External Ophthalmoparesis Research Articles

Mitochondrial neurogastrointestinal encephalomyopathy in three siblings

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase (TP) gene causes mitochondrial genomic dysfunction. Patients suffer from gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis, myopathy and polyneuropathy. Magnetic resonance imaging (MRI) shows leukoencephalopathy. We describe clinical, genetic and neuroradiological features of three brothers affected with MNGIE. Clinical examination, laboratory analyses, MRI and magnetic resonance spectroscopy (MRS) of the brain, and genetic analysis have been performed in all six members of the family with the three patients with MNGIE. Two of them are monozygous twins. They all suffered from gastrointestinal dysmotility, cachexia, ophthalmoplegia, muscular atrophies, and polyneuropathy. Urinary thymidine was elevated in the patients related to the severity of clinical disease, and urinary thymidine (normally not detectable) was also found in a heterozygous carrier. Brain MRI showed leukoencephalopathy in all patients; however, their cognitive functioning was normal. Brain MRS demonstrated reduced N-acetylaspartate and choline in severely affected areas. MRI of heterozygous carriers was normal. A new mutation (T92N) in the TP gene was identified. Urinary thymidine is for the first time reported to be detectable in a heterozygous carrier. MRS findings indicate loss of neurons, axons, and glial cells in patients with MNGIE, but not in heterozygous carriers.

Anesthetic management in MNGIE Syndrome

We describe the anesthesia management of a 15-year-old girl, diagnosed with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), who presented with gastrointestinal perforation. MNGIE is an autosomal recessive disease associated with multiple deletions and depletion of mitochondrial DNA in skeletal muscle. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, severe gastrointestinal dysmotility, peripheral neuropathy, and leukoencephalopathy. We report on the anaesthetic management of a paediatric patient with MNGIE, and briefly discuss the pathophysiology and anaesthetic implications of this disorder. We describe the successful administration of a general anesthesia without muscle relaxants, maintenance in a patient with MNGIE.

Estudo neurofisiológico na síndrome miastênica congênita do canal lento: relato de caso

The slow-channel syndrome is one of the congenital myasthenic syndromes attributed to inherited kinetic disorders of the ion channel of the acetylcholine receptor of the neuromuscular junction. This is a case report of 25-years-old man with progressive ptosis and limitation of ocular movements since infancy, presented a 6-years history of worse of the external ophthalmoparesis and muscular weakness in the shoulders and hands. The motor nerve conduction studies after a supramaximal single stimulus disclosed a double compound muscle action potential (CMAP) that disappeared after a voluntary contraction of 30 seconds. Repetitive stimulation of facial and spinal accessory nerves showed a CMAP decrement greater than 10% with disappeared of the second potential. The patient received fluoxetine with mild improvement of muscular weakness, but persisted with: ptosis, limitation of ocular movements and repetitive CMAP in the motor nerve conduction study. The characteristic of disease are discussed.

Bedeutung der mitochondrialen DNA-Analyse in der Diagnostik der chronisch-progressiven externen Ophthalmoplegie (CPEO)

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial cytopathy presenting with ptosis and external ophthalmoparesis. Mitochondrial disorders are characterized by a broad clinical spectrum and genetic background with marked genotype/phenotype variability. The routine diagnostic work-up usually includes clinical and laboratory examinations as well as histological and histochemical analysis of skeletal muscle biopsy. In our case only an additional molecular biological examination allowed the diagnosis of CPEO. We report a 35-year-old woman with a 7-years history of slowly progressive diplopia due to impaired ocular motility and bilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, lower limb skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA. Although clinical, laboratory, histological and biochemical analyses did not give any hints suggesting a mitochondrial cytopathy, molecular genetic testing of total DNA from skeletal muscle tissue by Southern blot analysis finally revealed a 3.8 kb mitochondrial DNA deletion with a degree of heteroplasmy of 45 %. In patients with unexplained binocular diplopia , oculomotor deficits and/or acquired ptosis, an underlying mitochondrial cytopathy should be considered. Even in the case of inconspicuous skeletal muscle histology and biochemistry, molecular genetic testing of skeletal muscle DNA is advisable in order to establish the diagnosis.

