Clinical and genetic features in a MELAS child with a 3271T>C mutation

A mitochondrial DNA 3271T>C point mutation was reported to be the second most common mutation (following the mutation 3243A>G) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in Japan. This mutation has rarely been reported in other countries. We present an 11-year-old Taiwanese girl with MELAS, who harbored the 3271T>C mutation and had manifested short stature, epilepsia partialis continua, and recurrent basal ganglia infarctions since age 6 years, and rapid intellectual regression, dysarthria, and unsteady gait since age 10 years. The proportion of 3271T>C mutant genomes in various tissues, including urinary sediments, hair follicles, blood leukocytes, and buccal mucosa cells from the patient and her mother, was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis and quantitative real-time polymerase chain reaction. The proportion of mutant load in the patient's muscles was near 100%. Except for muscle, the highest mutation load was detected in urinary sediments of the patient by both methods. This is the first report involving mutant load analysis with quantitative real-time polymerase chain reaction in the 3271T>C mutation. The results suggest that urinary sediments may be an alternative tissue of choice which can be obtained noninvasively in the diagnosis of mitochondrial DNA 3271T>C mutations.     

Clinical,physiological, and histological features in a kindred with the T3271C MELAS mutation

The majority of patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) have an A→G mutation at nucleotide 3243 in mitochondrial transfer (t)RNA. To date there have only been 10 reported cases of MELAS syndrome in patients with a T→C mutation at position 3271 of mitochondrial tRNA. Although many of the clinical features are similar between patients with these different mutations, it appears that the age at onset is later for the 3271 mutation. This report provides information from a North American kindred with the 3271 mutation (n = 6 proven; n = 2 probable; n = 3 possible) that adds clinical, physiological, histological, and molecular information to the pool of information on this rare disorder. Many of these features were similar to previous reports of both 3243 and 3271 patients. We conclude that the phenotypic expression of these different mutations are similar, but the age of onset for 3271 patients is later than for 3243 patients. © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 25–33, 1998.     

Clinical and genetic features in two families with MELAS and the T3271C mutation in mitochondrial DNA

The majority of patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) have the A3243G point mutation. The much rarer T3271C mutation has been reported predominantly in Japanese subjects. Our objective was to better define the clinical phenotype and mutation load in patients with MELAS and the T3271C mutation in mitochondrial DNA. We present clinical and molecular genetic data in two pedigrees with the T3271C mutation. The age at onset was 8 years in one proband and 14 years in the other. Both patients had migrainelike headache, seizures, and strokelike episodes. Mutation loads were quantified in multiple tissues from the patients and from family members by polymerase chain reaction-restriction fragment length polymorphism analysis. The symptoms in both probands were typical of MELAS, and, contrary to previous reports, onset was early. Hearing loss was less common than in typical MELAS, and ragged red fibers were absent. The proportion of mutant genomes was consistently and markedly greater in DNA from urinary sediment than from blood. In the mother of one proband, mutant genomes were detected only in DNA from hair follicles and cheek mucosa The phenotype of patients with the T3271C mutation might not be as distinct as that of the A3243G mutation, as previously described. Our data also suggest that urine is a better source of DNA than blood for diagnosis and that multiple tissues should be studied in maternal relatives, especially when the mutation cannot be detected in blood.     

MELAS syndrome in a patient with a point mutation in MTTS1

Background, Objective and Methods –  We describe a female patient with a mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome. As a child, she developed epilepsy and stroke-like episodes giving cognitive impairment and ataxia but no hearing impairment. At the age of 44 years, she suffered a cerebral sinus thrombosis which was warfarin treated. One month later, she developed an episode of severe acidosis associated with encephalopathy and myelopathy.
Results –  She was found to harbour a 7512T>C mutation in the mitochondrial encoded tRNA^Ser(UCN) gene ( MTTS1 ). The mutation load was 91% in muscle and 24% in blood. Enzyme histochemical analysis of the muscle tissue showed numerous cytochrome c oxidase (COX)-negative fibres. Restriction fragment length polymorphism (RFLP) analysis of single muscle fibres showed significantly higher level (median 97%, range: 94–99%) of the mutation in the COX-negative fibres compared with COX-positive fibres (median 36%, range: 12–91%), demonstrating the pathogenic effect of the mutation. Different levels of heteroplasmy (range 34–61%) were detected in hair shafts analysed by RFLP.
Conclusion –  This case adds to the spectrum of clinical presentations, i.e. sinus thrombosis, in patients having MTTS1 mutations.     

