Research Notes: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

Mitochondrion. 2007 Feb-Apr.
MELAS and L-arginine therapy.
Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Katayama K, Matsuishi T.
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi Machi, Kurume, Fukuoka, Japan.

We investigated the endothelial function in MELAS patients and also evaluated the therapeutic effects of L-arginine. Concentrations of L-arginine during the acute phase of MELAS were significantly lower than in control subjects. L-arginine infusions significantly improved all symptoms suggesting stroke within 30 min, and oral administration significantly decreased frequency and severity of stroke-like episodes. Flow-mediated dilation (FMD) in patients showed a significant decrease than those in the controls. Two years of oral supplementation of L-arginine significantly improved endothelial function to the control levels and was harmonized with the normalized plasma levels of L-arginine in patients. L-arginine therapy showed promise in treating stroke-like episodes in MELAS.

Eur Neurol. 2007 Mar 26.
Statins Provoking MELAS Syndrome. A Case Report.
Thomas JE, Lee N, Thompson PD.
Department of Internal Medicine, University of Connecticut, Farmington, Conn., USA.

Background: Statins inhibit the production of 2,3-dimethoxy,5-methyl,6-polyisoprene parabenzoquinone also known as ubiquinone or coenzyme Q10 (CoQ10), which is required for mitochondrial electron transport. Idiopathic or primary CoQ10 deficiencies have been known to cause mitochondrial encephalomyopathy. Methods: We present the case of a patient with mitochondrial syndrome, consisting of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), whose symptoms were temporally related to statin therapy. Conclusion: Statins may provoke symptoms related to MELAS in susceptible individuals.

Neurology. 2006 Jun 13.
Endothelial dysfunction in MELAS improved by l-arginine supplementation.
Koga Y, Akita Y, Junko N, Yatsuga S, Povalko N, Fukiyama R, Ishii M, Matsuishi T.
Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.

The authors evaluated endothelial function in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) by flow-mediated vasodilation (FMD) and found a significant decrease vs controls. Two years of supplementation with oral l-arginine, a nitric oxide precursor, significantly improved endothelial function to control levels and was harmonized with the normalized plasma levels of l-arginine in patients. l-Arginine therapy improved endothelial dysfunction and showed promise in treating strokelike episodes in MELAS.

Neth J Med. 2006 Mar.
Overview on visceral manifestations of mitochondrial disorders.
Finsterer J.
Neurological Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.
[ Free full text ]

Mitochondriopathies (MCPs) that reach adult age not only manifest in the central and peripheral nervous systems, eyes, ears, and dermis, but also in visceral organs, such as endocrine organs, heart, liver, guts, kidneys and blood. Visceral manifestations occur as part of a multisystem involvement or rarely as single organ affection. Endocrinological abnormalities are found in the MELAS, MERRF , KSS , MID and DID MOAD syndromes. Cardiac involvement occurs in the MELAS, MERRF , KSS , CPEO, LHO N, NARP, and Leigh syndromes. Gastrointestinal manifestations are common in the MERRF , MNGI E, DID MOAD, and Leigh syndromes. Mitochondrial syndromes with renal manifestations are the KSS , Pearson, DID MOAD, and Leigh syndromes. The haematopoetic system is affected in the KSS , MERRF , and Leigh syndromes. In addition, visceral manifestations are found in many nonsyndromic MCPs. Although there is no causal therapy for MCPs, adequate symptomatic therapy, particularly of visceral manifestations, markedly improves quality of life and prognosis of these still often neglected or overlooked disorders.

CNS Drugs. 2006.
The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options.
Scaglia F, Northrop JL.
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

Mitochondrial encephalomyopathies are a multisystemic group of disorders that are characterised by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Among this group of disorders, the mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome is one of the most frequently occurring, maternally inherited mitochondrial disorders. As the name implies, stroke-like episodes are the defining feature of the MELAS syndrome, often occurring before the age of 15 years. The clinical course of this disorder is highly variable, ranging from asymptomatic, with normal early development, to progressive muscle weakness, lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, encephalopathy and premature death. This syndrome is associated with a number of point mutations in the mitochondrial DNA, with over 80% of the mutations occurring in the dihydrouridine loop of the mitochondrial transfer RNA(Leu(UUR)) [tRNA(Leu)((UUR))] gene. The pathophysiology of the disease is not completely understood; however, several different mechanisms are proposed to contribute to this disease. These include decreased aminoacylation of mitochondrial tRNA, resulting in decreased mitochondrial protein synthesis; changes in calcium homeostasis; and alterations in nitric oxide metabolism. Currently, no consensus criteria exist for treating the MELAS syndrome or mitochondrial dysfunction in other diseases. Many of the therapeutic strategies used have been adopted as the result of isolated case reports or limited clinical studies that have included a heterogeneous population of patients with the MELAS syndrome, other defects in oxidative phosphorylation or lactic acidosis due to disorders of pyruvate metabolism. Current approaches to the treatment of the MELAS syndrome are based on the use of antioxidants, respiratory chain substrates and cofactors in the form of vitamins; however, no consistent benefits have been observed with these treatments.

