Ophthalmoplegia in Mitochondrial Disease

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p < 0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.

Oftalmoplegía externa congénita parcial y bilateral en un adolescente / Partial and bilateral congenital external ophthalmoplegia in an adolescent

Se presenta el caso clínico de un paciente de 18 años de edad, quien fue atendido en la consulta de estrabología del Hospital Oftalmológico Amistad Argelia-Cuba de la República de Argelia por presentar fotofobia, ptosis palpebral, mala visión y estrabismo divergente. Se le hizo un examen oftalmológico completo, prueba de prisma, luces de worth y se constató que tenía una oftalmoplejía congénita externa parcial y bilateral con ambliopía, sin manifestaciones neurológicas. Se le indicó tratamiento con vitaminas y no se realizó propuesta quirúrgica debido a la cantidad de músculos afectados y el gran riesgo de una diplopía residual

The case report of an 18 years patient is presented who was assisted in the estrabism service of Amistad Argelia-Cuba Ophthalmologic Hospital in the Republic of Algeria due to photophobia, ptosis palpebral, poor vision and divergent strabismus. A complete ophthalmologic exam was carried out, prism test, worth lights and it was verified that he had a partial and bilateral external congenital ophthalmoplegia with amblyopia, without neurological manifestations. Treatment with vitamins was indicated and there was no surgical proposal due to the quantity of affected muscles and the great risk of a residual diplopia

Kearns-sayre Syndrome Treated with Permanent Pacemaker Insertion for Complete Atrioventricular Block / 고신대학교의과대학학술지

Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder associated with progressive external ophthalmoplegia, atypical pigmentary degeneration of the retina, and complete heart block. KSS can lead to a risk of sudden death because of the potential progression of conduction abnormalities such as right or left bundle branch block or complete atrioventricular (AV) block. Here we describe the case of a KSS patient with type I diabetes who experienced syncope in the presence of complete AV block, confirmed by muscular biopsy.

Reporte de familia: distrofia muscular oculofaríngea / Family report: Muscular Dystrophy Oculopharyngeal

Antecedentes: La Distrofia Muscular Oculofaríngea es un trastorno hereditario de rara ocurrencia. Este síndrome se caracteriza fundamentalmente por ptosis palpebral progresiva, disfagia y debilidad proximal de las extremidades. Casos Clínicos: Se presenta una familia en la cual se encontraron dos casos afectados, en la confección del árbol genealógico se encontró consanguineidad entre los padres apoyando la existencia de un posible patrón hereditario para esta alteración. Conclusión: El conocimiento de esta entidad es fundamental para sospecharla, por lo infrecuente de esta condición y las pocas publicaciones en la literatura latinoamericana de estos casos se presenta la siguiente revisión...(AU)

[Effect of group exercising and adjusting the brace at shorter intervals on cobb angle and quality of life of patients with idiopathic scoliosis]

Objective: Bracing along with exercising is the most effective protocol in patients with idiopathic scoliosis which have Cobb angles of 25 to 45 degrees. However, since the psychological aspects of scoliosis treatment may affect the quality of life, and the exact time for adjusting the pads of Milwaukee brace is unknown; Therefore the aim of this study was evaluating the effect of exercising in a group, with adjusting the brace in shorter intervals, in compare to routine protocol, in the treatment of idiopathic scoliosis

Materials and Methods: Thirty-four patients with idiopathic scoliosis which had Cobb angles of 50 to 15 degrees were included in this study and were divided into experimental and control groups. The patients of two groups participated in an eleven-week treatment program, differ between the two groups. Quality of life scores of both groups were evaluated before and after intervention using SRS-22 questionnaire, as well as scoliosis angles before and after the intervention according to the primary and secondary radiographic X-rays

Results: Statistical analysis was performed using Paired T-Test in each group, and Independent T-Test between the two groups before and after treatment. The severity of scoliosis curvature and satisfaction domain of the experimental group was reduced significantly in compared with the control group, after intervention [P=0.04]. Moreover in the case of the quality of life in patients with Cobb angles less than 30 degrees, compared with patients with Cobb angles greater than 31 degrees, in the domains of selfimage, satisfaction, and total score, the difference was significant [P<0.05]

