Late-onset Leigh syndrome with myoclonic epilepsy with ragged-red fibers

We report the case of a boy with myoclonic epilepsy with ragged-red fibers (MERRF) who had astatic seizures since 2 years of age and later developed ataxia, absence seizures, and myoclonus. Almost homoplasmic A8344G mutation of mitochondrial DNA (m.8344A>G mutation) was detected in lymphocytes. He developed late-onset Leigh syndrome (LS) when he contracted pneumonia at 6 years. He developed bulbar palsy and deep coma. MRI demonstrated lesions in the brainstem, basal ganglia, and cerebral cortex. Three similar cases have been reported; two carried the almost-homoplasmic m.8344A>G mutation in muscle tissue. These suggested that almost homoplastic m.8344A>G mutation developed clinical phenotype of MERRF in the early stage and late-onset Leigh syndrome in the late course of the disease.     

Unusual exocrine complication of pancreatitis in mitochondrial disease

No association between mitochondrial disease and pancreatitis has yet been established, although diabetes mellitus and diseases caused by exocrine insufficiency, such as Pearson syndrome, are the commonest pancreatic complications of mitochondrial diseases. Here, we report 2 cases of mitochondrial disease complicated by pancreatitis as an unusual pancreatic exocrine manifestation. One patient was a 10-year-old girl with mild retardation of psychomotor development who had experienced recurrent pancreatitis since the age of 4 years. Chronic progressive external ophthalmoplegia (CPEO) due to m.8344A>G mutation was diagnosed when the patient was 10 years old. The other patient was a 28-year-old woman who was diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to m.3243A>G mutation at 10 years of age. She had experienced regular recurrent vomiting since the age of 16 and suffered an episode of critical pancreatitis at 23 years. In both cases, no possible etiological, morphological, or genetic factors for pancreatitis were identified, including anomalous pancreaticobiliary duct. A combination therapy of the standard treatment for chronic pancreatitis and supportive therapy for mitochondrial energy production may be beneficial to prevent the recurrence of acute pancreatitis complicating mitochondrial diseases. The pathophysiological mechanism of pancreatitis in mitochondrial disease has not been adequately established; however, our observations suggest that pancreatitis should be included in the list of pancreatic complications of mitochondrial disease.     

Association of the MELAS m.3243A>G mutation with myositis and the superiority of urine over muscle,blood and hair for mutation detection

A patient with a known family history of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) due to the MT-TL1 m.3243A>G mutation presented with mild myalgia and very minor upper limb proximal muscle weakness. Muscle histology revealed low levels of cytochrome oxidase-negative fibres and non-specific myositis. Using the last “hot cycle” polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), the MELAS MT-TL1 m.3243A>G mutation was only detected in urine, and not in hair, blood or skeletal muscle. This report highlights the need to screen various tissues to achieve an accurate mitochondrial genetic diagnosis and suggests the likelihood of myositis arising secondary to the MELAS MT-TL1 m.3243A>G mutation.     

Neuroimaging characteristics in mitochondrial encephalopathies associated with the m.3243A>G MTTL1 mutation

Stroke-like lesions (SLL) are common radiological findings in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (SLE; MELAS) harboring the m.3243A>G MTTL1 mutation. Imaging patterns in the m.3243A>G mutation carriers with encephalopathies lacking SLE have not been systematically examined to date. The aim of this study was to analyze brain imaging findings in encephalopathies associated with the m.3243A>G mutation irrespective of the presence or absence of SLE. Brain MRI and cranial CT scans from 11 m.3243A>G mutation carriers with encephalopathies were analyzed by two neuroradiologists in consensus. We evaluated stroke-like lesions (SLL), deep grey matter (DGM) changes on T1- and T2-weighted MR images, calcification on CT, brain atrophy, and white matter (WM) changes. SLL were present in all patients showing the full MELAS phenotype with SLE (4/11). Seven patients did not show SLE. DGM changes with T1 hyperintensity and T2 hypointensity were a distinctive finding in most patients (7/11) and present in the majority of m.3243A>G mutation carriers lacking SLE (5/7). DGM changes were also seen in half of our MELAS patients with SLL (2/4), though less pronounced. Brain atrophy was a prominent finding in general and accentuated in the cerebellum. In contrast, WM changes were rather mild and more prevalent and pronounced in MELAS. Our data stress that the distinction between MELAS with SLE and m.3243A>G mutation carriers lacking SLE is rather artificial. In clinical practice, mitochondrial disorders associated with the m.3243A>G mutation should be taken into consideration in encephalopathies with DGM changes, even when SLE and SLL are lacking.     

Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation

We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation.     

Distal weakness with respiratory insufficiency caused by the m.8344A > G “MERRF” mutation

The m.8344A > G mutation in the mt-tRNA^Lys gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A > G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A > G ‘MERRF’ mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A > G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A > G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative.     

Mutism and acute behavioral disorders revealing MELAS syndrome

Introduction

MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a rare genetic mitochondrial disease which can cause cerebral (cerebrovascular accident, migraine, mental deterioration..), sensorial (bilateral symmetrical deafness) and peripheral (muscular involvement, neuropathy) disorders potentially associated with diabetes, renal or cardiac disorders, or growth retardation. Eighty percent of the patients have the 3243 A > G mutation in the leucine RNA transfer gene. Clinical manifestations leading to discovery of the mutation can be extremely varied, affecting patients of different age groups.

Clinical case

We report the case of a 49-year-old man who presented acute fits of confusion followed by mutism and praxic disorders. History taking revealed recently diagnosed type 2 diabetes, axonal neuropathy, and bilateral symmetrical deafness requiring hearing aids. The initial MRI showed FLAIR sequences with bi-parietal abnormalities, no signs of recent stroke on the DW/B10000 sequences, and basal ganglia calcifications. Blood tests and morphological findings ruled out a vascular origin. Search for lactic acidosis remained constantly negative in blood samples despite positive cerebrospinal fluid samples (N × 3). The 3243 A > G mitochondrial DNA mutation was identified. The neuropsychological evaluation revealed a serious dysexecutive syndrome with a major impact on the patient's self sufficiency.

Conclusion

Neurocognitive disorders are not common in MELAS syndrome. Brain MRI results and the presence of extra-neurological signs can be helpful for diagnosis.     

A boy with muscle weakness, hypercarbia, and the mitochondrial DNA A3243G mutation

The point mutation in the mitochondrial genome tRNA(Leu_ (A3243G) is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). We report a boy presenting with respiratory compromise and hypercarbia owing to severe muscle weakness. Historically, he demonstrated idiopathic growth hormone deficiency, retarded bone age, and exercise avoidance. Owing to severe respiratory compromise out of proportion to expected recovery, a metabolic work-up was performed. Muscle biopsy demonstrated abnormal mitochondria structure and heteroplasmic A3243G mutation. Idiopathic growth hormone deficiency and retarded bone age have not been previously reported in MELAS, and these findings delayed testing for mitochondrial disease. This case demonstrates that isolated muscle weakness in the context of other organ system abnormalities should make the investigator consider MELAS. (J Child Neurol 2006;21:77-79).     

MELAS phenotype associated with m.3302A>G mutation in mitochondrial tRNA gene

The m.3302A>G mutation in the mitochondrial tRNA^Leu(UUR) gene has been identified in only 12 patients from 6 families, all manifesting adult-onset slowly progressive myopathy with minor central nervous system involvement. An 11-year-old boy presented with progressive proximal-dominant muscle weakness from age 7 years. At age 10, he developed recurrent stroke-like episodes. Mitochondrial myopathy, encephalopathy, lactic acidosis, plus stroke-like episodes (MELAS) was diagnosed by clinical symptoms and muscle biopsy findings. Mitochondrial gene analysis revealed a heteroplasmic m.3302A>G mutation. Histological examination showed strongly SDH reactive blood vessels (SSVs), not present in previous cases with myopathies due to the m.3302A>G mutation. These findings broaden the phenotypic spectrum of this mutation.     

The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender?