Neurology. 2005 Feb 22.
L-arginine improves the symptoms of strokelike episodes in MELAS.
Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, Fujimoto S, Matsuishi T.
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-Machi, Kurume City, Fukuoka, Japan.

Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered L-arginine intravenously at the acute phase or orally at the interictal phase. L-arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.

Pediatr Neurol. 2004 Nov.
Paralytic ileus in MELAS with phenotypic features of MNGIE.
Chang TM, Chi CS, Tsai CR, Lee HF, Li MC.
Department of Pediatric Neurology, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.

This report describes a child having the syndrome of overlapping phenotypic features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Mitochondrial DNA analysis revealed a point mutation at position A3243G, whereas activity of thymidine phosphorylase and its corresponding gene analysis were normal. The most striking feature of this case was paralysis of one segment of the terminal ileum observed on laparotomy. The electron microscopic findings of the resected ileum and colon by limited right hemicolectomy disclosed accumulation of numerous enlarged mitochondria with ill-defined cristae which were similar to mitochondria reported in three previous MELAS cases and one MNGIE case with intestinal dysmotility. We emphasize that the MELAS and MNGIE phenotypes overlapped in this case and that the mechanism of acute ileus in MELAS was associated with functional paralysis of the intestine.

J Intern Med. 2003 Mar.
Intestinal pseudo-obstruction and urinary retention: cardinal features of a mitochondrial DNA-related disease.
Garcia-Velasco A, Gomez-Escalonilla C, Guerra-Vales JM, Cabello A, Campos Y, Arenas J.
Department of Internal Medicine, Universitary Hospital 12 de Octubre, Madrid, Spain.

The syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystemic disorder associated in most of the patients with an A to G transition at nucleotide position 3243 in the transfer RNA (tRNA)Leu(UUR) (A3243G) of the mitochondrial DNA. This syndrome is characterized by the preponderant involvement of skeletal muscle and central nervous system, but urinary or gastrointestinal symptoms are seldom documented. Here we report an unusual case of a 52-year-old woman with a clinical phenotype characterized by encephalopathy, left hemiparesis, urinary retention and gastrointestinal pseudo-obstruction. She had the classical A3243G mitochondrial DNA point mutation of MELAS syndrome. We also present a clinically heterogeneous multigenerational pedigree with several affected members in the maternal lineage.

Dtsch Med Wochenschr. 2002 Mar 22.
Intestinal pseudoobstructions and gastric necrosis in mitochondrial myopathy. [Article in German]
Muehlenberg K, Fiedler A, Schaumann I, Muller-Felber W, Wiedmann KH.
Med. Klinik II, Gastroenterologie, Infektionskrankheiten, Rheumatologie/Immunologie, Krankenhaus Barmherzige Bruder Regensburg, Germany.

HISTORY AND CLINICAL FINDINGS: A 24-year-old female patient suffered for 4 months from recurrent abdominal pain, vomiting and diarrhea. Signs of an acute abdomen were the initial reason for admitting the patient to our hospital. The slim, pale patient had a complete bloated abdomen. Neurological status was normal. INVESTIGATIONS, TREATMENT AND COURSE: Radiographic examination showed a paralytic ileus with a megacolon. The recurrent abdominal symptoms were due to a covered perforation of the stomach. This was shrunken, scarred and had to be resected. Further intestinal pseudoobstructions were accompanied by substantial exsudations in the lungs, intestines and abdomen. At this time mutism like behavior patterns and an ophthalmoplegia appeared. Leukoencephalopathy in brain MRI scans and increased liquor-lactate suggested mitochondrial myopathy. DIAGNOSIS: The diagnosis of a mitochondrial myopathy was confirmed by increased liquor-lactate level, muscle biopsy with ragged-red fibers as well as abnormal mitochondrias and molecular-genetic investigations (mtDNA point mutation A3243G). Associations to MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MNGIE (mitochondrial neuro-gastrointestinal encephalomyopathy) syndrome are discussed. CONCLUSIONS: Unclear recurrent gastrointestinal symptoms even in the absence of neurological changes may reflect a mitochondrial disease. This applies especially to young patients with recurrent anorexia, vomiting and pseudoobstruction. In case of additional symptoms like ophthalmopathy, deafness, diabetes mellitus or signs of a MELAS syndrome the search for a mitochondrial system disorder is mandatory.

