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.     

Increased number of mitochondria in capillaries distributed in stroke‐like lesions of two patients with MELAS

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) using immunohistochemical staining with an anti‐mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42‐year‐old man with a disease duration of 53 days, and in case 2, the patient was a 62‐year‐old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke‐like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke‐like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.     

Heterogeneous phenotypic manifestations of maternally inherited deafness associated with the mitochondrial A3243G mutation. Case report

The A3243G mutation is one of the most frequent mutations of mitochondrial DNA. The phenotypic expression of the A3243G mutation is variable and causes a wide range of syndromic and non-syndromic clinical disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is the most frequent syndromic manifestation of the A3243G mutation. Stroke-like episodes seem to be the dominant feature of MELAS. We have investigated the case of a family with A3243G mutation, in which a dominant symptom in three generations was the maternally inherited hearing loss with absence of stroke-like episodes. Besides deafness, we found also other clinical features such as myopathy, neuropathy, migraine, ataxia, short stature, diabetes mellitus, and cardiomyopathy.     

Novel non‐sense GCH1 mutation in a South African family diagnosed with dopa‐responsive dystonia

Background: Dopa‐responsive dystonia (DRD), a movement disorder characterized by onset in early childhood and a dramatic response to low doses of levodopa, has been shown to be caused by a number of different mutations in the GCH1 gene. Methods: We identified a South African family which presented with DRD in three family members. Polymerase chain reaction (PCR) primers were designed to span all six exons of GCH1 and the PCR products were screened for pathogenic mutations using direct sequencing. Results: A novel non‐sense mutation (c.233delT; p.I78fsX79) was identified in the DRD patients, which would produce a markedly truncated protein of only 78 amino acids. This mutation was also present in a number of asymptomatic family members. Conclusions: A novel non‐sense mutation in the GCH1 gene can be associated with DRD and reduced penetrance in South African patients.     

MELAS型线粒体脑肌病的脑部MRI表现(附三例报道)

目的 总结分析MELAs型线粒体脑肌病的脑部MRI表现.方法 回顾性分析3例MELAS型线粒体脑肌病患者的临床资料和MRI表现.结果 MRI显示MELAS型线粒体脑肌病表现为以颞叶、顶、枕叶为主的皮层及皮层下白质病变,病变多呈双侧非对称性分布,部分患者以累及基底节为主要表现,T2WI和液体衰减翻转恢复序列对病变的显示有独特的作用,DWI、ADC图及增强扫描能够诊断及鉴别诊断线粒体脑肌病及卒中,MRS对其诊断可以起到辅助作用.结论 MELAS型线粒体脑肌病在MRI图像上具有特征性,MRI影像表现结合临床资料对本病多能作出正确的诊断.     

A new mutation of GCH1 in triplets family with dopa‐responsive dystonia

Background: Dopa‐responsive dystonia (DRD) is associated with mutations of the GCH1. We first report four female siblings with DRD from one family, including three monozygotic triplets patients clinically and genetically. Methods: We performed GCH1 analysis by direct sequencing of PCR product amplified with primers designed to cover the entire exons of GCH1 in those four patients and their mother. Results: In all four patients with DRD, a new frameshift mutation (c.729delG; p.A190fsX191) was identified in the exon 5 of GCH1. Conclusions: The frameshift mutation results in truncated GCH1 protein which is suspected to result in loss of function of the catalytic GTP‐cyclohydrol domain.     

Blepharospasm and limb dystonia caused by Mohr‐Tranebjaerg syndrome with a novel splice‐site mutation in the deafness/dystonia peptide gene

Mohr‐Tranebjaerg syndrome (MTS) is an X‐linked disorder characterized by childhood‐onset progressive deafness, dystonia, spasticity, mental deterioration, and blindness. It is due to mutations in the deafness/dystonia peptide (DDP1) gene. We describe a sporadic 42‐year‐old man with MTS presenting with postlingual deafness, adult‐onset progressive dystonia with marked arm tremor, mild spasticity of the legs, and visual disturbance due to a novel mutation (g to a transition at the invariant gt of the 5′ splice donor site of exon 1) in the DDP1 gene. This case, and a review of previously reported cases, highlights a variety of potential diagnostic pitfalls in this condition. © 2007 Movement Disorder Society     

