Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by ROBO3 gene mutations. To date, the number of confirmed HGPPS cases caused by gene mutations is estimated at 76. However, HGPPS caused by ROBO3 gene mutation has not been reported in the Chinese population. In this study, the clinical data, brain imaging features, somatosensory evoked potentials (SEP), and ROBO3 gene mutations were obtained for two Chinese patients with HGPPS. The proband was an 11-year-old boy. He developed horizontal eye movement disorder at the age of 1 year and scoliosis at the age of 11 years. Two eyeballs fixed in the midline position were revealed by neurological examination. A dorsal cleft in the pons and a butterfly-shaped medulla were shown by brain magnetic resonance imaging. Again, most corticospinal bundles did not cross in the brainstem, as revealed by diffusion tensor imaging. SEP confirmed that most somatosensory projections were uncrossed. The proband's 7-year-old brother exhibited similar clinical manifestations and imaging features. The brothers had compound heterozygous mutations c.3165G>A (p.W1055X) and c.955G>A (p.E319K) of the ROBO3 gene. The c.3165G>A mutation is a novel nonsense mutation that has not been previously reported. This study reports the first two cases of HGPPS carrying a novel ROBO3 gene mutation in patients from a Chinese family, thereby expanding the disease spectrum. Reports from the literature show that missense mutation is the most common mutational type in the ROBO3 gene. Early ROBO3 gene detection is required for patients exhibiting early-onset eyeball movement disorder to confirm HGPPS disease.

Electrophysiological study of neuromuscular junction in congenital myasthenic syndromes, congenital myopathies, and chronic progressive external ophthalmoplegia.

This study was designed to analyze the sensitivity, specificity, and accuracy of jitter parameters combined with repetitive nerve stimulation (RNS) in congenital myasthenic syndrome (CMS), chronic progressive external ophthalmoplegia (CPEO), and congenital myopathies (CM). Jitter was obtained with a concentric needle electrode during voluntary activation of the Orbicularis Oculi muscle in CMS (n = 21), CPEO (n = 20), and CM (n = 18) patients and in controls (n = 14). RNS (3 Hz) was performed in six different muscles for all patients (Abductor Digiti Minimi, Tibialis Anterior, upper Trapezius, Deltoideus, Orbicularis Oculi, and Nasalis). RNS was abnormal in 90.5% of CMS patients and in only one CM patient. Jitter was abnormal in 95.2% of CMS, 20% of CPEO, and 11.1% of CM patients. No patient with CPEO or CM presented a mean jitter higher than 53.6 µs or more than 30% abnormal individual jitter (> 45 µs). No patient with CPEO or CM and mild abnormal jitter values presented an abnormal decrement. Jitter and RNS assessment are valuable tools for diagnosing neuromuscular transmission abnormalities in CMS patients. A mean jitter value above 53.6 µs or the presence of more than 30% abnormal individual jitter (> 45 µs) strongly suggests CMS compared with CPEO and CM.

Progressive external ophthalmoplegia due to a recurrent de novo m.15990C>T MT-TP (mt-tRNAPro) gene variant.

Progressive external ophthalmoplegia is typically associated with single or multiple mtDNA deletions but occasionally mtDNA single nucleotide variants within mitochondrial transfer RNAs (mt-tRNAs) are identified. We report a 34-year-old female sporadic patient with progressive external ophthalmoplegia accompanied by exercise intolerance but neither fixed weakness nor multisystemic involvement. Histopathologically, abundant COX-deficient fibres were present in muscle with immunofluorescence analysis confirming the loss of mitochondrial complex I and IV proteins. Molecular genetic analysis identified a rare heteroplasmic m.15990C>T mt-tRNAPro variant reported previously in a single patient with childhood-onset myopathy. The variant in our patient was restricted to muscle. Single muscle fibre analysis identified higher heteroplasmy load in COX-deficient fibres than COX-normal fibres, confirming segregation of high heteroplasmic load with a biochemical defect. Our case highlights the phenotypic variability typically observed with pathogenic mt-tRNA mutations, whilst the identification of a second case with the m.15990C>T mutation not only confirms pathogenicity but shows that de novo mt-tRNA point mutations can arise in multiple, unrelated patients.

Intrafamilial "DOA-plus" phenotype variability related to different OMI/HTRA2 expression.