Acta Neuropathol (Berl). 2000 Dec.
Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar pathology.
Mori O, Yamazaki M, Ohaki Y, Arai Y, Oguro T, Shimizu H, Asano G.
Department of Pathology, Nippon Medical School, Tokyo, Japan.

A 67-year-old woman had frequent subacute ileus, hearing difficulty, muscle atrophy and stroke-like episodes. Computed tomography revealed multiple low-density areas, which did not correlate with the vascular supply, in the cerebral cortex. She had metabolic disturbance comprising lactic acidosis and elevated pyruvate level. Her skeletal muscle biopsy specimen showed ragged-red fibers, and mitochondrial DNA analysis revealed a point mutation at position 3243, findings consistent with MELAS. Examination of her small intestine revealed a necrotic zone and numerous abnormal large mitochondria in the smooth muscle cells, vascular media and endothelium, and intestinal ganglion cells. The cerebral cortex showed multiple microcystic necrotic foci in cerebral cortex. Cactus-like pathology resembling the changes associated with Menkes' kinky hair disease and torpedoes were observed in the cerebellar Purkinje cells. The intestinal dysmotility due to MELAS and cerebellar changes were presumed to be associated with a disturbance of copper metabolism.

J Pediatr Surg. 1998 Dec.
Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y.
Children's Research Hospital, Department of Pediatrics, Kyoto Prefectural University of Medicine, Japan.

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is an uncommon neuromuscular disorder caused by mitochondrial dysfunctions that result in headaches, seizures, and progressive dementia. The authors describe a clinical case study of gastrointestinal manifestations in a pedigree with MELAS, in which all three children, ages 11, 8, and 6, demonstrated acute onset of intestinal obstruction. They unexpectedly showed severe abdominal distension and vomiting. Their parents had no clinical manifestation. The first female sibling underwent an emergent laparotomy because she was diagnosed to have intestinal strangulation. She had postoperative complications caused by progressive lactic acidosis and died the next day. The second and third sisters had similar onsets of the disease and were treated with gastrointestinal decompression and intravenous administration of lactate-free fluid and coenzyme Q10. Genetic testing using blood samples showed an A-to-G point mutation at nucleotide position 3243 in the tRNALeu(UUR) region in the mitochondrial DNA. In MELAS children who demonstrate acute onset of gastrointestinal manifestations, a careful review of family history and an elevation of serum lactate and pyruvate levels may enable a differential diagnosis to be made of acute abdomen to avoid unnecessary surgical intervention.

Neth J Med. 1998 Jul.
Ileus in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes.
Hiel JA, Verrips A, Keyser A, Jansen TL, Wesseling P, de Coo R, Gabreels FJ.
Department of Neurology, St. Joseph Hospital, Veldhoven, Netherlands.

Patient: A 39-year-old woman with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) who developed paralytic ileus and died of irreversible shock. Methods: Abdominal X-ray, autopsy using light microscopy, electron microscopy and mitochondrial DNA analysis. Results: Paralytic ileus was diagnosed. Several hours after admission the patient died from irreversible shock. At autopsy, ultrastructural examination of the small intestine revealed abnormal accumulation of mitochondria in smooth muscle cells. DNA analysis of the intestinal tissue showed a tRNALeu(UUR) A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The amount of mutated mitochondrial DNA was markedly higher in the lamina muscularis than in the mucosa: 30% vs; 8%. Conclusions: Paralytic ileus may be due to mutated mitochondrial DNA which ultimately leads to smooth muscle dysfunction in the small intestine. Recognizing mitochondrial DNA abnormalities as a new etiopathogenetic factor of paralytic ileus may become more important in clinical medicine in the near future.

Acta Neuropathol (Berl). 1998 Jul.
Mitochondrial encephalomyopathy showing prominent microvacuolation and necrosis of intestinal smooth muscle cells: a case diagnosed by rectal biopsy.
Kuroiwa T, Kuwata T, Nakayama T, Takemura T, Sakuta M, Ichinose S, Goto Y, Okeda R.
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Japan.