A novel mutation of the ε‐sarcoglycan gene in a Chinese family with myoclonus‐dystonia syndrome

In a Chinese myoclonus‐dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the ε‐sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real‐time PCR, suggesting that the nonsense mutation might interference with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family. © 2008 Movement Disorder Society     

GCH1 mutation and clinical study of Chinese patients with dopa‐responsive dystonia

Dopa‐responsive dystonia (DRD) is typically caused by heterozygous mutations in GTP cyclohydrolase 1 gene (GCH1). Our aim was to investigate the clinical and genetic features of Chinese DRD patients. We analyzed a cohort of Chinese DRD patients' clinical data. Mutation of the GCH1 gene was screened by direct sequencing. Additionally, multiplex ligation‐dependent probe amplification (MLPA) assay targeting the GCH1 and the TH gene to evaluate large exon deletion or duplicate mutation of the genes were performed in point mutation‐negative patients. Ten sporadic DRD patients and two pedigrees including six patients were included in the study. The onset age ranged from 3 to 15 years old. All patients initially presented with walking problems due to lower limb dystonia. The delay between onset and diagnosis ranged from 1 to 42 years old. The symptoms were completely or near‐completely abolished with low dose levodopa treatment (dosages ranged from 25 mg to 400 mg/day). Direct sequencing in 14 patients found two known mutations (Gly203Arg in exon 5 in four unrelated patients and Met102Lys in exon 1 in one patient) and one new mutation (Thr186Ile mutation in exon 5 in two unrelated pedigrees). A heterozygous exon 2 deletion in the GCH1 gene was found in one of three point mutation‐negative patients by MLPA analysis. Our clinical findings in DRD patients were consistent with other studies. GCH1 gene mutations were quite common in Chinese patients. MPLA should be performed in routine deletion analysis of GCH1 in point mutation‐negative DRD patients. © 2010 Movement Disorder Society     

Clinicopathological findings of a mitochondrial encephalopathy,lactic acidosis,and stroke‐like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT‐ND1

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT‐ND1. A 41‐year‐old woman had experienced multiple stroke‐like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid‐attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase‐reactive blood vessels. L‐arginine therapy improved her consciousness and prevented further stroke‐like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct‐like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L‐arginine treatment.     

Epileptic encephalopathy with features of rapid‐onset dystonia Parkinsonism and alternating hemiplegia of childhood: a novel combination phenotype associated with ATP1A3 mutation

Mutations in ATP1A3 have been found to cause rapid‐onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four‐year, nine‐month‐old boy with episodes of frequent and recurrent status epilepticus, who first began having generalized tonic‐clonic seizures at four months of age. Development was normal until the age of four months, and markedly slowed down after the onset of seizures. Between the age of seven months and two and a half years, the patient had recurrent attacks of unilateral and bilateral hemiplegia. At the age of 21 months, after a febrile illness with status epilepticus, he regressed and developed continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms. Extensive neurological and genetic workup revealed a de novo p.V589F ATP1A3 mutation (NM_152296.5:c.1765G>T, NC_000019.9:g.42482344C>A). This is a novel mutation associated with a novel phenotype that shares features with epileptic encephalopathy, alternating hemiplegia of childhood, and rapid‐onset dystonia Parkinsonism.     

Novel GCH1 mutation in a Brazilian family with dopa‐responsive dystonia

Dopa responsive Dystonia (DRD) was first described in 1971 and typically begins at childhood with gait dysfunction caused by foot dystonia progressing to affect other extremities. There is marked diurnal fluctuation and sustained improvement of symptoms with low dose levodopa therapy. Heterozygous mutation of the gene GCH1 has been shown to cause DRD. We studied GCH1 in nine patients with DRD from six families of Federal University of Minas Gerais Movement Disorders Clinic. We identified three mutations; two affected siblings carried a novel T209P mutation and two siblings from another family were compound heterozygous carriers of Met211Val and Lys224Arg mutations. To our knowledge this is the first report of GCH1 mutations underlying DRD in patients from Brazil. © 2007 Movement Disorder Society     

Neonatal tremor episodes and hyperekplexia‐like presentation at onset in a child with SCN8A developmental and epileptic encephalopathy

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four‐year‐old boy presenting with severe non‐epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non‐epileptic episodes of severe tremor and hyperekplexia‐like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com ].     