Conclusion: Adjusting the brace at shorter intervals along with exercising as a group, during the eleven weeks of treatment, has increased satisfaction and reduced the scoliosis Cobb angles of patients

Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

Treatment of Eyelid Ptosis due to Kearns-Sayre Syndrome Using Frontalis Suspension

Blepharoptosis is a common indication for surgery in plastic surgery units, yet its possible underlying pathology frequently remains unidentified. A 52-year-old man with a 20-year history of progressive bilateral ptosis (right>left) presented with recurrent ptosis of both eyes; he had undergone an operation on the levator aponeurosis 12 years prior. Due to the suspicion of an underlying disease, he was evaluated further. Chronic progressive external ophthalmoplegia in transition to the more severe syndromic variant Kearns-Sayre syndrome, a mitochondrial disorder causing myopathy, was diagnosed. The patient was treated with coenzyme Q10, and he underwent ptosis surgery on both eyes. This case illustrates a potentially multi-systemic disease that was diagnosed by a further evaluation of a common symptom, in this case worsening blepharoptosis. Awareness of myopathic symptoms is necessary to prevent overlooking serious yet improvable conditions.

Síndrome de Kearns-Sayre, presentación de un caso clínico / Kearns-Sayre Syndrome

El síndrome de Kearns Sayre es una mitocondriopatía caracterizada por disfunciones multiorgánicas que clásicamente se desarrolla antes de los veinte años de edad. Esta rara enfermedad fue descrita en 1958 por Thomas P. Kearns y George P. Sayre a través del reporte de un caso que representaba la triada clínica de oftalmoplejia externa, retinopatía pigmentaria y bloqueos de la conducción cardíaca; siendo esta última alteración la que determina el pronóstico. Aún no se cuenta con un tratamiento curativo para esta enfermedad. En este artículo presentamos el caso clínico de una paciente de 39 años a la que se realizó el diagnóstico de Kearns-Sayre.

Espectro clínico de pacientes con hallazgos histopatológicos y/o moleculares compatibles con enfermedad mitochondrial / Clinical spectrum of patients with histopathological and/or molecular findings compatible with mitochondrial disease

Objetivo: Describir el espectro clínico de pacientes con diagnóstico definitivo de Enfermedad Mitocondrial, y su correlación con hallazgos bioquímicos, neuroimagenológicos, neuropatológicos, y moleculares. Método: Se revisaron las historias clínicas de pacientes con Enfermedad Mitocondrial evaluados durante el período 1990-2011. Resultados: Se incluyeron 41 pacientes, con una edad media inicial de 3,7 años. Identificamos cuatro grupos:1) Síndromes clásicos (65%): a) MELAS del inglés “Mitochondrial encephalomyopathy, lacticacidosis, and stroke-like episodes”, (diez), b) Síndrome de Leigh (diez) c) Síndrome de Kearns –Sayre (cinco), d) PEO del inglés “Progressive External Ophthalmoplegia” plus (OEP plus) (dos), 2) Miopatía: nueve (21,5%) 3) Encefalomiopatías inespecíficas: cinco (12%). Se realizó biopsia muscular en 37 pacientes. Un 70% evidenció fibras rojo rasgadas, cuatro (10,5%) fibras citocromo oxidasa negativas y ocho (14,7%) incremento de la actividad oxidativa subsarcolemal y en la microscopia electrónica alteraciones del tamaño y número de mitocondrias. En 14 se completaron estudios moleculares: Siete presentaron una mutación puntual A3243G en el ADN mitocondrial (MELAS), un paciente una mutación en el ADN mitocondrial A1351G (Síndrome de Leigh) y un paciente una deleción del ADN mitocondrial (OEP plus). Conclusiones: Se pudo corroborar la existencia en nuestro medio de síndromes asociados a patología mitocondrial tradicionalmente reconocidos. Un grupo de pacientes con encefalomiopatías denominadas inespecíficas presentaron un cuadro clínico variable, hallazgos de laboratorio y de imágenes poco orientadores y fue la sospecha de una enfermedad mitocondrial lo que nos llevó a realizar la biopsia que finalmente fue diagnóstica. Es posible que este grupo sea más numeroso y las limitaciones que implica realizar una biopsia muscular se facilite con los estudios moleculares.

