Journal of Pediatric Ophthalmology and Strabismus

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Short Subjects 

Leigh’s Disease Associated With a Dorsal Midbrain Syndrome

Stephanie K. West, BM, MRCOphth; Lesley Connors, BSc(Hons), DBO(D); Timothy C. S. Cox, FRCR; Timothy P. Coker, MRCP, FRCS, FRCOphth

Abstract

Leigh’s disease is a rare progressive neurodegenerative condition caused by a mitochondrial cytopathy. The authors present the case of a 9-year-old girl with dorsal midbrain syndrome causing convergence retraction nystagmus. Magnetic resonance imaging, skin biopsy, and genetic testing confirmed the cause to be Leigh’s disease due to two SURF1 mutations. To the authors’ knowledge, this is the first reported case of dorsal midbrain syndrome caused by a mitochondrial cytopathy.

Abstract

Leigh’s disease is a rare progressive neurodegenerative condition caused by a mitochondrial cytopathy. The authors present the case of a 9-year-old girl with dorsal midbrain syndrome causing convergence retraction nystagmus. Magnetic resonance imaging, skin biopsy, and genetic testing confirmed the cause to be Leigh’s disease due to two SURF1 mutations. To the authors’ knowledge, this is the first reported case of dorsal midbrain syndrome caused by a mitochondrial cytopathy.

From Queen Elizabeth II Hospital, Hertfordshire, United Kingdom.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Stephanie K. West, BM, MRCOphth, Ophthalmology Department, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AG, UK.

Received: November 24, 2006
Accepted: January 25, 2008
Posted Online: September 22, 2009

Introduction

Convergence–retraction nystagmus is caused by pathology in the dorsal midbrain and is part of Parinaud’s syndrome. To the authors’ knowledge, this report describes the first case caused by mitochondrial cytopathy.

Case Report

A 9-year-old girl was evaluated by an orthoptist in the clinic after experiencing oscillopsia. The patient had been assessed in infancy for poor feeding. She had been a “floppy” baby and was late to reach milestones. She had poor balance and coordination, but otherwise had been well, with previously normal eye movements.

On examination, visual acuity was 6/12 in each eye, improving to 6/9 with pinhole. Extraocular movements showed greatly reduced pursuit and saccades in elevation and convergence–retraction nystagmus on attempted up gaze. Pupils were normal with no light–near dissociation, eyelids were in the normal position with no Collier sign, and fundi were healthy. These findings suggested a dorsal midbrain abnormality. Magnetic resonance imaging scan showed bilateral, symmetrical hyperintensity in the superior colliculi and cortical cerebellar abnormalities (Figure).

Magnetic Resonance Imaging Showing Bilateral, Symmetrical Hyperintensity in the Superior Colliculi and Cortical Cerebellar Abnormalities.

Figure. Magnetic Resonance Imaging Showing Bilateral, Symmetrical Hyperintensity in the Superior Colliculi and Cortical Cerebellar Abnormalities.

Two weeks later, the patient was admitted with headache, abdominal pain, difficulty walking, and increasingly aggressive behavior. Further evaluation of the magnetic resonance imaging scan suggested that the appearance was consistent with mitochondrial cytopathy. Findings on lumbar puncture were normal, and no lactic acidosis was detected. Skin biopsy showed that cytochrome C oxidase activity was 11 nmol/mg protein/min (normal: 30 to 90 nmol/mg protein/min). Genetic testing subsequently showed two SURF1 complementary DNA mutations: the common ins AT/del TCTGCCAGCC mutation at the end of exon 4 and a novel mutation, a G > A substitution at position +5 in splice donor site of intron 7, producing a mutant protein. These findings were consistent with a diagnosis of Leigh’s disease.