Absence of maternal A3243G mtDNA mutation and reversible hyperglycemia in a patient with MELAS syndrome

We report the unusual features of a female patient who had MELAS-specific A3243G mutation in mitochondrial DNA (mtDNA) and diabetes mellitus (DM). The patient showed mitochondrial myopathy, encephalopathy, lactic acidosis, and deafness but lacked the stroke-like episode. Acute hyperglycemia was noted after one attack of status epilepticus. Molecular genetic analysis demonstrated a heteroplasmic A3243G point mutation in the mtDNAs of muscle, blood cells and hair follicles. Glucagon stimulation test exhibited marked depression of pancreatic beta-cell function. However, in a further study neither this mutation, nor MELAS syndrome or DM, was found in all of her maternal relatives. A series of follow-up studies for beta-cell function also showed gradual improvement. The pedigree study led us to believe that this A3243G mutation arose from the germ line cells or occurred later in somatic tissues of the patient. We also suggest that the A3243G mutation of mtDNA may elicit the pathogenesis of a subtype of DM. Nevertheless, environmental stress may be another important factor for provocation of the disease.     

Atypical MELAS associated with mitochondrial tRNA gene A8296G mutation

We report on a unique patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting optic atrophy, cardiomyopathy, and bilateral striatal necrosis before stoke-like episodes became apparent. Skeletal muscle total mitochondrial DNA analysis identified a heteroplasmic A to G point mutation in the tRNA^Lys gene at position 8296. Skeletal muscle pathology revealed typical MELAS findings, including ragged-red fibers cytochrome c oxidase positive strongly succinate dehydrogenase-reactive blood vessels. Recent reports describe the 8296 mutation identified in patients with diabetes mellitus or myoclonus epilepsy with ragged-red fibers, not MELAS. We conclude that the 8296 mutation is likely to be pathogenic and that it may be not only a mutation responsible for diabetes mellitus or myoclonus epilepsy with ragged-red fibers but also for MELAS.     

A case with late-onset MELAS with hallucination and delusion]

We report a 53-year-old male patient with late onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes(MELAS) with hallucination and delusion. The patient manifested various neurological symptoms including perceptive deafness, muscle weakness of limbs with loss of consciousness, sensory abnormalities in hands, feet and a face, abnormal sense of taste, tremor, palsy of upward eye movement and weak deep tendon reflexes prior to the psychotic episode. He was diagnosed as MELAS, because of high serum lactic acid and pyruvic acid, and the point mutation in the mitochondrial DNA 3243. SPECT imaging showed decreased perfusion in occipital cortex and thalamus. These SPECT changes improved after disappearing visual hallucination. Hallucination might be caused by delirium due to stroke-like episode. Dysfunction in the occipital cortex and thalamus might be involved with this perfusion change.     

Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF

BACKGROUND: The mitochondrial DNA gene encoding subunit 5 of complex I (ND5) has turned out to be a hot spot for mutations associated with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and various overlap syndromes. OBJECTIVE: To describe a novel mutation in the ND5 gene in a young man man with an overlap syndrome of MELAS and myoclonus epilepsy with ragged-red fibers. DESIGN: Case report. PATIENT: A 25-year-old man had recurrent strokes, seizures, and myoclonus. His mother also had multiple strokes. A muscle biopsy specimen showed no ragged-red fibers but several strongly succinate dehydrogenase-reactive blood vessels. RESULTS: Biochemical analysis showed isolated complex I deficiency and molecular analysis revealed a novel heteroplasmic mutation (G13042A) in the ND5 gene. CONCLUSIONS: These data confirm that ND5 is a genetic hot spot for overlap syndromes, including MELAS and strokelike and myoclonus epilepsy with ragged-red fibers.     