Dominant Optic Atrophy and Deafness (DOAD) may be associated with one or more of the following disorders such as myopathy, progressive external ophthalmoplegia, peripheral neuropathy, and cerebellar atrophy ("DOA-plus"). Intra- and interfamilial variability of the "DOA-plus" phenotype is frequently observed in the majority of the patients carrying the same mutation in the OPA1 gene. We are describing two familial cases of "DOA-plus" carrying the same c.1334G>A (p.Arg445His) mutation in OPA1 and disclosing different clinical, pathological and biochemical features. The two patients showed different expression levels of the mitochondrial OMI/HTRA2 molecule, which acts as a mitochondrial stress sensor and has been described to interplay with OPA1 in in vitro studies. Our data offer the cue to inquire the role of OMI/HTRA2 as a modifier gene in determining the "DOAplus" phenotype variability.

Exophthalmos in Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA (mtDNA) deletion syndrome that typically presents before 20 years of age and is characterized by chronic progressive external ophthalmoplegia, pigmentary retinopathy, and a combination of cardiac conduction defects, cerebellar ataxia, and elevated cerebrospinal fluid protein levels. The mtDNA defects interfere with oxidative phosphorylation and can affect a number of cellular energy processes in various organs. We report the case of a 15-year-old girl with KSS that was uniquely associated with bilateral, symmetrical exophthalmos.

Strabismus surgery for diplopia in chronic progressive external ophthalmoplegia.

BACKGROUND: To report midterm outcomes of strabismus strategy for management of diplopia in chronic progressive external ophthalmoplegia and specific surgical planning rationale. DESIGN: Retrospective interventional case series. RESULTS: Two patients, a 26-year-old male and a 36-year-old female, diagnosed with chronic progressive external ophthalmoplegia presented with blepharoptosis and intermittent diplopia. Ocular motility examination was significant for bilateral profound impairment of adduction with relative preservation of abduction, infraduction and elevation. Control of intermittent exotropia gradually worsened over 3 and 1.5 years of follow-up, respectively, in the presence of documented stability of the angle of exodeviation. Strabismus surgery involving modest amounts of bilateral medial rectus resection and lateral rectus recessions was undertaken. Surgical intervention was successful in controlling alignment in primary position and alleviating diplopia and asthenopia after 9 and 8 years of follow-up time, respectively, despite slow progression of ophthalmoplegia. CONCLUSION: Bilateral selective impairment of adduction and intermittent exotropia may be the presenting ocular motility disturbance in chronic progressive external ophthalmoplegia. Properly designed strabismus surgery may provide sustainable, in the midterm, control of alignment and symptomatic relief in selected patients with CPEO.

Surgical Technique for Pulled in Two Syndrome: Three Cases With Chronic Progressive External Ophthalmoplegia.

The authors describe three examples of "pulled in two syndrome" (PITS) from a series of 13 patients undergoing strabismus surgery with underlying chronic progressive external ophthalmoplegia (CPEO) and illustrate techniques for recovery of the "pulled in two" extraocular muscle should the complication arise. In all cases, a rectus muscle snapped under minimal tension while held on a strabismus hook during strabismus surgery. Two patients suffered from CPEO as a result of genetic mitochondrial disease, whereas one resulted from presumed mitochondrial toxicity induced by HAART. In cases 1 and 3, the proximal medial rectus segment was retrieved and reattached. In case 2, the fragmented superior rectus muscle was too friable to be reattached. All three patients were satisfied with the outcome, having reduced their angles of misalignment postoperatively. All three had improved cosmesis, and the two who had complained of diplopia preoperatively found their diplopia to be eliminated or improved. With anticipation of muscle friability in patients with previous extraocular surgery or degenerative muscle changes such as CPEO, the likelihood of the complication arising may be reduced. Should it occur, the loss of a snapped rectus muscle may be avoided through careful manipulation of the globe. [J Pediatr Ophthalmol Strabismus. 2017;54:e83-e87.].

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia.

OBJECTIVE: To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. METHODS: CPEO patients (n=13) with large size deletion of mitochondrial DNA and matching healthy controls (n=22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. RESULTS: Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath. CONCLUSION: CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. SIGNIFICANCE: This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.

Horizontal gaze palsy and progressive scoliosis in a patient with congenital esotropia and inability to abduct. A case report. / Parálisis de la mirada horizontal y escoliosis progresiva en un paciente con endotropia congénita y limitación de abducción. A propósito de un caso.