The m.3243A>G “MELAS” (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) mutation is one of the most common point mutations of the mitochondrial DNA, but its phenotypic variability is incompletely understood. The aim of this study was to revise the phenotypic spectrum associated with the mitochondrial m.3243A>G mutation in 126 Italian carriers of the mutation, by a retrospective, database-based study (“Nation-wide Italian Collaborative Network of Mitochondrial Diseases”). Our results confirmed the high clinical heterogeneity of the m.3243A>G mutation. Hearing loss and diabetes were the most frequent clinical features, followed by stroke-like episodes. “MIDD” (maternally-inherited diabetes and deafness) and “PEO” (progressive external ophthalmoplegia) are nosographic terms without any real prognostic value, because these patients may be even more prone to the development of multisystem complications such as stroke-like episodes and heart involvement. The “MELAS” acronym is convincing and useful to denote patients with histological, biochemical and/or molecular evidence of mitochondrial disease who experience stroke-like episodes. Of note, we observed for the first time that male gender could represent a risk factor for the development of stroke-like episodes in Italian m.3243A>G carriers. Gender effect is not a new concept in mitochondrial medicine, but it has never been observed in MELAS. A better elucidation of the complex network linking mitochondrial dysfunction, apoptosis, estrogen effects and stroke-like episodes may hold therapeutic promises.     

The pathogenic m.3243A>T mitochondrial DNA mutation is associated with a variable neurological phenotype

The m.3243A>G point mutation in the mitochondrial tRNA^Leu(UUR) (MTTL1) gene is a common cause of mitochondrial DNA disease and is associated with a variety of clinical presentations. A different mutation occurring at the same site – an m.3243A>T transversion – is less prevalent, but has previously been observed in two patients with encephalopathy and lactic acidosis. We report the investigations of a further two patients with the m.3243A>T mutation who presented with either a chronic progressive external ophthalmoplegia (CPEO) phenotype or sensorineural hearing loss, with single fibre mutation studies confirming segregation of the m.3243A>T mutation with COX deficiency.     

A novel tRNA(Val) mitochondrial DNA mutation causing MELAS

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common mitochondrial disease due to mitochondrial DNA (mtDNA) mutations. At least 15 distinct mtDNA mutations have been associated with MELAS, and about 80% of the cases are caused by the A3243G tRNA(Leu(UUR)) gene mutation. We report here a novel tRNA(Val) mutation in a 37-year-old woman with manifestations of MELAS, and compare her clinicopathological phenotype with other rare cases associated tRNA(Val) mutations.     

Clinical features of A3243G mitochondrial tRNA mutation

Mitochondrial cytopathy is a heterogeneous group of disorders with a wide range of clinical features. To evaluate the incidence and clinical heterogeneity of A3243G mitochondrial tRNA mutation in the Korean population, we evaluated patients who were clinically suggestive of having mitochondrial encephalomyopathy. Eighty-five patients were included in this study. All showed clinical features of mitochondrial encephalomyopathy and had three or more of the following clinical manifestations: (1) psychomotor regression, (2) hyperlacticacidemia, (3) recurrent stoke-like episodes, (4) idiopathic cardiomyopathy, (5) sensoryneural hearing loss, (6) diabetes mellitus, (7) myopathy, (8) renal disease and (9) relatives with known mitochondrial disease. The patients were clinically classified as MELAS, MERRF, Leigh syndrome, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia and uncertain. Of the 85 patients, 19 had the A3243G mutation (22.3%). Thirty-one patients showed typical clinical characteristics of MELAS. Fourteen of those 31 patients had A3243G mutation (45.1%). Four patients harboring A3243G mutations showed atypical and heterogeneous clinical features, unlike MELAS. This study revealed the frequent occurrence of A3243G mutation in Korean patients with mitochondrial disorders and their clinical features can be heterogeneous. It will be helpful to screen the presence of A3243G mutation for the genetic diagnosis of mitochondrial encephalomyopathy in Korea.     

