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PubMed1998

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report.

Autopsy reports of patients with mitochondrial encephalopathy with lactic acidosis and strokelike episode (MELAS) are rare. This report documents the clinical and autopsy findings of a 47-year-old woman with MELAS syndrome. The diagnosis was corroborated by documenting a mitochondrial DNA mutation tRNA-Leu (UUR) at position 3243. The patient's clinical history was marked by schizophrenia, peptic ulcer disease, constipation requiring hemicolectomy, migraine headaches, deafness, and a left temporal lobe infarct. At autopsy, a muscle biopsy demonstrated numerous ragged red fibers and a partial cytochrome C oxidase deficiency. By electron microscopy, increased numbers of slightly hypertrophic mitochondria were observed focally within myocytes and vessel walls; paracrystalline mitochondrial inclusions were not seen. The brain at autopsy showed mild cerebral atrophy and diffuse cortical gliosis. Prominent bilateral basal ganglia calcifications and vascular sclerosis were present, and a small remote left temporal lobe infarct was seen.

DNA Mutational Analysis↗
PubMed2004

The MELAS syndrome. Review of the literature: the role of the otologist.

The mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare congenital disorder of mitochondrial DNA (mt-DNA). Patients with this syndrome may present to the otolaryngologist with sensorineural hearing loss (SNHL), which is genetic in origin. A high index of suspicion is required because this hearing loss is part of a syndrome for which early diagnosis and intervention is required.

DNA, Mitochondrial↗
PubMed1998

Sensorineural hearing loss in MELAS syndrome--case report.

A mitochondrial tRNA mutation at nucleotide 3,243 is known to be found in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). We report a 30 year-old female patient of MELAS, diagnosed 5 years ago, who presented herself to our ENT outpatient department because of her bilateral tinnitus and progressive hearing impairment since 4 years ago. Two sequential pure tone audiograms showed bilateral symmetrical progressive sensorineural hearing loss, especially in the high frequency area in 1993 and 1996. The pure tone average was R-45 dB, L-47 dB in 1993 and R-62 dB, L-67 dB in 1996. Hearing loss is an important feature in MELAS syndrome and reported to be seen in about 30% of patients. It is often the first clinical symptom, too. In any case, mitochondrial cytopathies need to be considered by the otologist in forming a diagnosis of sensorineural hearing loss (SNHL), particularly in cases, which present adult-onset progressive hearing loss and neurologic symptoms before 50 years of age.

Adult↗
PubMed1996

Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations.

Laminar cortical necrosis has been described in many conditions of cellular energy depletion, such as hypoxia and hypoglycemia. In MELAS, a genetic defect in mitochondrial protein synthesis leads to impairment of oxidative phosphorylation, with subsequent insufficient energy production within the cell. Neurons are more vulnerable to energy depletion than glial cells and vascular elements, and among the layers of the cerebral cortex the lower laminae are more vulnerable than the superficial layers. We studied a child with severe MELAS syndrome two months before death with MR and compared the images to autopsy findings, including macroscopic specimens and light and electron microscopy. The MR images showed an excellent correlation with the neuropathological results and displayed the various degrees of damage to the brain tissue caused by deficient energy production. Acute laminar cortical necrosis was seen as swelling of the cortex with intracortical hyperintense bands in T2-weighted images. The subacute stage with focal cortical hemorrhage was displayed as hyperintensity of the gyral surface in T1-weighted and hypointensity in T2-weighted images, with T2-hyperintensity and swelling of the rest of the cortex and underlying white matter. Severe cortical atrophy represented the chronic stage.

Atrophy↗
PubMed2001

An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.

We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome. The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit. The patient was heteroplasmic for the mutation in both muscle and blood, but the mutation was not detected in the patient's mother. A marked reduction of complex I activity was found in the patient's muscular tissue. This is the first report of a mutation in the ND6 subunit causing MELAS. Our data confirm the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and confirms that MELAS can be caused by mutation in polypeptide-coding mtDNA genes.

Base Sequence↗
PubMed1994

MELAS syndrome with mitochondrial tRNA(Leu(UUR)) gene mutation in a Chinese family.

The clinical features of a patient in a Chinese family with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) are reported. The study revealed that hearing and visual impairments and miscarriages may be early clinical presentations in MELAS. A heteroplasmic A to G transition in the tRNA(Leu(UUR)) gene was noted at the nucleotide pair 3243 in the mitochondrial DNA of muscle, blood, and hair follicles of the proband and his maternal relatives. Quantitative analysis of the mutated mitochondrial DNA revealed variable proportions in different tissues and subjects of maternal lineage in the family. Muscle tissue contained a higher proportion of the mutant mitochondria than other tissues examined. The function of the reproductive system of the proband seems to be impaired. In one clinically healthy sibling, the 3243rd point mutation was found in sperm mitochondrial DNA, although sperm motility was not affected. It seems that biochemical defects in mitochondrial respiration and oxidative phosphorylation are tissue specific expressions of the 3243rd point mutation in the mitochondrial DNA of the affected target tissues.

Adolescent↗
PubMed1998

Cochlear origin of hearing loss in MELAS syndrome.