CASE REPORT: The case is presented on a 4- year-old child with congenital esotropia, limitation of abduction, cross-fixation, and thoracolumbar scoliosis. Genetic testing of ROBO3 gene confirmed the diagnosis of horizontal gaze palsy and scoliosis (HGPSS) DISCUSSION: HGPPS is a rare congenital disorder characterised by absence of conjugate horizontal eye movements and progressive scoliosis developed in childhood and adolescence. We highlight this motility disorder as a part of the differential diagnosis of early childhood esotropia with cross- fixation and limitation of abduction.

Chronic Progressive External Ophthalmoplegia in the Absence of Ptosis.

Classically defined as bilateral, symmetric, and progressive ophthalmoparesis with myopathic ptosis, chronic progressive external ophthalmoplegia (CPEO) rarely has been reported in the absence of ptosis. We describe 2 patients with CPEO and without ptosis who presented with binocular diplopia related to small-angle esodeviations, poor fusional amplitudes, and slow saccades. In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy.

Factors affecting eyelid crease formation before and after silicone frontalis suspension for adult-onset myogenic ptosis.

PURPOSE: To evaluate factors that affect eyelid crease formation before and after frontalis suspension. DESIGN: Nonrandomized, comparative, interventional case series. METHODS: Sixty-three patients (125 eyes) with myogenic ptosis were included. Data collected included age, gender, previous surgeries, follow up, as well as pre- and postoperative margin reflex distance, palpebral fissure height, and levator function. Intraoperative maneuvers of incorporation of the levator aponeurosis into the skin closure, conservative fat excision, and conservative skin excision were recorded. Pre- and postoperative eyelid creases were graded by 2 masked, independent observers as "good," "fair," or "poor." RESULTS: The weighted κ coefficient between the graders was 0.68 (95% CI, 0.58-0.79) preoperatively and 0.70 (95% CI, 0.61-0.79) postoperatively. Evaluating preoperative eyelid crease grades, there was no significant difference with regard to age or gender (p = 0.83 or 0.69, respectively). Eyelid crease grade correlated with margin reflex distance (p = 0.0004) and palpebral fissure height (p = 0.002). There was no significant correlation of eyelid crease with levator function (p = 0.104). After frontalis sling, intraoperative maneuvers of incorporation of the levator aponeurosis into the incision, skin preservation, and fat preservation correlated with postoperative eyelid crease (p = 0.0004, 0.059, and 0.033, respectively). CONCLUSIONS: Preoperative levator function in patients with adult onset myogenic ptosis may be an inaccurate measure of true levator palpebrae strength. Reliance on levator function alone in decision making for surgical intervention in these patients may be misguided. The inclusion of the intraoperative maneuvers of incorporation of the levator aponeurosis into the skin incision and preservation of fat and skin results in a stronger eyelid crease after frontalis sling surgery.

[Retinal ganglion cell layer and visual function in patients with progressive external ophthalmoplegia caused by common mtDNA deletion]. / Retinalis idegrostréteg és látásfunkciók az mtDNS common deléciója által okozott progresszív ophthalmoplegia externa esetében.

AIM: Mitochondrial (mt) disorders are metabolic conditions with multiorgan involvement, which often cause neuroophtalmological symptoms. The aim of the study was to investigate the relation between progressive external ophthalmoplegia (PEO), visual pathway and mitochondrial DNA (mtDNA) mutations in patients younger than 55 years of age. METHODS: Five female patients (35 to 53 years of age) with mithochondrial disease were investigated. Automated threshold perimetry (Octopus G2 test), scanning laser polarimetry (GDx-VCC and GDx-ECC) and Fourier-domain optical coherence tomography (RTVue-100 OCT) were used in addition to detailed ophthalmological examination and evaluation of visually evoked potentials (VEP). Frequent mutations of the mtDNA were investigated in the patients' blood and muscle samples. RESULTS: PEO of various severity levels was found in all patients, using clinical tests. Genetic testing showed "common deletion" of mtDNA in all cases. For both eyes of 4 patients functional and structural ophthalmic tests had normal results. In one patient decreased visual acuity, reduced retinal nerve fiber layer thickness and prolonged L3 VEP latency time were found without optic disc damage and visual field deterioration. CONCLUSION: In 4 of our 5 patients with PEO due to common deletion of mtDNA retinal ganglion cells and visual function remained normal for a long period of life.

Progressive external ophthalmoplegia in southwestern Finland: a clinical and genetic study.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecular etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. METHODS: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. RESULTS: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. CONCLUSIONS: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.