线粒体基因G13513A突变导致的线粒体脑肌病六例临床表型分析

目的 报告6例mtDNA G13513A点突变引起的线粒体脑肌病患者的临床、影像学特点,总结mtDNA G13513A突变所致的线粒体病的临床表型.方法 对35例mtDNA常见突变(包括大片段缺失及A3243G、T3271C、A8344G、T8993G/C点突变)检查为阴性的线粒体脑肌病患者,用线粒体DNA全长测序和(或)聚合酶链反应-限制性片段长度多态法检测mtDNA G13513A点突变,分析阳性患者的临床特点,复习文献报道的mtDNA G13513A所致线粒体病的病例.结果 35例患者中有6例存在mtDNA G13513A突变.该6例患者均出现偏盲、轻偏瘫或偏身感觉障碍等卒中样发作表现,其中3例成人发病者以卒中样发作为主要症状,伴随癫痫、头痛、身材矮小、神经性耳聋等,头颅MRI显示以顶-枕-颢叶受累为主的大片病灶,符合成人型线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)的临床和影像学特点;3例青少年发病者除卒中样发作外,还有构音障碍、共济失调、眼外肌瘫痪等脑干受累的症状,MRI检查可见枕-颞叶大脑皮质非对称性病灶,以及双侧基底节和脑干的对称性病灶,符合青少年型MELAS-Leigh叠加综合征的临床和影像学特点.肌肉病理检查在5例患者发现不整红边纤维.经复习文献,发现mtDNA G13513A突变患者还存在婴幼儿型Leigh或Leigh样综合征表型.结论 mtDNA G13513A点突变是线粒体脑肌病较常见的致病性突变,主要导致Leigh综合征、MELAS-Leigh叠加综合征或MELAS综合征,其临床表型具有年龄依赖性.

Abstract：

Objective To report 6 Chinese patients with mitochondrial encephalomyopathy caused by mitochondrial DNA(mtDNA)G13513A mutation and discuss the mitochondrial phenotype associated with this mutation based on the data of our patient series as well as the reports by others.Methods Direct sequencing of polymerase chain reaction(PCR)products or PCR-RFLP analysis Was performed to screen mtDNA G13513A mutation in 35 cases with mitoehondrial encephalomyopathy.who carried no mtDNA common mutations(1arge 8eale deletion,A3243G,T3271 C,A8344G,or T8993G/C).The clinical features,MRI changes were retrospectively collected and analyzed.Published studies of all patients with mtDNA G13513A mutation were also reviewed.Results Six patients were identified carrying mtDNA G13513A mutation.All patients presented stroke-like episodes with hemianopsia.hemiparesis or hemiparesthesia.Three adult patients presented clinical and radiological features of adult-onset mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),including stroke-like episodes,epilepsy,headache,short stature,sensorineural deafness,multifocal lesions on parietal,occipital and temporal lobes on cranial MRI scans.Three iuvenile.onset patients presented the clinical and brain MRI features of MELAS-Leigh syndrome(LS)overlap syndrome.In addition to the stroke-like episodes,they also showed brain stem lesions with dysarthria,ataxia,and ophthalmopJegia. Brain MRI revealed asymmetrical lesions in the cortex of the oecipital and temporal lobes,as well as symmetrical lesions in the bilateral basal ganglia and brainstem.Muslce biopsy showed ragged redfibem in 5 patients.The infant-onset LS or Leigh-like syndrome with mtDNA G135 13A was described in the English literature.Conclusions mtDNA G13513A mutation is a common pathogenic mutmion for mitochondrial encephalomyopathy,which can result in Leigh syndrome,MELAS-LS overlap syndrome and adult MELAS.The onset of various phenotypes is relatively age-dependent.     

Autopsied case with MERRF/MELAS overlap syndrome accompanied by stroke‐like episodes localized to the precentral gyrus

We present an autopsied case with A8344G‐mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes (MELAS) overlap syndrome accompanied by stroke‐like episodes localized to the precentral gyrus. A 16‐year‐old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho‐logically, multifocal laminar necrosis, which is responsible for stroke‐like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti‐mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)‐reactive blood vessels were also noted. Stroke‐like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke‐like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G‐mutated MERRF/MELAS overlap syndrome.     

Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA<Superscript>Val</Superscript> causing MNGIE-like gastrointestinal dysmotility and cachexia

While mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is typically associated with mutations in the nuclear gene encoding for thymidine phosphorylase (ECGF1, TYMP), a similar clinical phenotype was described in patients carrying mutations in the nuclear-encoded polymerase gamma (POLG1) as well as a few mitochondrial tRNA genes. Here we report a novel mutation in the mitochondrial tRNA^Val (MTTV) gene in a girl presenting with clinical symptoms of MNGIE-like gastrointestinal dysmotility and cachexia. Clinical, histological, biochemical and single cell investigations were performed. The heteroplasmic m.1630A>G mutation was detected in the mitochondrial tRNA^Val (MTTV) gene in the patient’s muscle, blood leukocytes and myoblasts, as well as in blood DNA of the unaffected mother. We provide clinical, biochemical, histological, and molecular genetic evidence on the single cell level for the pathogenicity of this mutation. Our finding adds to the genetic heterogeneity of MNGIE-like gastrointestinal symptoms and highlights the importance of a thorough genetic workup in case of suspected mitochondrial disease.     

Transition from Leigh syndrome to MELAS syndrome in a patient with heteroplasmic MT-ND3 m.10158T>C

An m.10158T>C mutation in MT-ND3, encoding a subunit of respiratory complex I, causes early-onset Leigh syndrome (LS), mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) syndrome, and LS and MELAS overlapping syndrome, presumably dependent on the ratio of heteroplasmy. Herein, we report a 4-year-old girl with heteroplasmic m.10158T>C mutation, showing an evolving age-dependent phenotype from LS to MELAS syndromes. She showed mild developmental delay during infancy, which was associated with magnetic resonance imaging lesions in the brain stem and basal ganglia. At the age of 4 years, she developed rapid neurological deterioration and intractable seizures, which was associated with recurrent multiple cerebral lesions as well as basal ganglia lesions. Her cerebral lesions were located predominantly in white matter and appeared at multiple areas simultaneously, unique characteristics that are distinct from typical MELAS. Two patients with LS-MELAS overlapping syndrome with m.10158T>C have been previously reported, however, this is the first patient with m.10158T>C showing significant age-dependent changes in clinical features and neuro-images, implying an age-dependent role of complex I in the developing brain.     

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A?>?G in the gene MT-TK, which encodes transfer RNA^Lysine, affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q₁₀ (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease.     

The m.3244G>A mutation in mtDNA is another cause of progressive external ophthalmoplegia

We sequenced all mitochondrial tRNA genes in a 61-year-old man with chronic progressive external ophthalmoplegia and mitochondrial myopathy but without mtDNA rearrangements, and identified a heteroplasmic m.3244G>A mutation in the tRNA^Leu(UUR) gene. This mutation had been previously associated with the MELAS phenotype, but not described in any detail.The mutation load in muscle was 84% and COX-negative fibers harbored greater levels of mutant genomes than COX-positive fibers. The m.3244G>A mutation affects a highly conserved nucleotide in the dihydrouridine loop and has been associated with a wobble modification deficiency of the mutant tRNA.     

A novel mutation in the mitochondrial tRNA for tryptophan causing a late‐onset mitochondrial encephalomyopathy

Sanaker PS, Nakkestad HL, Downham E, Bindoff LA. A novel mutation in the mitochondrial tRNA for tryptophan causing a late‐onset mitochondrial encephalomyopathy.
Acta Neurol Scand: 2010: 121: 109–113.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Mitochondrial DNA (mtDNA) mutations are increasingly being recognized as causes of late‐onset disease. We report a patient with a late‐onset mitochondrial encephalomyopathy caused by a novel G > C transition in mtDNA at position 5556 in the gene encoding the tRNA for tryptophan (MTTW). Aims – To investigate the cause of disease and assess the pathogenicity of this new mutation. Methods – Clinical, histopathological and gene sequencing studies. Quantification of the mutation was performed in different tissues from the patient and two relatives and in single muscle fibres. Results – The mutation was heteroplasmic, segregated in biochemically affected muscle fibres and was absent in blood. The level of mutation in skeletal muscle was higher than in brain, although the brain was clinically the most affected tissue. Discussion – The 5556G > C mutation appears sporadic. It was not found in any of the family members tested, although some of them manifested disorders that can be associated with mtDNA disease. In addition to reporting the eighth mutation in MTTW, our case illustrates the challenges posed when assigning pathogenicity to mtDNA mutations.