Correlation between clinical and molecular features in two MELAS families.

We describe the clinical, morphological, biochemical presentation in two MELAS families, and correlate it with the distribution and proportion of mitochondrial DNA carrying the A to G transition at nt 3243. Family A was characterized by late onset MELAS in two members, CPEO in one, and mild CNS involvement in another. 20-61% of mtDNA of affected and unaffected individuals was mutated in muscle, 2-18% in blood. There was no obvious correlation between clinical picture and proportion of mutated mtDNA. In family B full MELAS syndrome appeared only in the third generation, but the mutation was also detected in muscle of asymptomatic individuals of the first and second generation. The proportion of mutated mtDNA in blood, and to a lesser extent in muscle, correlated with the severity of the clinical presentation. The MELAS mutation is consistently detected in all asymptomatic maternal relatives of MELAS patients. We conclude that different clinical presentations of mitochondrial encephalomyopathy may coexist in the same family, and correlation between clinical severity and molecular abnormality is not always recognizable. Presence of the MELAS mutation in muscle and blood is a necessary but not sufficient condition for the expression of the typical MELAS phenotype.     

MELAS syndrome: correlation between clinical features and molecular genetic analysis

The clinical manifestations and mitochondrial DNA (mtDNA) mutations in a Taiwanese family with a female proband exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome are reported. Clinically, the proband had a stroke-like episode with right hemiparesis, hemianopsia and mental dysfunction as well as short stature, hearing impairments, and elevated lactate levels. Brain magnetic resonance images showed multiple increased signal intensities over the left frontal, parietal and temporal areas. There were no ragged-red fibers, but paracrystalline inclusion bodies were shown in the muscle biopsies under electron microscopic examination. A deficiency of NADH-CoQ reductase was also found in biochemical studies of the muscles. The family survey revealed no abnormal findings except for headache and episodic vomiting in her mother. The molecular analysis of mtDNA disclosed a mutation from A to G at the nucleotide pair 3243 of the mitochondrial transfer RNA^Leu gene in the blood, hair follicles and/or muscle of the maternal relatives. A characteristic finding of the MELAS family is variation of percentage of mutated mtDNA in various tissues and individuals. However, a higher proportion of mutated mtDNA was noted in the proband than that in the asymptomatic or oligosymptomatic family members. From the data, the variable clinical phenotypes in this MELAS family can be explained at least partly, by the different proportions of mutant mtDNA in the target tissues of the profound and maternal relatives.     

Dystonia: clinical features,genetics, and treatment

PURPOSE OF REVIEW: The present review covers recent advances in dystonia research related to dystonia genetics and treatment. These have led to the discovery of novel dystonia genes and loci, to changing classification schemes, and to the introduction of improved and new treatment options. RECENT FINDINGS: Currently 13 different forms of dystonia can be distinguished on a genetic basis (dystonia types 1-13). Recently, a novel gene locus (DYT13) was detected in a family with segmental dystonia, and the gene causing myoclonus-dystonia was identified (SGCE). Furthermore, a novel mutation in the DYT1 gene is associated with a myoclonus-dystonia phenotype. Regarding dystonia treatment, patients refractory to botulinum toxin type A can now be treated with botulinum toxin type B. Selective peripheral denervation remains an effective form of treatment for patients with secondary, but probably not with primary botulinum toxin treatment failure. Finally, a renaissance of functional surgical ablative procedures has taken place, with high frequency deep brain stimulation being introduced in dystonia treatment. Bilateral pallidotomy or pallidal stimulation may provide major benefit especially in patients with generalized, disabling dystonia with the most dramatic improvements in dystonia type 1 patients. Neurostimulation may also be effective in primary segmental axial dystonia, myoclonus-dystonia, and tardive dystonia. SUMMARY: The recent mapping of additional dystonia gene loci, the identification of novel dystonia genes, and the characterization of proteins encoded by these genes have enhanced our understanding of various forms and aspects of the dystonias and have opened up new avenues for research. Treatment options include both medical and surgical therapies, with deep brain simulation being the most recent development.     