Pathomechanism and clinical presentation of neurobehavioral disturbances in a patient with MELAS syndrome]

The authors present the results of a longitudinal study of the neurobehavioral disturbances seen in K.S., a 22-year-old female patient with a mitochondrial cytopathy (MELAS) caused by the novel mutation C8293T. K.S. became ill in 1994 at the age of 16. She was referred for diagnosis to several different clinics. Four years after onset, the clinical diagnosis was established in the Department of Medical Rehabilitation at the Cracow Rehabilitation Center; the diagnosis was not confirmed until six years after onset, following the discovery of the mutation in the patient's mtDNA at Columbia University. Since 1996 the patient has presented with progressive dementia and periodic stroke-like episodes that produced fluctuating neurological symptoms. The essential pathomechanism of the neurobehavioral disturbances consists in the fragmentation of complex cerebral processes into their constituent elements; individual functions are frequently correctly executed on a lower level of cerebral organization, but the patient is unable to combine them into a sensible whole. The authors discuss the theoretical and clinical significance of the results presented here.     

A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted. Electromyography revealed both myogenic and neurogenic muscular changes, and nerve conduction studies demonstrated a sensory-motor neuropathy. Biopsy showed ragged-red fibers with strongly stained SDH-positive vessels in skeletal muscles, and a marked loss of myelinated fibers of the sural nerves. Mitochondrial (mt) DNA analyses of peripheral blood, muscles and nerves revealed that all members had a heteroplasmic np3271 (T-C) point mutation in the mitochondrial tRNA-Leu gene (UUR). This family is unique, in that all patients presented with a myoclonus epilepsy with ragged-red fibers-like phenotype and had a distinctive peripheral neuropathy, while the detected mtDNA 327l (T-C) mutation has been reported to date only in rare cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes     

Invasive aspergillosis in a patient with MELAS syndrome

Invasive infection with the opportunistic fungus Aspergillus fumigatus predominantly affects people with impaired cell mediated immunity. The case of a 31 year old woman with no identified cause for immunosuppression who presented with severe refractory aspergillosis of the paranasal sinuses is reported. She subsequently developed clinical and molecular evidence of mitochondrial encephalomyopathy with lactic acidosis and stroke-like events (MELAS) syndrome. It is proposed that MELAS syndrome may represent an unusual risk factor for the development of invasive aspergillosis and mechanisms are supported by which mitochondrial dysfunction may predispose to this.     

An infant with a mitochondrial A3243G mutation demonstrating the MELAS phenotype

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a syndrome associated with mitochondrial DNA mutations such as A3243G, the most common mutation. Ragged-red fibers and strongly succinate dehydrogenase-reactive blood vessels in the muscle are diagnostic pathologic features of MELAS. In general, the first typical attack of MELAS occurs in children at school age; it is rare for stroke-like episodes to occur in early infancy. This report describes a 4-month-old male harboring A3243G, whose phenotype at onset was consistent with that of MELAS in infancy. The patient was admitted because of disturbances of consciousness and ventilatory insufficiency. Remarkable lactic acidosis was observed. MRI revealed several bilateral lesions. Periodic lateralized epileptic discharges on the EEG suggested regional lesions. Biopsied muscle displayed scattered ragged-red fibers and succinate dehydrogenase-reactive blood vessels; over 90% of muscle mitochondrial DNA had A3243G. This case suggests that MELAS can develop in early infancy with its typical clinical presentation. The high percentage of A3243G may contribute to the early onset of the MELAS phenotype in this patient.     

A patient with dermatomyositis and systemic sclerosis with preferential facioscapulohumeral muscle involvement and fatal cardiomyopathy]

We report a 23-year-old man suffering from an overlap syndrome of systemic scleroderma and dermatomyositis who died from severe dilated cardiomyopathy. Because his weakness involved predominantly muscles in the facio-scapulo-humeral regions, he was initially thought to have facioscapulohumeral muscular dystrophy (FSHD) at other hospitals. However, he had also Raynaud phenomenon and low voltages on electrocardiogram. His apparent facial weakness was mainly due to atrophic skin changes. Unlike FSHD, the deltoid and levator scapulae muscles were also atrophic. Deltoid muscle biopsy performed one year earlier at another hospital showed mild myopathic changes without inflammation, but there were scattered thick-walled endomysial capillaries, suggesting inflammatory myopathy. Biceps brachii muscle biopsy in our hospital showed marked inflammation with perifascicular atrophy. In this patient, the cardiac muscle involvement progressed together with the skeletal muscle inflammation before scleroderma became apparent.     