A 40-year-old woman who developed intestinal dysmobility was found, at rectal biopsy, to have marked microvacuolation of mucosal muscle layer cells, which corresponded to increased accumulation of abnormal mitochondria. Skeletal muscle biopsy specimens showed ragged-red fibers, vessels strongly reactive for succinic dehydrogenase, and focal deficiency of cytochrome c oxidase. Autopsy performed at the age of 50 revealed prominent accumulation of abnormal mitochondria in the intestinal smooth muscle cells with a mottled distribution of focal necrosis, multiple small cerebral infarcts with diffuse neuronal loss, and rarefaction of the perivascular white matter. Mitochondrial DNA analysis showed a point mutation at position 3243. This case, showing features of both mitochondrial neurogastrointestinal encephalomyopathy and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), indicates that routine intestinal biopsy can detect mitochondrial encephalomyopathy with gastrointestinal involvement. The main intestinal changes were extensive accumulation of abnormal mitochondria in the leiomyocytes and scattered focal necrosis.

Diabetologia. 1994 Aug.
Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNA(LEU(UUR)) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS).
Suzuki S, Hinokio Y, Hirai S, Onoda M, Matsumoto M, Ohtomo M, Kawasaki H, Satoh Y, Akai H, Abe K, et al.
Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.

Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA(LEU(UUR)) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively.(

Jpn J Psychiatry Neurol. 1993 Sep.
MELAS without ragged red fibers or lactic acidosis diagnosed by mitochondrial DNA testing.
Ujike H, Wakagi T, Kohira I, Kuroda S, Otsuki S, Sato T.
Department of Neuropsychiatry, Okayama University Medical School, Japan.

A case of mitochondrial encephalomyopathy with lactic acidosis, a stroke-like episode (MELAS) without ragged red fiber, diagnosed by mitochondrial DNA testing, is reported. A 37-year-old woman experienced a sudden and recurrent headache with vomiting and stroke-like episodes. Brain CT and MRI showed multiple infarction in the temporal lobes, not corresponding to artery distribution. However, the plasma levels of lactate and pyruvate were normal, and showed no increased after aerobic exercise. Biopsied muscle showed no evidence of ragged red fibers and deficient activity of mitochondrial enzymes in the respiratory chain. The final diagnosis was made by mitochondrial DNA testing. A southern blot analysis after Apa I digestion revealed the A-to-G mutation in the tRNA(Leu(UUR)), which is specific to MELAS.

Endocr J. 1997 Dec.
A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction.
Joko T, Iwashige K, Hashimoto T, Ono Y, Kobayashi K, Sekiguchi N, Kuroki T, Yanase T, Takayanagi R, Umeda F, Nawata H.
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

A 45-year-old woman with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had muscular atrophy, severe cerebral and cerebellar atrophy, and cardiac hypertrophy. She also had diabetes mellitus treated with insulin, and sensorineural hearing loss. Ragged-red fibers were observed on muscle biopsy and an adenine to guanine transition mutation at position 3243 of her mitochondrial DNA was confirmed. Further investigations revealed that she also had hypothalamo-pituitary dysfunction. It appears that diabetes mellitus, hypothalamo-pituitary dysfunction, and the other abnormalities are all associated with mitochondrial dysfunction in this patient.

J Pediatr. 1994 Nov.
Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
Dougherty FE, Ernst SG, Aprille JR.
Division of Genetics and Metabolism, Children's Hospital of Boston, Massachusetts.

We report a clinically heterogeneous, multigenerational pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with a mutation at nucleotide 3243 in the mitochondrial DNA tRNA(Leu)(UUR) gene. Our findings suggest that the mutation at nucleotide 3243 is not always associated with the classic MELAS phenotype and that other symptoms (notably cardiac and gastrointestinal abnormalities) should raise the suspicion of a mitochondrial disorder.

Acta Pathol Jpn. 1992 Nov.
An autopsy case of mitochondrial encephalomyopathy (MELAS) with special reference to extra-neuromuscular abnormalities.
Ban S, Mori N, Saito K, Mizukami K, Suzuki T, Shiraishi H.
Institute of Pathological Anatomy, Hitachi General Hospital, Japan.

An autopsy case of a 37-year-old man with mitochondrial encephalomyopathy is reported. Ragged-red fibers and crystalline inclusions in mitochondria were revealed by biopsy of the striated muscle of the patient. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was diagnosed clinically. In addition to severe atrophy and degeneration of the generalized striated muscles and many foci of laminar necrosis of the cerebral cortex, the following abnormalities were observed: 1) hypertrophy of the myocardium, 2) fatty change of the liver, 3) focal sclerosis of the glomeruli and dilatation of the tubules of the kidneys, 4) hyalinous degeneration of the Langerhans' islands of the pancreas and 5) wavy change of the smooth muscle fibers of the muscularis propria of the gastrointestinal tract. We suggest that mitochondrial encephalomyopathy affects various organs and tissues, among which susceptibility of the muscular tissues - skeletal muscle, myocardium and smooth muscle - is high.