Discussion

Dorsal midbrain syndrome is characterized by up gaze paresis (often worse for saccades than for pursuit), convergence–retraction nystagmus, pupillary light–near dissociation, and eyelid retraction. In children, the most common cause is hydrocephalus, which may be congenital or acquired (eg, third ventricle tumors). Other causes include pineal tumors, arteriovenous malformations, and encephalitis.1

Leigh first described “subacute necrotizing encephalomyelopathy” in 1951.2 This condition is now considered part of a heterogeneous group of progressive neurodegenerative conditions presenting with variable clinical features.3 The diagnosis is based on common characteristic magnetic resonance imaging findings, biochemistry, genetic analysis, and neuropathologic changes.

Symptoms typically start in the first few months of life and progress to death within 2 years, but later onset or slower progression often occurs. Clinical presentation is variable; patients often exhibit psychomotor retardation, vomiting, failure to thrive, and signs of brain stem and basal ganglia dysfunction.4 Ophthalmologic signs and symptoms are common and include nystagmus, ophthalmoplegia, strabismus, and optic nerve atrophy.5 The authors are unaware of any previous reports of presentation with convergence retraction nystagmus.

Clinically, magnetic resonance imaging findings are characteristic, showing lesions as hypointense on T1 and hyperintense on T2.6–8 In the current case, this finding was limited to the superior colliculi (Figure), which could explain the absence of light–near dissociation or eyelid retraction normally associated with dorsal midbrain lesions.

The disease is caused by defects in different enzymes involved in energy metabolism, the result of mutations in either nuclear or mitochondrial DNA. There is a defect of cytochrome C oxidase and cytochrome C oxidase assembly genes, including SURF1.9 The defined biochemical defects account for approximately 50% of all patients,10 and cytochrome C oxidase deficiency is one of the most common.11

Neuropathologically, necrotic lesions, associated with demyelination, gliosis, and capillary proliferation, occur bilaterally and symmetrically, typically in the basal ganglia and brain stem.

This case highlights another cause of convergence–retraction nystagmus and a new presentation of Leigh’s disease.

References

  1. Brodsky MC, Baker RS, Hammed LM. Pediatric Neuro-Ophthalmology. New York: Springer; 1996:262.
  2. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurgery Psychiatry. 1951;14:216–221. doi:10.1136/jnnp.14.3.216 [CrossRef]
  3. DiMauro S, DeVivo DC. Genetic heterogeneity in Leigh syndrome. Ann Neurol. 1996;40:5–7. doi:10.1002/ana.410400104 [CrossRef]
  4. Pincus JH. Subacute necrotizing encephalomyelopathy (Leigh’s disease): a consideration of clinical features and etiology. Dev Med Child Neurol. 1972;14:87–101.
  5. Hayashi N, Geraghty MT, Green WR. Ocular histopathologic study of a patient with the T 8993-G point mutation in Leigh’s syndrome. Ophthalmology. 2000;107:1397–1402. doi:10.1016/S0161-6420(00)00110-X [CrossRef]
  6. Arii J, Tanabe Y. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol. 2000;21:1502–1509.
  7. Greenberg SB, Faerber EN, Riviello JJ, de Leon G, Capitanio MA. Subacute necrotizing encephalomyelopathy (Leigh disease): CT and MRI appearances. Pediatr Radiol. 1990;21:5–8. doi:10.1007/BF02010803 [CrossRef]
  8. Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect. AJNR Am J Neuroradiol. 1990;11:379–384.
  9. Tiranti V, Munaro M, Sandonà D, et al. Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh’s syndrome: genetic evidence based on patient’s-derived rho degrees transformants. Hum Mol Genet. 1995;4:2017–2023. doi:10.1093/hmg/4.11.2017 [CrossRef]
  10. Rahman S, Brown RM, Chong WK, Wilson CJ, Brown GK. A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol. 2001;49:797–800. doi:10.1002/ana.1060 [CrossRef]
  11. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343–351. doi:10.1002/ana.410390311 [CrossRef]
Authors

From Queen Elizabeth II Hospital, Hertfordshire, United Kingdom.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Stephanie K. West, BM, MRCOphth, Ophthalmology Department, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AG, UK.

Received: November 24, 2006
Accepted: January 25, 2008
Posted Online: September 22, 2009

10.3928/01913913-20090903-09

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