mtDNA A3243G MELAS mutation is not associated with multigenerational female migraine

The authors searched for mitochondrial DNA (mtDNA) A3243G mutation in peripheral blood leukocytes from female migraine patients with pure matrilinear history of migraine along two or three generations. The current study was designed to exclude any male transmission of the disease. The mutation was absent in all patients. We conclude that mtDNA A3243G mutation does not contribute to the pathogenesis of pure matrilinear multigenerational migraine with or without aura.     

Nerve conduction abnormalities in patients with MELAS and the A3243G mutation

BACKGROUND: Mitochondrial DNA point mutations are especially deleterious to tissues with high energy demand, including the peripheral nervous system. Neuropathy has been associated with several mitochondrial diseases, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). OBJECTIVE: To evaluate nerve conduction in a genotypically and phenotypically homogeneous group of patients with MELAS and the A3243G mutation. DESIGN: We studied 30 patients with MELAS and the A3243G mutation using neurophysiological techniques, medical history questionnaires, laboratory tests, and a standardized neurological examination. RESULTS: Twenty-three subjects (77%) had abnormal nerve conduction measures. Symptoms suggestive of neuropathy were present in only half of the patients, but almost all had decreased reflexes or distal sensory findings on examination. Nerve conduction abnormalities were predominantly axonal and sensory and mainly present in the legs. Patients with nerve conduction abnormalities tended to be older and were more likely male. CONCLUSIONS: Peripheral nerve impairment is common in those with MELAS and the A3243G mutation, and may be subclinical. Male sex and older age may add to the genetic disposition to develop neuropathy.     

A case of MELAS presenting juvenile-onset hyperglycemic chorea-ballism]

We report herein the case of a 28-year-old man presenting with hyperglycemic chorea-ballism (HCB) in addition to mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). He was admitted to a local hospital due to weight loss, general fatigue and thirst. The patient had diabetes mellitus, with a blood glucose level of 738 mg/dl and HbA1c of 19.8%. Although insulin therapy improved hyperglycemia, he noticed involuntary movements in the right upper and lower limbs, which subsequently extended to the left side. The patient was thus transferred to our hospital. He displayed short stature (154 cm) and emaciation, and a maternal family history of diabetes mellitus was elicited. He had no history of stroke-like episode, headache, vomiting and seizure. Neurological examination revealed low intelligence (IQ 57), mild sensorineural deafness, and chorea-ballism in the extremities and head without ptosis or eye movement disturbance. Brain computed tomography (CT) demonstrated areas of high density, while T1-weighted magnetic resonance imaging (MRI) revealed extreme hyperintensity and T2-weighted MRI showed hyperintensity in bilateral caudate nuclei, putamina and globi pallidus. HCB was diagnosed. In, CSF, lactate level was increased to 43.9 mg/dl (n, 4-16), pyruvate level was 1.65 mg/dl (n, 0.3-0.9) and total protein concentration was 59 mg/dl. Histological examination of a biopsy sample from the biceps brachii muscle demonstrated ragged-red fibers. An A3243G point mutation in the tRNA(Leu(UUR)) gene was detected, indicating the presence of MELAS. Involuntary movements improved on treatment with haloperidol up to 4.5 mg/day. HCB usually appears in elderly individuals, and cases less than 40-years-old are very rare. The mitochondrial dysfunction in MELAS may accelerate development of HCB.     

Mitochondrial 3243 A-->G mutation (MELAS mutation) associated with painful muscle stiffness.

The mitochondrial mutation A-->G at nucleotide position 3243 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and other mitochondrial encephalomyopathies. We found this mutation in a 61-year-old patient who developed at the age of 54 a myopathy with painful muscle stiffness as the predominant symptom. Additionally hypacusis, a mild hemisensory syndrome and impaired glucose tolerance were present. Muscle histopathology showed few ragged red fibers. The mutation was detected heteroplasmatically in DNA from muscle and blood. So far painful muscle stiffness has not been a known phenotype of the 3243 mutation.