Wide expressivity variation and high but no gender‐related penetrance in two dopa‐responsive dystonia families with a novel GCH‐I mutation

We describe the clinical and molecular correlates in two Italian families with dopa‐responsive dystonia (DRD) and the same novel mutation of GTP‐cyclohydrolase I (GCH‐I) gene. Thirty‐five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5‐base pair insertion at codon 242 within exon 6 of GTP‐cyclohydrolase I (GCH‐I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH‐I gene mutation penetrance. © 2004 Movement Disorder Society     

A novel mutation in the GTP cyclohydrolase I gene associated with a broad range of clinical presentations in a family with autosomal dominant dopa-responsive dystonia

We examined a large family of Ashkenazi Jewish origin with autosomal dominant dopa-responsive dystonia (DRD). Mutation analysis of the GTP cyclohydrolase I gene revealed in affected members a novel point mutation (a C/A change in exon 1) resulting in a threonine-to-lysine substitution at residue 94. The mutation was characterized by variable expressivity and was associated with either a 'classical' DRD phenotype or various atypical phenotypes, such as subtle transitory equinovarus postures of the feet or isolated hand tremor. This observation demonstrates the significance of the molecular testing in establishing the clinical diagnosis of DRD. Copyright Lippincott Williams & Wilkins     

Heterogeneity of presentation and outcome in the Irish rapid‐onset dystonia–Parkinsonism kindred

The authors report a 7‐year follow‐up video study and molecular data on the Irish rapid‐onset dystonia–Parkinsonism kindred. All affected patients tested had a missense mutation in the Na⁺/K⁺ ‐ATPase α3 subunit (ATP1A3), twice previously identified, suggestive of a mutation hotspot. Clinical presentation, progression, and outcome in this kindred is varied. Some patients remain stable over many years, others worsen, have a fluctuating course, or improve over time. To date there have been no effective treatments for this disorder, although Na⁺/K⁺ ATPase may be a future therapeutic target. The broad phenotypic spectrum of RDP described in the text and detailed in the video, should be considered when evaluating patients with dystonia. © 2007 Movement Disorder Society     

Protection against stroke with glucagon‐like peptide 1 receptor agonists: a systematic review and meta‐analysis

In experimental stroke models pretreatment with the newly introduced antidiabetic agents, glucagon‐like peptide 1 receptor (GLP‐1R) agonists, has been shown to exert neuroprotective effects. Published evidence with regard to the effect of treatment with GLP‐1R agonists on the risk of stroke was evaluated. Data from prospective randomized placebo‐controlled trials up to October 2018 involving GLP‐1R agonists which reported cardiovascular outcomes as primary end‐points of efficacy and/or safety were meta‐analysed. Five eligible multicentre randomized placebo‐controlled trials (ELIXA, LEADER, SUSTAIN, EXSCEL and HARMONY) were included. The pooled analysis (n = 42 358) showed a significant reduction by 13% in the risk of total stroke from treatment with GLP‐1R agonists versus placebo (risk ratio 0.87, 95% confidence interval 0.78–0.98, P = 0.021) with no significant heterogeneity between trials (Q = 4.094, P = 0.393, I² = 2.307%). When only fatal stroke was included (this applied for the ELIXA, LEADER, EXSCEL and HARMONY trials), active treatment was associated with a non‐significant reduction by 16% compared with placebo (risk ratio 0.84, 95% confidence interval 0.60–1.17, P = 0.29). The findings of this meta‐analysis support the evidence from earlier experimental studies calling attention to potential ‘stroke protective’ effects from treatment with GLP‐1R.     

Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene

We report a novel nonsense mitochondrial cytochrome b mutation (G15170A) in a 40-year-old woman with progressive exercise intolerance and lactic acidosis. Muscle biopsy showed several cytochrome c oxidase-positive ragged-red fibers, and reduced activities of respiratory chain complexes I and III. This mutation, resulting in the loss of 228 amino acids of the protein, was very abundant in the patient's muscle, but undetectable in lymphocytes and fibroblasts. Clinical and laboratory data indicate that this defect is the primary cause of the disease, thus adding a new mutation in the cytochrome b gene among the growing number of patients with exercise intolerance and lactic acidosis.