Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant

Abstract

RTN4IP1 pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the RTN4IP1 gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.

Keywords

OPA10 syndrome - RTN4IP1 pathogenic variants - complex movement disorder - chorea - optic neuropathy

Publication History

Received: 25 June 2019

Accepted: 23 January 2020

Article published online:
11 May 2020

• References

• 1 Bagli E, Zikou AK, Agnantis N, Kitsos G. Mitochondrial membrane dynamics and inherited optic neuropathies. In Vivo 31 2017; [phone]
• 2 Yu-Wai-Man P, Chinnery PF. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. Ophthalmology 120 2013; [phone].e1
• 3 Lenaers G, Hamel C, Delettre C. et al. Dominant optic atrophy. Orphanet J Rare Dis 7 2012; (01) 46
• 4 Yu-Wai-Man P, Newman NJ. Inherited eye-related disorders due to mitochondrial dysfunction. Hum Mol Genet 26 (R1): 2017; R12-R20
• 5 Gerber S, Charif M, Chevrollier A. et al. Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. Brain 140 2017; (10) 2586-2596
• 6 Carelli V, Schimpf S, Fuhrmann N. et al. A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16. Hum Mol Genet 20 2011; (10) 1893-1905
• 7 Angebault C, Guichet PO, Talmat-Amar Y. et al. Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies. Am J Hum Genet 97 2015; [phone]
• 8 Charif M, Nasca A, Thompson K. et al. Neurologic phenotypes associated with mutations in RTN4IP1 (OPA10) in children and young adults. JAMA Neurol 75 2018; [phone]
• 9 Rubegni A, Ferrari AR, Pasquariello R, Canapicchi R, Santorelli FM, Nesti C. Relapsing-remitting course of cystic leukoencephalopathy. Pediatr Neurol 89 2018; 63-65
• 10 Okamoto N, Miya F, Hatsukawa Y. et al. Siblings with optic neuropathy and RTN4IP1 mutation. J Hum Genet 62 2017; (10) 927-929
• 11 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17 2015; [phone]
• 12 Zou XH, Guo XX, Su HZ. et al. Whole exome sequencing identifies two novel mutations in the reticulon 4-interacting protein 1 gene in a Chinese family with autosomal recessive optic neuropathies. J Mol Neurosci 68 2019; [phone]
• 13 Lahiri D, Sawale VM, Banerjee S, Dubey S, Roy BK, Das SK. Chorea-ballism as a dominant clinical manifestation in heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation in mitochondrial genome: a case report. J Med Case Reports 13 2019; (01) 63
• 14 Caparros-Lefebvre D, Destée A, Petit H. Late onset familial dystonia: could mitochondrial deficits induce a diffuse lesioning process of the whole basal ganglia system?. J Neurol Neurosurg Psychiatry 63 1997; [phone]