Optic Atrophy in a Patient With Atypical Pantothenate Kinase-Associated Neurodegeneration

We describe a 50-year-old man who developed eight-and-a-half syndrome associated with an ipsilateral trigeminal nerve palsy because of a post-transplant lymphoproliferative disorder. This case widens the spectrum of eight-and-a-half syndrome to include a thirteen-and-a-half syndrome.

Clinical Observation Optic Atrophy in a Patient With Atypical Pantothenate Kinase-Associated Neurodegeneration Jinu Han, MD, Do Wook Kim, MD, Chul-Ho Lee, BS, Sueng-Han Han, MD Abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegeneration with brain iron accumulation and characterized by extrapyramidal signs, vision loss, and intellectual decline. PKAN is caused by mutations in the PANK2 gene, which codes for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the coenzyme A biosynthetic pathway. Visual failure in this disorder is typically due to pigmentary retinopathy. Yet our patient, a 13-year-old girl with PKAN, developed bilateral optic atrophy and the appearance of the retina and electroretinography were normal. Optic atrophy is a rare finding in patients with PKAN. It is important for the clinician to consider PKAN in the differential diagnosis of patients presenting with signs of extrapyramidal dysfunction, cognitive decline, and vision loss because of optic atrophy. Journal of Neuro-Ophthalmology 2016;36:182-186 doi: 10.1097/WNO.0000000000000335 © 2016 by North American Neuro-Ophthalmology Society PKAN, the onset of extrapyramidal signs occurs later and the progression of disease is slower. In addition, there are hypointense lesions in the globi pallidi and substantia nigra without central high signal intensity (4). Ophthalmological findings in patients with PKAN previously described include pigmentary retinopathy with an abnormal electroretinogram (ERG), Adie-like pupils, and abnormal vertical saccades (5-8). We are aware of only 2 reports of patients with PKAN who developed optic atrophy (9,10). We describe a 13-year-old girl with PKAN who experienced visual loss. Ophthalmoscopy revealed temporal pallor of both optic discs associated with loss of retinal nerve fiber layer (RNFL) on optical coherence tomography (OCT). ERG testing was normal. CASE REPORT P antothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome, is a rare autosomal recessive disorder characterized by extrapyramidal dysfunction, and visual and mental deterioration (1). Typical PKAN onset occurs early in the first decade of life with rapid progression (2). In such cases, T2 magnetic resonance imaging (MRI) shows hypointense signals in the globi pallidi and substantia nigra consistent with abnormal iron accumulation. Also, there is an area of central hyperintensity surrounding the hypointense signal, termed the "the eye of the tiger sign" (3). In the atypical form of Department of Ophthalmology (JH, DWK, S-HH), Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea; and Division of Clinical Genetics (C-HL), Department of Pediatrics, Severance Children's Hospital, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. The authors report no conflicts of interest. Address correspondence to Sueng-Han Han, MD, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 135-720, South Korea; E-mail: [e-mail] 182 A 13-year-old girl was evaluated in the pediatric neurology clinic for gait disturbance and vision loss. She exhibited normal development and good school performance until the age of 10 years. At that time, she developed postural instability (frequent stumbling), followed by cognitive impairment and progressive dystonia (walking on toes). Her parents reported that the child complained of a tingling sensation below her ankles and observed recurrent episodes of mood lability. There was no history of consanguinity or family history of ophthalmologic or neurologic disease. Visual acuity was 20/40 in each eye and funduscopy showed bilateral temporal optic disc pallor. Neurological examination revealed that the patient had intact toe gait, but abnormal heel gait. Finger-to-nose testing was normal but tandem gait revealed swaying to both sides, which may have been due to lower extremity weakness. Romberg test results were negative. Results of electroencephalography, electromyography with motor and sensory velocity studies, and visual evoked potentials were within normal limits. Biochemical laboratory tests were all normal, including blood and urine levels Han et al: J Neuro-Ophthalmol 2016; 36: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Temporal optic disc pallor is present in both eyes. FIG. 2. Spectral-domain optical coherence tomography demonstrates marked loss of retinal nerve fiber layer, particularly in the papillomacular bundle of each eye. The macular cube scan reveals loss of ganglion cell-inner plexiform layer thickness. RNFL, retinal nerve fiber layer. Han et al: J Neuro-Ophthalmol 2016; 36: 182-186 183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation of copper, ceruloplasmin, ferritin, complete blood count, liver function, lactate and pyruvate levels, and amino acid and organic acid screenings, with the exception of elevated serum creatine kinase (300 IU/L; normal, 135 IU/L). Genetic analysis of mitochondrial DNA and the dominant optic atrophy (OPA1) gene showed no mutations. MRI scans of the