No To Hattatsu. 1991 Nov.
MELAS without ragged-red fibers: a case report. [Article in Japanese]
Mimaki N, Hasegawa H, Nonaka I.
Department of Pediatrics, South Kurashiki Hospital, Okayama.

A female patient who had clinical characteristics of MELAS but with no apparent muscle symptoms was reported. She was in good health until 12 years and 5 months of age when she began to have afebrile generalized tonic-clonic convulsions. Thereafter, she had repeated stroke-like episodes, including headache, vomiting, convulsions, hemiparesis and left ehemianopsia. She had neither muscle weakness, fatigability nor atrophy. Laboratory examinations disclosed elevated lactate and pyruvate levels in the serum and cerebrospinal fluids, transient focal low density areas on brain CT and right sensorineural deafness by audiometry. No ragged-red fibers (RRF) were found in the first biopsy at 13 years and 6 months of age, and two RRF-like fibers containing red granular materials in the subsarcolemnal regions in the second at 15 years and 3 months of age. A biochemical assay on the two biopsied muscles demonstrated normal enzyme activities in the mitochondrial electron transport system. She was diagnosed as having MELAS because of remarkable mitochondrial abnormalities in smooth muscle cells in the intramuscular arterioles which were clearly demonstrated by succinic dehydrogenase (SDH) stain and on electron microscopy. It was suggested that the stroke-like episodes in this patient were induced by a preferential damage to the mitochondria in the blood vessel walls. Thus, we conclude that a simple method of identifying the strongly SDH-reactive blood vessels (SSV) in frozen sections is critical in supporting or making diagnosis of MELAS.

No To Hattatsu. 1991 Jul.
Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS. [Article in Japanese]
Matsuzaki M, Izumi T, Ebato K, Suzuki H, Shishikura K, Osawa M, Fukuyama Y, Shimizu N.
Department of Pediatrics, Tokyo Women's Medical College.

A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, in which a pituitary growth hormone (GH) secretion deficiency of hypothalamic origin was revealed through neuro-endocrinological examinations, was described. The case was a 10-year-old girl, who had been suffering from generalized tonic seizures since age 5, four episodes of alternating hemiplegia since age 6, stunted growth since age 7, and simple partial motor seizures as well as gelastic seizures since age 8. Marked elevation of lactate and pyruvate in both serum and CSF, abundant ragged red fibers in biopsied muscle, and low density areas in the left occipital lobe and bilateral globus pallidus in addition to diffuse brain atrophy on CT scan and MRI of the head were demonstrated, although the activities of muscle enzymes complex I-IV were within normal ranges. Pituitary GH secretion was deficient under the loadings with insulin, L-DOPA, sleep, and a single growth hormone releasing factor (GRF) administration, but normal GH response was registered under the repetitive stimulation with GRF. Activities of other hormonal axes were normal. It is likely that short stature commonly observed in MELAS patients is due to hypothalamic dysfunction, which might be brought out by chronic ischemia and energy deficiency of the diencephalon based upon mitochondrial abnormality of that region. It is likely that gelastic seizure in this case is due to hypothalamic dysfunction.

Rinsho Shinkeigaku. 1991 Feb.
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) associated with hypothalamo-pituitary hypofunction - a case report. [Article in Japanese]
Ishii A, Watanabe S, Ohkoshi N, Mizusawa H, Kanazawa I.
Department of Neurology, University of Tsukuba.

A case of 25-year-old woman with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) was reported. She had short stature, episodic vomiting with headache, several episodes with homonymous hemianopsia, progressive intellectual decline, generalized convulsion, muscular atrophy, sensory disturbance on the left side of the body, and primary amenorrhea. Lactate, pyruvate and the lactate to pyruvate ratio were elevated in the serum and cerebrospinal fluid. Muscle biopsy revealed ragged-red fibers. On electron microscopy there were subsarcolemmal aggregations of abnormal mitochondria with proliferation of crista and inclusions. Activities of the respiratory chain enzymes of the muscle mitochondria were normal. She showed a failure of GH response to arginine and levodopa and delayed response of serum GH to growth hormone releasing factor (GRF). She also showed decreased gonadotropin levels and delayed response of the hormone to LH-RH. In this case, a dysfunction of the hypothalamo-pituitary axis may be related to the short stature and primary amenorrhea. It is suggested that the hypothalamo-pituitary hypofunction may be one of the characteristic features in MELAS.