There have been few studies investigating the mechanism and nature of the hearing loss that occurs in the mitochondrial disorders. We studied 18 patients with the MELAS A3243G point mutation from four different kindreds. Pure tone audiometry, speech discrimination testing, acoustic reflexes, tympanometry, and brain stem auditory evoked responses were performed to localize the site of pathology in the auditory pathways. In 12 patients, we performed electrocochleography and otoacoustic emissions to assess cochlear involvement. Neuroimaging and promontory nerve stimulation were performed to exclude retrocochlear pathology. Audiological testing confirmed sensorineural hearing loss in 14 of the 18 patients studied; hearing loss was usually gradual in onset, was symmetrical, and initially affected the higher frequencies. In some patients, there were features that distinguished the hearing loss from presbyacusis, including a young age at onset, asymmetrical involvement, stepwise progression, and partial recovery. We treated one patient who had profound bilateral hearing loss with cochlear implantation; this restored good functional hearing. Hearing loss in MELAS syndrome appears to be due to dysfunction of the cochlea, probably resulting from metabolic failure of the stria vascularis and outer hair cells. Cochlear implantation is a therapeutic option worth considering in those patients who become deaf.

Adolescent↗
PubMed2005

Resistance to cisatracurium in a patient with MELAS syndrome.

There are conflicting reports on the response of mitochondrial myopathy patients to the neuromuscular blocking drugs, showing either normal response or marked sensitivity. We present a patient with MELAS syndrome who underwent Nissen fundoplication and gastrojejunostomy. Marked resistance to the nondepolarizing muscle relaxant, cisatracurium was observed. The anesthesia management, as well as the various causes of resistance to cisatracurium in this patient are discussed.

Adolescent↗
PubMedDate not supplied

Random mitotic segregation of mitochondrial DNA in MELAS syndrome.

We describe the heterogeneity of clinical features and molecular genetic characteristics of the probands and other members in two families with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. A point mutation at the 3243rd nucleotide position of mtDNA was found only in some of the maternal lineage members of the two families. Furthermore, the proportions of mutant mtDNA were varied and found only in some tissues of the individuals. Intriguingly, in some subjects, the mutant mtDNA was found in blood cells or hair follicles but was absent in muscles. The data do not support the notion of a selective advantage of wild-type mtDNA to rapidly replicating cells. We suggest that a rapid replicative segregation may occur in early embryogenesis.

Adolescent↗
PubMed2000

Endocrine disorders in two sisters affected by MELAS syndrome.

A variety of endocrine and metabolic defects, including hypothalamopituitary hypofunction and diabetes mellitus, has been reported in association with mitochondrial disorders. We describe two sisters affected by mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome in whom DNA analysis showed an A-->G transition at the 3243rd nucleotide position on the transfer RNALeu(UUR) gene with 65% and 45% of mutant-type mitochondrial DNA present in the blood cells of the younger and the older sister, respectively. The younger sister had severe involvement of the central nervous system with mental retardation, epilepsia partialis continua, and strokelike episodes. Endocrine investigations showed an extensive neuroendocrine dysfunction with growth hormone deficiency, hypothalamopituitary hypothyroidism, prepubertal gonadotropin levels, and absence of any secondary sexual characteristics at the age of 12 6/12 years. The neurologically normal older sister was affected by diabetes mellitus and had normal hypothalamopituitary function. Our report confirms that the endocrine system can be affected differently by the same mitochondrial DNA mutation, depending on the heteroplasmia phenomenon. A complete endocrine evaluation must be performed in patients affected by mitochondrial disease and the existence of a mitochondrial disorder should be taken into account in patients with endocrine abnormalities, even if neuromuscular signs are lacking.

Adolescent↗
PubMed1997

[MELAS syndrome with pure vascular manifestation?].

Two stroke-like episodes then a grand mal seizure occurred within nine years in a 42-year-old patient. Neuroradiological findings (CT-scan and MRI) led to the diagnosis of incomplete MELAS syndrome. MRI with T2-weighted images (TR: 1000ms; TE: 35ms) showed two small asignal lesions possibly resulting from hemosiderine. Metabolic studies are required to help decide on muscular biopsies. Histological findings are needed for diagnosis of this form of mitochondrial cytopathy with only stroke-like manifestations.

Adult↗
PubMed2000

Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study.

It is widely held that changes in the distribution of mutant mtDNAs underlie the progressive nature of mtDNA diseases, but there are few data documenting such changes. We compared the levels of 3243 A-->G mutant mtDNA in blood at birth from Guthrie cards and at the time of diagnosis in a blood DNA sample from patients with mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome. Paired blood DNA samples separated by 9-19 years were obtained from six patients with MELAS. Quantification of mutant load, by means of a solid-phase minisequencing technique, demonstrated a decline (range 12%-29%) in the proportion of mutant mtDNA in all cases (P=.0015, paired t-test). These results suggest that mutant mtDNA is slowly selected from rapidly dividing blood cells in MELAS.

Adolescent↗
PubMed2001

Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation.