brain and whole spine were unremarkable. Genetic testing for early-onset torsion dystonia (GAC deletion c.901_903 delGAG), dopa-responsive dystonia (GCH1), and myotonic dystrophy (DM kinase CAG repeats) showed no mutations. Eight months later, the patient was reevaluated because of deterioration of cognitive and motor function, and progression of visual impairment. Visual acuity was 20/80 bilaterally, pupillary reactions and eye movements were normal. Bilateral temporal optic disc pallor was present (Fig. 1), OCT confirmed RNFL loss (Fig. 2) and ERG testing was normal. On neurological examination, the patient demonstrated a tendency toward dystonic posturing of the right hand and gait ataxia. Repeat brain MRI showed symmetric T2 hypointensity without focal hyperintensity that involved the globi pallidi and substantia nigra bilaterally (Fig. 3). Direct sequencing of the PANK2 gene revealed a heterozygous mutation of the splice site variant, IVS c.540-13_540-12insTTCCCC, which resulted in elongation of the polypyrimidine tract of the splice acceptor site of intron 4 (Fig. 4). DISCUSSION Our patient developed bilateral temporal optic atrophy related to a PANK2 mutation. We are aware of only 2 reports documenting optic atrophy as a presenting sign of PKAN. Battistella et al (9) described a 16-year-old boy who had 20/80 acuity bilaterally and pale optic discs. MRI T2 sequences revealed areas of decreased signal in the globi pallidi and substantial nigra. Casteals et al (10) evaluated an 8-year-old girl who experienced bilateral vision loss with optic atrophy 3 years before developing behavioral and motor changes. In both case reports, ERG testing was normal and no pigmenting retinopathy was observed. Both patients showed slow clinical progression and MRI changes were consistent with an atypical form of PKAN. Neither patient had genetic testing or mitochondrial DNA sequencing. The later onset and slower progression of the disease noted in our patient were compatible with atypical PKAN, and her c.540-13_540insTTCCCC mutation has been reported previously in patients with the atypical form (11). In atypical PKAN, extrapyramidal symptoms can be more variable and the "eye of the tiger sign" on MRI may be absent. The differential diagnosis includes the "plus form" of Leber hereditary optic neuropathy (12) and dominant optic atrophy. In addition, previous literature suggests that temporal optic disc pallor is characteristic of PLA2G6related neurodegenerative with brain iron accumulation and serve as a distinguishing sign from a PANK2-related disorder (13). Our report contradicts this observation. The PANK2 enzyme is active in mitochondria as it regulates the biosynthesis of coenzyme A. PANK2 protein is ubiquitously expressed in tissues, including the retina and basal ganglia and excessive iron overload by the PANK2 mutation results in oxidative DNA damage, which promotes neurodegeneration in the brain and retina (14). Increased oxidative stress preferentially affects the smallcaliber fibers in the papillomacular bundle of the RNFL, which consumes large amounts of ATP (15). It has been proposed that downregulation of transcription in the photoreceptor recycling pathway may have an important role in retinal degeneration (16). Although the exact pathophysiology of retinal degeneration is not clear, PANK2 is a mitochondrial protein and altered mitochondrial membrane potential has been reported in PANK2-defective neurons FIG. 3. Axial brain magnetic resonance imaging. There are areas of hypointensity in the globi pallidi on FLAIR (A) and substantial nigra bilaterally on T2 scan (B). 184 Han et al: J Neuro-Ophthalmol 2016; 36: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 4. Genetic analysis reveals a splicing site mutation of c.540-13_540-12insTTCCCC in intron 4 of PANK2. from knockout mice (17). Possibly, the pathoetiology of optic atrophy in patients with PANK2 mutations is similar to other mitochondrial optic neuropathies. In conclusion, PKAN, particularly the atypical form, should be considered when evaluating patients presenting with extrapyramidal symptoms, such as chorea or dystonia, cognitive decline, and optic atrophy. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Han and S.-H. Han; b. Acquisition of data: J. Han and C.-H. Lee; c. Analysis and interpretation of data: J. Han and D. W. Kim. Category 2: a. Drafting the article: J. Han and D. W. Kim; b. Revising it for intellectual content: C.-H. Lee, S.-H. Han. Category 3: a. Final approval of the completed article: J. Han, D. W. Kim, C.-H. Lee, and S.-H. Han. REFERENCES 1. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med. 2003;348:33-40. 2. Dooling EC, Schoene WC, Richardson EP. Hallervorden-Spatz syndrome. Arch Neurol. 1974;30:70-83. 3. Renaud DL, Kotagal S. Pantothenate-kinase associated neurodegeneration (PKAN) "eye of the tiger" sign. Pediatr Neurol. 2007;36:70-71. Han et al: J Neuro-Ophthalmol 2016; 36: 182-186 4. Parashari UC, Aga P, Parihar A, Singh R, Joshi V. Case report: MR spectroscopy in pantothenate kinase-2 associated neurodegeneration. Indian J Radiol Imaging. 2010;20:188-191. 5. Gadodia A, Kumar A, Sankhyan N, Sharma S, Vasisht N. Images in neurology. 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Han et al: J Neuro-Ophthalmol 2016; 36: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.