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.

In vivo mitochondrial matrix proteome profiling reveals RTN4IP1/OPA10 as an antioxidant NADPH oxidoreductase

“…Our results may also provide insights into the treatment of patients with genetic defects of RTN4IP1. These patients suffer from optic neuropathy and ataxia 37,38,[61][62][63] , and our results suggest that delivery of antioxidant molecules or CoQ supplements may help to relieve these symptoms.…”

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

“…To date, several mutations have been identified in different patients, including 15 single-nucleotide change mutations and two deletion mutations) in three separate studies [3,4,[10][11][12][13][14]34,35], as summarized in Table S1 and shown in Figure 5C. Thereof, 15 variants cause various single amino acid changes, two variants lead to truncations, and one variant presumably causes aberrant splicing.…”

“…Optic atrophy, seizures, nystagmus, and global developmental delay are the most common symptoms associated with pathogenic variants in the RTN4IP1. In addition, deafness, brain MRI abnormalities, stridor, and abnormal electroencephalograms were seen in severely affected patients with premature death due to the deleterious effect of the variants on RTN4IP1 activity and structure [9,13].…”

“…Additionally, in some cases, pathogenic RTN4IP1 variants cause color vision impairment, optic disc pallor, central scotoma, decreased visual field sensitivity, reduced thickness of the retinal nerve fiber layer, and reduced or absent visual evoked potentials [3,10]. Moreover, RTN4IP1 mutations may also result in extraocular manifestations appearing as mitochondrial encephalopathies, such as mild ataxia, intellectual disability, and rare generalized seizures [4,10,[12][13][14]. Visual dysfunction and abnormalities start in early childhood [3,10,11,14].…”

Whole Genome Sequencing Identifies a Partial Deletion of RTN4IP1 in a Patient With Isolated Optic Atrophy

“…By contrast, only 1 of 15 (6.7%) individuals with isolated OA had a LOF variant. Although the p.(Arg103His) variant is believed to cause a milder isolated ocular phenotype, neurological impairment with generalized chorea, intellectual disability, and midbrain MRI abnormalities have been observed in 1 homozygote (5). To date, only 1 case has been reported with a large deletion spanning the entire gene in RTN4IP1 -associated disease.…”