Genetics of Mitochondrial Myopathies

Mitochondrion is an intracellular organelle with its own genome. Its function in cellular metabolism is indispensable that mitochondrial dysfunction gives rise to multisystemic failure. The manifestation is most prominent with tissues of high energy demand such as muscle and nerve. Mitochondrial myopathies occur not only by mutations in mitochondrial genome, but also by defects in nuclear genes or secondarily by toxic insult on mitochondrial replication. Currently curative treatment modality does not exist and symptomatic treatment remains mainstay. Administration of L-arginine holds great promise according to the recent reports. Advances in mitochondrial RNA import might enable a new therapeutic strategy.

Autosomal Dominant Type of Chronic Progressive External Ophthalmoplegia With Elevated Acetylcholine Receptor Binding Antibody

External ophthalmoplegia and ptosis are common manifestations of mitochondrial cytopathy, such as chronic progressive external ophthalmoplegia (CPEO). However, these symptoms and signs may also be presenting features of myasthenia gravis (MG). There are a few reports of CPEO with elevated acetylcholine receptor antibody (AchR-Ab). We report a case of AD-type CPEO with elevated acetylcholine receptor binding antibody. We confirmed a mutation on the SLC25A4 gene by molecular analysis.

Migraña oftalmopléjica: variantes y secuelas: comunicación de cuatro observaciones / Ophthalmoplegic migraine: variants and consequences: communication of four observations

La migraña oftalmopléjica es una condición de la infancia caracterízada por crisis de severa cefalea hemicraneal seguida de parálisis ipsolateral de los nervios tercero, cuarto o sexto. Modernamente se explica mediante la teoría trigémino-vascular de la migraña. Aunque suele ser autolimitada puede dejar secuelas. Los autores comunican los casos de cuatro pacientes: tres niños con parálisis del tercer nervio craneal: una de ellas, desarrolló en el tiempo una regeneración aberrante secundaria, situación excepcional descrita en la literatura internacional en menos de diez pacientes. El último, un adulto con dos episodios de parálisis del sexto nervio craneal y una del tercer nervio. Se discuten sus manifestaciones clínicas y neurorradiológicas.

Ophthalmoplegic migraine in childhood is a painful migraine or headache complicated by an isolated III, IV or VI oculo-motor nerve palsy followed by total resolution without sequelae. The pathogenesis is unclear, however, more recently an hypothesis of trigeminovascular system activation have been proposed. The authors reported four patients with ophthalmoplegic migraine: three children with third cranial nerve palsy; one of them developed secondary aberrant regeneration of the third nerve. It is an exceptional case, because in the international literature less than ten patients had been reported. One case was an adult patient with recurrent nerve palsy (two episodes of sixth cranial nerve palsy and one event of third nerve palsy). Clinical and neuroradiological manifestations are discussed.

SLC25A4 and C10ORF2 Mutations in Autosomal Dominant Progressive External Ophthalmoplegia