Lack of gastrointestinal symptoms in a 60-year-old patient with MNGIE

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive multisystem disorder caused by mutations in the thymidine phosphorylase gene ( TP ).1 The disease is characterized by onset between the first and fifth decades of life, ptosis, progressive external ophthalmoparesis, peripheral neuropathy, and leukoencephalopathy.1,2⇓ Gastrointestinal (GI) involvement is a major hallmark of the disease, and all reported patients have GI dysmotility.2-4⇓⇓ We report a 60-year-old woman born after a normal pregnancy. She had bilateral ptosis since childhood and tremor affecting hands and head since age 2 years. She was 145 cm tall and weighed 41 kg at age 60 years. Neurologic examination at age 60 years showed bilateral ptosis with bilateral external ophthalmoplegia. Optic fundi were normal without retinitis. Strength was normal, but she had areflexia. She also had action and rest tremor. Her maternal grandfather and her daughter had tremor. Echocardiography revealed a mild thickening in the septum heart muscle. She had no GI symptoms. A radionuclide gastric emptying test showed mild gastroparesis. Laboratory data showed elevated venous lactate at rest (4.1 mmol/L; normal, 0.9 to 2.7). Brain MRI revealed diffuse hyperintense signal affecting the white matter of the cerebral hemispheres, midbrain, and pons. Abundant cytochrome c oxidase (COX)-negative ragged-red fibers and lipid droplets were found in biceps muscle biopsy (figure). The patient’s sister had short stature, and the patient’s …

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family.

The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication.

Peritonitis agudas y divertículos del intestino delgado en una paciente con encefalomiopatía neurogastrointestinal mitocondrial

Jejunal and ileal diverticula are acquired lesions that are often associated with intestinal motility disturbances like those occurring in myopathies and neuropathies with visceral affection. Mitochondrial neurogastrointestinal encephalomyopathy is characterized by gastrointestinal dysmotility, cachexia, ptosis with external ophthalmoparesis, neuropathy, leukoencephalopathy and laboratory evidence of mitochondrial alteration.A female patient that since 9 months age presented digestive symptoms: diarrhea, nauseous, vomits, slow digestions and abdominal pain. She had myopia. At the age of 20, in a seven months period, she precised urgent abdominal surgical intervention in three occasions for acute diffuse peritonitis related to jejunal and ileal diverticula. She presented cachexia, mild palpebral ptosis, external ophthalmoparesis, hypertrophic major auricular nerves, scoliosis, pes cavus, distal weakness and hypoesthesia in extremities, bilateral neurosensorial hypoacusia and lactic acidosis. The electroneurographic study was compatible with severe chronic demyelinating sensitive motor polyneuropathy. In the cerebral MR leukoencephalopathy was detected. In muscular tissue it was seen alteration in all fibers type I with numerous lipid vacuoles and an increase of mitochondrial number in the form of thick grains and subsarcolemmal mitochondrial bags. There was no ragged red fibers nor ultrastructural mitochondrial alterations. There was chain respiratory complex III deficiency.In patients with intestinal dysmotility manifestations and jejunal and ileal diverticula neuropathies and myopathies with visceral affection must be suspected, among them MNGIE syndrome.

MNGIE: from nuclear DNA to mitochondrial DNA.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a unique autosomal recessive disorder with mitochondrial DNA alterations. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Muscle biopsies typically reveal mitochondrial abnormalities including ragged-red fibers and focal cytochrome c oxidase deficiency. Analysis of mitochondrial DNA in skeletal muscle shows partial depletion, multiple deletions, or both. To identify the cause of MNGIE, we mapped the disease locus to chromosome 22q13.32-qter. Within this region, we identified the gene encoding thymidine phosphorylase as the MNGIE gene. We have identified homozygous or compound-heterozygous thymidine phosphorylase gene mutations in 35 MNGIE patients (21 families) from diverse ethnic groups, including: Ashkenazi Jewish, Western European, Jamaican, Hispanic, and Japanese. We confirmed pathogenicity of the mutations by a spectrophotometric assay of thymidine phosphorylase activity with peripheral leukocytes of 15 MNGIE patients. Thymidine phosphorylase enzymatic activity was severely reduced, thus enabling us to conclude that the loss-of-function mutations in thymidine phosphorylase gene cause MNGIE. Thymidine phosphorylase catabolizes thymidine to thymine. In agreement with this notion, we noted that plasma thymidine level is increased more than 20-fold in MNGIE patients compared to controls. Therefore, we have hypothesized that increased thymidine causes mitochondrial nucleotide pool imbalance which, in turn, leads to motochondrial DNA alterations, via a mitochondria-specific thymidine salvage pathway. The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism.

Paralytic strabismus.

