Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029089 (ophthalmoplegia)
 3,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
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PMID:Multi-system neurological disease is common in patients with OPA1 mutations. 2514 16

Pathogenic mutations in the OPA1 gene can be associated with Autosomal Dominant Optic Atrophy (ADOA). In approximately 20 % of patients with OPA1 mutations, a more complex neurodegenerative disorder with extraocular manifestations, known as ADOA Plus, can arise. 12 members of a multigenerational family were assessed clinically and screened for a genetic mutation in OPA1. Eight family members displayed manifestations consistent with ADOA Plus and four did not. Affected members of the oldest available generation displayed the most severe phenotype, which included severe optic atrophy, deafness, ptosis, ophthalmoplegia, proximal myopathy, neuropathy and ataxia. The next generation was less severely affected but several members displayed manifestations only after the fifth decade. Genetic analysis revealed a heterozygous variant in the OPA1 gene (c.1053T>A, p.Asp351Glu) that segregated with disease. The affected family members described here exhibited visual loss later than is typical for OPA1-related disease, as well as later onset of other neurological abnormalities in the fifth or sixth decades of life that progressed to severe neurological disability by the seventh decade. These findings expand the clinical spectrum of OPA1-related disease associated with a novel OPA1 mutation.
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PMID:A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family. 2619 96