BACKGROUND AND PURPOSE: Progressive external ophthalmoplegia (PEO) with Mendelian inheritance is a heterogeneous group of diseases associated with multiple deletions of mitochondrial DNA (mtDNA), which results from the disturbed replication and maintenance of mtDNA secondary to the mutations of nuclear genes including POLG, SLC25A4, C10ORF2, POLG2, OPA1, and RRM2B. The aim of this study was to identify the genetic defects underlying the pathology and clinical features in two Korean kindreds with autosomal dominant PEO. METHODS: Two pathologically proven PEO patients with a clear autosomal dominant pattern of inheritance were selected. To exclude a large-scale rearrangement, a long-range polymerase chain reaction (PCR) was performed using DNA extracted from biopsied muscle tissue taken from each patient. All coding regions and exon-intron boundaries of POLG, SLC25A4, C10ORF2, and POLG2 were amplified by PCR and directly sequenced. RESULTS: One patient showed multiple deletions of mtDNA on long-range PCR analysis, and two known heterozygous missense mutations in SLC25A4 (p.Asp104Gly) and C10ORF2 (p.Glu479Lys) were identified in each patient. The p.Asp104Gly mutation in SLC25A4 was identified in the patient with an early onset, slowly progressive, pure PEO phenotype, while the p.Glu479Lys mutation in C10ORF2 was identified in the other patient, with a late-onset disease and PEO plus phenotype. CONCLUSIONS: Two mutations affecting nuclear genes were identified in Korean patients with autosomal dominant PEO. Further studies are necessary to identify the clear pathogenetic mechanisms and establish genotype-phenotype correlations in autosomal dominant PEO.

Correção da blefaroptose na oftalmoplegia crônicaprogressiva / Blepharoptosis treatment for chronic progressive external ophtalmoplegia

Introdução: Ptose palpebral corresponde à abertura anormal da pálpebra superior em decorrênciada perda parcial ou total da função do músculo elevador (músculo levantador da pálpebrasuperior), ocasionada por doença adquirida ou congênita. Método: Neste trabalho, descreve-sea evolução e os resultados obtidos com a suspensão palpebral dinâmica com enxerto de fáscialata fixada ao tarso e músculo frontal. Resultados: No período entre 2000 a 2007, foram operadosseis pacientes portadores de blefaroptose bilateral consequente a oftalmoplegia crônicaprogressiva, os quais apresentaram resultado satisfatório com a técnica descrita.

Introduction: Palpebral ptosis is a superior eyelid abnormal opening due partial or totalelevator muscle function, caused by acquired or congenital pathology. Methods: In thispaper, we describe the evolution and results gotten with the dynamic palpebral suspensionwith fascial sling to tarsal and to frontal muscle. Results: Six patients with chronic progressiveexternal ophtalmoplegia blepharoptosis were operated between 2000 and 2008. Wedescribed satisfactory results with the technique.

Síndrome de Kearns-Sayre / Kearns-Sayre syndrome

A síndrome de Kearns-Sayre é uma patologia rara, que acarreta piora da qualidade de vida; caracteriza-se por oftalmoplegia externa progressiva, fraqueza muscular e distúrbios na condução cardíaca. A entidade integra um grupo de desordens do metabolismo mitocondrial, denominadas miopatias mitocondriais ou citopatias mitocondriais.

Kearns-Sayres syndrome is a rare pathology which leads to a worse quality of life of the individual; it is characterized by progressive external ophthalmoplegia, muscular weakness, and cardiac conduction defects. The disease belongs to a group of mitochondrial metabolic disorders, named mitochondrial myopathies of mitochondrial cytopathies.

Observation on therapeutic effect of acupuncture combined with western medicine on paralytic strabismus / 中国针灸

<p><b>OBJECTIVE</b>To find out a better therapy for paralytic strabismus.</p><p><b>METHODS</b>Ninety cases were randomly divided into an acupuncture-medicine group, an acupuncture group, a western medicine group, 30 cases in each group. The acupuncture-medicine group were treated with acupuncture at Shuigou (GV 26), Fengchi (GB 20), Yifeng (TE 17), Yiming (EX-HN 14), Taiyang (EX-HN 5), Jingming (BL 1), Cuanzhu (BL 2), etc. intramuscular injection of Vit B1 and Vit B12, and oral administration of ATP; the acupuncture group were treated with simple acupuncture, and the western medicine group were treated with simple western medicine. Their therapeutic effects were compared.</p><p><b>RESULTS</b>The cured rate of 66.7% in the acupuncture-medicine group was significantly higher than 26.7% in the acupuncture group and 26.7% in the western medicine group (both P < 0.01).</p><p><b>CONCLUSION</b>Acupuncture combined with western medicine has obvious therapeutic effect, which is better than that of simple acupuncture or simple western medicine.</p>