In the past 12 months there have been many interesting publications on paralytic strabismus. Many investigators have reported on various imaging techniques helping both the clinician and the basic scientist better evaluate the causes and effects of paralytic strabismus on the extraocular muscle environment. Some interesting cases of neurologic and systemic associations have also been reported, including a unilateral pupil-sparing third nerve paralysis developing after the use of sildenafil citrate (Viagra; Pfizer, New York, New York). Advances in genetics are now helping us further understand complex entities such as progressive external ophthalmoparesis and congenital fibrosis syndrome. At the other end of the spectrum, colleagues are reporting clinical findings to help specify the diagnosis of conditions as diverse as degenerative ataxic disorders and masked bilateral superior oblique muscle paresis. Unfortunately, there were very few papers on proven new effective surgical techniques for the treatment of paralytic strabismus this year. Finally, to help clarify terminology, and when at all possible depending on the reports reviewed, the following nomenclature will be used in this paper: paralysis--complete loss of function of a muscle or group of muscles innervated by a specified (when applicable) cranial nerve or branch; paresis--incomplete loss of function; and palsy--when the authors failed to specify the degree of weakness.

Mitochondrial DNA Analysis in Ocular Myopathy

We analyzed 29 patients with progressive external ophthalmoparesis (PEO) either alone or as part of a multisystem disorder. Ragged-red fibers were very abundant (10–20%) in 15 patients, and many of them were also cytochrome c oxidase-negative. Biochemical analysis of the respiratory chain showed partial defects of single or multiple complexes in 18 patients (64%). Eleven PEO patients (38%) harbored single large-scale mtDNA deletions in muscle, which averaged 5.4 kb in size and 47% in relative abundance. One PEO patient harbored the A3243G mutation (MELAS mutation) in muscle (63%). Our findings, the first reported in Portuguese patients, confirm that single large-scale mtDNA deletions are a significant cause of PEO. Although ophthalmoparesis was the main clinical feature in the majority of patients, the clinical spectrum is broad, ranging from severe encephalopathy of childhood to a milder, though disabling, muscle weakness in adults.

Mitochondrial ocular myopathy: a clinical, laboratory, and morphologic study

We studied 63 patients suffering from mitochondrial ocular myopathy, who were distributed into four groups according to ther clinical manifestations. Patients in Group I presented only bilateral palpebral ptosis; patients in Group II presented palpebral ptosis and bilateral external ophthalmoparesis; patients in Group III had dysphagia and/or dysphonia accompanied by palpebral ptosis and/or bilateral external ophthalmoparesis; patients in Group IV presented a clinical picture of muscular weakness in the upper and lower limbs and face, accompanied by palpebral ptosis and/ [...]

Early Predictors of Poor Outcome in Congenital Fiber-Type Disproportion Myopathy

We report the cases of eight children with histologic findings in the muscle of congenital fiber-type disproportion myopathy. Five had severe muscle weakness at birth; three of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors.

Mitochondrial abnormalities in extraocular muscles in myotonic dystrophy

This is the first description of ‘ragged red fibers’ in extraocular muscles of myotonic dystrophy. Muscle biopsies were obtained from the biceps brachii and superior rectus of a 53-year-old man who had suffered from chronic progressive myotonia and muscular weakness in limbs, blepharoptosis, external ophthalmoparesis, myotonic cataract, and foveal pigmentary dystrophy. The extraocular as well as skeletal muscle cells showed centrally placed multiple nuclei with type 1 fiber predominance and increased intermyofibrillary connective tissue. About 20% of extraocular muscle fibers were identified as ‘ragged red fibers’ with the modified Gomori trichrome stain, most of which showed reduced activity in the cytochrome c oxidase reaction. An increased number of enlarged mitochondria were clustered beneath the sarcolemma and between the myofibrils, some of which contained irregularly or circularly arranged cristae and paracrystalline inclusions. Biochemical assessments showed in both skeletal and extraocular muscle...

The orthostatic hypotension syndrome of Shy-Drager. A clinicopathologic report.

CHRONIC orthostatic hypotension may develop in the course of a number of different neurologic diseases. 1-3 Among others, we have encountered it in multiple sclerosis and in a high cervical calcified hematomyelia. Shy and Drager 4 directed attention to a progressive neurologic disorder in which orthostatic hypotension was a significant feature along with urinary and rectal incontinence, anhidrosis, iris atrophy, external ophthal-moparesis, rigidity, tremor, loss of associated movements, impotence, atonic bladder, generalized weakness, fasciculations, and neuropathic muscle wasting. They demonstrated pathologic changes in the autonomic nervous system, the corticobulbar and corticospinal tracts, certain of the basal ganglia, and portions of the cerebellar system in one of their patients. They concluded that the progressive clinical course of the disease and the extensive neuropathologic changes indicated that this was a primary degenerative disease of the central nervous system (CNS). Subsequent reports 5,6 have helped to fortify their idea and to