 1) or additional findings (see below), the diagnosis can only be confirmed either by polymerase gamma gene sequencing, liver biopsy, or postmortem examination. 3. Additional clinical findings: (at least 2 of the 11 findings must be present) a. Brain proton magnetic resonance spectroscopy showing reduced N-acetyl aspartate, normal creatine, and elevated lactate. b. Elevated cerebral spinal fluid protein (.100 mg/dL). c. Cerebral volume loss (central . cortical, with ventriculomegaly) on repeat MRI or computed tomography studies. d. At least 1 electroencephalogram showing a multifocal paroxysmal activity with high-amplitude delta slowing (200–1,000 mV) and spikes/polyspikes (10–100 mV, 12–25 Hz). e. Cortical blindness or optic atrophy. f. Abnormal visual evoked potentials and normal electroretinogram. g. Quantitative mitochondrial DNA depletion in skeletal muscle or liver (35% mean). h. Deficiency in polymerase gamma enzymatic activity (#10%) in skeletal muscle or liver. i. Elevated blood or cerebral spinal fluid lactate (3 mM) on at least 1 occasion in the absence of acute liver failure. j. Isolated complex IV or a combination I, III, and IV electron transport complex defects (#20% of normal) on liver respiratory chain testing. k. A sibling confirmed to have Alpers-Huttenlocher syndrome. Adapted from Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013 Mar;48(3):167-78. 10.1016/j.pediatrneurol.2012.09.014 Kini T et al: J Neuro-Ophthalmol 2023; 43: e6-e8 e7 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Others include childhood myocerebrohepatopathy, myoclonic epilepsy myopathy sensory ataxia, ataxia neuropathy spectrum, and autosomal recessive (AR) or autosomal dominant (AD) progressive external ophthalmoplegia. Alpers has AR inheritance and affects 1 in 100,000 people with primary effects on muscle, nerve, and brain, organs that are energy dependent and are prone to oxidative damage. The mutation in mitochondrial DNA replicase results in reduced levels of polymerase Y that is essential for replication. Phenotypic manifestations occur when mitochondrial DNA function reaches a critical nadir (1). Alpers typically has early age of onset within the first decade of life between ages of 2–4 years; however, some can present later in their second decade. The typical presentation involves regression of mental and motor abilities, liver involvement, ataxia, myoclonus, choreoathetosis, neuropathy, areflexia, and hypotonia. Interestingly, our patient never displayed involvement of his liver. Seizures could occasionally herald the onset of the disease or could set in later. It is notable that once seizures start, the disease is known to progress quite rapidly (1). Valproate use in these patients can accelerate the liver damage and is typically avoided for seizure management. EEG typically shows occipital predominant epileptiform discharges. Diagnosis of Alpers is based on meeting the diagnostic criteria as outlined in Table 1 and genetic testing (2). Muscle biopsy may be additionally helpful. Our patient had refractory seizures and psychomotor regression, but did not have evidence of hepatopathy; however, the patient met diagnostic criteria from having a sibling with the diagnosis, optic atrophy, and confirmation with a genetic testing. Ocular involvement in AHS includes vision loss secondary to neuronal loss in calcarine cortex and visual halluci- e8 nations from occipital seizures. Central and peripheral neuronal loss can cause cranial neuropathies. Progressive external ophthalmoplegia has been reported to occur with POLG mutations that could be AD or AR (Lamantea) (3). Although pigmentary retinopathies and cone/rod dysfunctions have been associated with Chronic Progressive external Ophthalmoplegia and other mitochondrial disorders such as Kearns–Sayre and Leigh syndrome, it has not been reported in AHS, making our case unique. AHS is a fatal disease without definitive cure, and treatment is directed toward symptom management and seizure precautions. With disease progression, the motor involvement significantly worsens, leaving patients to use a wheelchair. Seizure onset heralds the onset of rapid clinical deterioration and ultimately become refractory to management, resulting in death. STATEMENT OF AUTHORSHIP Conception and design: A. Kini; Acquisition of data: F. Raslau, Z. Mahuwala; Analysis and interpretation of data: P. Sudhakar. Drafting the manuscript: A. Kini; Revising it for intellectual content: Z. Mahuwala, P. Sudhakar, F. Raslau. Final approval of the completed manuscript: P. Sudhakar. REFERENCES 1. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. AlpersHuttenlocher syndrome. Pediatr Neurol. 2013;48:167–178. 2. Bastiaensen LA. Pigment changes of the retina in chronic progressive external ophthalmoplegia (CPEO). Acta Ophthalmol Suppl. 1978;138:5–36. 3. Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28:211–212. Kini T et al: J Neuro-Ophthalmol 2023; 43: e6-e8 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.