Oftalmopatía distiroidea / Dysthiroid Ophtalmopathy

La oftalmopatía distiroidea es la causa más frecuente de proptosis uni o bilateral en el adulto. Afecta con más frecuencia a las mujeres entre los 25 y los 50 años, aunque el curso es más agresivo en los hombres. Se relaciona con hipertiroidismo (91%), tiroiditis de Hashimoto (3%) y eutiroidismo (6%). Hisotpatológicamente se observa un aumento de glucosaminoglicanos en el tejido conectivo de grasa orbitaria y músculos extraoculares. Las manifestaciones clínicas son, en orden de frecuencia, la retracción palpebral, la proptosis, la diplopia y la neuropatía óptica por compresión.

A Case of the Hypercalcemia Induced by the Coenzyme Q10 and Alphacalcidol Treatment in a Patient with Kearns-Sayre Syndrome and Hypoparathyroidism / 대한소아내분비학회지

Kearns-Sayre Syndrome (KSS) is rare mitochondrial disorder characterized by chronic progressive external ophthalmoplegia, atypical retinal pigmentation and complete heart block. It is occasionally combined endocrinologic symptoms such as hypoparathyroidism, short stature, diabetes mellitus and hypothyroidism. We reported the effect of Coenzyme Q10 on total serum calcium concentration in 17 years old girl with KSS and hypoparathyroidism. The patients was treated with alfacalcidol (1alpha-OHD3), Coenzyme Q10 and oral calcium agent. Total serum calcium concentration had even remained within normal range and hypercalcemia was developed suddenly after treatment of combination of Coenzyme Q10 and alfacalcidol (1alpha-OHD3). After stop of all medication, her total calcium concentration was decreased to 7.6 mg/dL and remained in normal range with oral calcium (2 g/day) and Coenzyme Q10 (150 mcg/day) daily. The action of Coenzyme Q10 is not clearly defined but, we could explain Coenzyme Q10 activates the capacity of the patient to produce the active form of Vitamin D, 1alpha-OHD3.

Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external opthalmoplagia.

BACKGROUND: Chronic progressive external ophthalmoplagia (CPEO) is a phenotypic mitochondrial disorder that affects external ocular and skeletal muscles and is associated with a single or multiple mitochondrial DNA (mtDNA) deletions and also nuclear gene mutations. There are also some reports about the relationship between CPEO and the nuclear Twinkle gene which encodes a kind of mitochondrial protein called Twinkle. AIMS: To study the mtDNA deletions and Twinkle gene G1423C point mutation in Iranian patients with CPEO. MATERIALS AND METHODS: We collected 23 muscle samples from patients with CPEO, 9 women (mean age 34.3 years) and 14 men (36.7 years). Multiplex polymerase chain reaction (PCR) method was used to find the presence of single or multiple deletions in mtDNA. Single stranded conformational polymorphism (SSCP) and restriction fragment length polymorphism (PCR-RFLP) methods were carried out to investigate point mutation (G1423C) in the Twinkle gene in all DNA samples. RESULTS: Different sizes of mtDNA deletions were detected in 16 patients (69.6%). Each of the 5.5, 7, 7.5 and 9 kb deletions existed only in 1 patient. Common deletion (4977bp) and 8 kb deletion were detected in 5 and 3 patients respectively. Multiple deletions were also present in 4 patients. Out of 23 patients included in our study, two cases (8.7%) had Twinkle gene mutation (G1423C) and 5 patients (21.7%) did not show any deletions in mtDNA or the Twinkle gene mutation. CONCLUSION: Our study provides evidence that the investigation of mtDNA and Twinkle gene mutations in CPEO may help with early diagnosis and prevention of the disease. Patients who did not show deletions in the mtDNA or G1423C mutation in the Twinkle gene may have other mtDNA, Twinkle or nuclear gene mutations.