The authors studied a 47-year-old patient who presented with an association of deafness, acute cerebral stroke-like episode, leukoencephalopathy, and extensive basal ganglia calcifications. Late onset and neuroradiologic findings were atypical for MELAS syndrome (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike episodes). A heteroplasmic G to A transition at nucleotide 4332 in the tRNA glutamine gene was identified in the patient's muscle mitochondrial DNA. The pathogenicity of the mutation was shown in single muscle fibers by the correlation between high mutation load and cytochrome c oxidase defect.

DNA, Mitochondrial↗
PubMed2001

[Clinical case of the month. MELAS syndrome].

A patient, born in 1961, was first examined for autoimmune hyperthyroïd at the age of 25. Then, several episodes of serious dehydration and alteration of general condition were followed by a severe encephalopathy with a symptomatology of stroke-like episodes, and during a hospitalization, a volvulus of the colon. Epilepsy developed also. A MELAS syndrome was diagnosed when she was 32 years old, based on her clinical metabolic history of the presence of Ragged-Red-Fibers at muscular biopsy and of the genetical analysis. At the age of 37, after a new episode of encephalopathy, the patient fell into a rapidly evolving coma and deces.

Adult↗
PubMed1997

Metabolic interventions against complex I deficiency in MELAS syndrome.

The mitochondrial DNA (mtDNA) codes for essential hydrophobic components of the system of oxidative phosphorylation. Diseases caused by mtDNA defects are manifested as variable clinical phenotypes and the symptoms represent the involvement of tissues with high energy demand. Various approaches have been taken to treat mitochondrial diseases by administration of redox compounds, enzyme activators, vitamins and coenzymes or dietary measures. The MELAS mutation at the base pair 3243 of mitochondrial DNA demolishes a transcription termination sequence located within the tRNA(Leu)[UUR] gene, resulting in synthesis of an abnormally large derivative of 16 S rRNA and defective translation. The activity of NADH:Q oxidoreductase (complex I) is often decreased and lactic acidosis is a typical clinical finding. We hypothesized that defective translation of the seven mitochondrially coded subunits (of the total 41) of complex I may alter its affinity to the NADH substrate in which case the activity decrease may be compensated for by increasing the NADH concentration. A MELAS patient was treated with oral nicotinamide for 5 months. The blood NAD content representing the NAD + NADH pool of erythrocytes rose 24 fold and the blood lactate + pyrovate concentration fell by 50%. All these metabolic alterations suggested an improvement of the function of complex I or the whole mitochondrial respiratory chain. However, the kinetic properties of the patient's complex I were similar to the reference values. A tempting explanation is that the free NADH concentration in mitochondria is normally at the level of K(m), so that the decreased activity of the respiratory chain can be compensated for by increased mitochondrial [NADH]. Another possibility would be that the substrate shuttles for transport of reducing power of cytosolic NADH into mitochondria (the malate aspartate or glycerol-3-phosphate shuttles) may be enhanced by increased total NAD + NADH. Because the malate-aspartate shuttle is actually a pump for reducing equivalents driven by the mitochondrial membrane energization, it is proposed that the exacerbations of the MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the active transport of the hydrogen from cytosolic NADH into the mitochondrion.

Administration, Oral↗
PubMed1995

[The MELAS syndrome and dilated-hypertrophic cardiomyopathy: a case report].

We describe a case of a 34-year-old male patient first hospitalized in February '93 for stroke (concomitant dilated-hypertrophic cardiomyopathy was noted), and then in April '93 for congestive heart failure. The presence of myopathy, encephalopathy, lactic acidosis and stroke episode allows for the diagnosis of MELAS syndrome, proven by a specific point mutation in mitochondrial DNA. In this case we were able to observe not only the electrocardiographic and echocardiographic features of hypertrophic cardiomyopathy, previously described in mitochondrial encephalomyopathies, but we were also able to monitor the rapid evolution of this cardiomyopathy towards the hypokinetic dilated form with severe impairment of systolic function; this transition was due to changes in the heart anatomy and structure with reduction in the left ventricular (LV) wall thickness and dilatation of all chambers. The remodeling of LV geometry seems to be not definite and capable of dynamic evolution, as suggested by clinical and echocardiographic findings evaluated six months after the hospitalization. In this patient, we obtained a mid-term favourable clinical outcome using inotropic drugs and Ubiquinone (coenzyme Q), an intermediate substrate of the energetic metabolism, which seems to be poorly synthetized because of the early enzymatic defects in the mitochondrial respiratory chain.

Adult↗
PubMed2005

Heart transplantation for progressive cardiomyopathy as a manifestation of MELAS syndrome.

Mitochondrial diseases represent a heterogeneous group of disorders associated with a wide array of clinical manifestations. The presentation of patients with mitochondrial pathology largely depends upon the dysfunction of organ systems with large metabolic/energy requirements, including cardiac, neurologic, and musculoskeletal. In particular, mitochondrial myocardial disease can be progressive resulting in congestive heart failure and end-stage heart disease. This article reviews the role of heart transplantation for a particular variant of mitochondrial disorder, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and discusses perioperative management issues related to transplantation for mitochondrial cardiomyopathies.

Adolescent↗