Parkinson's disease: clinical features, epidemiology and genetics

Genetic and epidemiological studies are critical to understanding the etiology of Parkinson's Disease (PD), and may lead to rational treatments for the disease. This article reviews the clinical features, epidemiology and genetics of PD, with emphasis on insights from recent genetic and epidemiological studies.     

MELAS型线粒体脑肌病的临床病理和基因研究

对８例ＭＥＬＡＳ型线粒体脑肌病进行临床病理研究，其中６例为家族性分别来自两个家系。２例为散发性。全组男７例，女１例，年龄１６～２２岁。其中一家系两代人４例，三兄弟均在１２～１４岁发病，１７～２０岁死亡，其姐之子１０岁发病。另一家系兄妹二人分别于２２岁和１４岁发病。临床症状以抽搐为主的癫痫样发作和卒中样发作、肢体瘫痪或轻偏瘫、缓解和反复发作、逐渐智力减退、同侧性偏盲和神经性聋等。４例最终因营养差衰竭死亡。其中１例尸检，１例脑活检，病理所见为大脑额、顶、颞、枕叶皮层灰质多发性局灶性、囊状层性海绵样改变，神经细胞变性、减少和脱失，胶质增生和血管增多。皮层病变相应区白质神经纤维亦减少脱失，双侧苍白球钙化外，其它深部白质、脑干、小脑和脊髓均未见明显病变。头颅ＣＴ示苍白球钙化，ＭＲＩ示半球额、顶、枕、颞叶多发性长Ｔ１和长Ｔ２异常信号，呈灶状、囊状和层性改变。肌活检均可见不整红边纤维和异常线粒体。诊断符合ＭＥＬＡＳ型。例８分子生物学基因检测发现ｍｔＤＮＡ中ｔＲＮＡ亮氨酸（Ｌｅｕ）基因核苷４２４３位点发生Ａ－Ｇ点突变，与文献ＭＥＬＡＳ所见一致。文章对临床病理和影像学所见等诊断进行讨论     

Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics

A 36-year-old man with myoclonic epilepsy and ragged-red fibers (MERRF) died after more than 18 years of follow-up study. He was 1 of 3 affected siblings and the offspring of an affected mother, suggesting maternal transmission. At autopsy, there was neuronal loss and gliosis in the dentate nucleus of the cerebellum and in the inferior olivary nucleus. Skeletal muscle showed ragged-red fibers, and paracrystalline inclusions in mitochondria by electron microscopy. Biochemical analysis showed a generalized partial defect of cytochrome c oxidase (COX) in mitochondria isolated from all tissues, including brain, heart, skeletal muscle, kidney, and liver. The Michaelis constant (Km) for cytochrome c was abnormally low, suggesting a defect of the mitochondrially encoded subunit II of COX. Immunological studies (enzyme-linked immunosorbent assay, dot-blot, Western blot, and immunohistochemistry) showed that the holoenzyme was decreased but subunit II was decreased more than the holocomplex or the nuclearly encoded subunit IV. However, Northern and Southern blots showed that the gene for subunit II, as well as the genes for subunits I, III, IV, and VIII, were of normal size and were normally transcribed. A point mutation or a small deletion of mitochondrial DNA, probably affecting the COX-II gene, may be responsible for the COX deficiency in this case of MERRF.     

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis

Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.     

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55-200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under-diagnosed, FXTAS is likely to be one of the most common single-gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.     

Facio-scapula-humeral muscular dystrophy: clinical picture and molecular genetics

Facioscapulohumeral muscular dystrophy (FSHD) is a disorder of muscle with a progressive, often asymmetric wasting and weakness of facial, shoulder girdle and lower limbs muscles. No FSHD gene has been identified so far. The FSHD locus is known to be 4q35. The paper presents the clinical picture of FSHD including atypical cases, as well as its inter- and intrafamilial clinical variability. Molecular pathology and diagnostics of the condition are discussed, with particular attention paid to DNA analysis in FSHD.     

Clinical features and molecular genetics of hereditary peripheral neuropathies

Hereditary peripheral neuropathies are the most common monogenetically inherited diseases of the nervous system. The prevalence of the Hereditary Motor and Sensory Neuropathy Type 1A (HMSN 1A or Charcot-Marie-Tooth Neuropathy 1A, CMT1A) alone is estimated to be as high as 1/5000. In 1991, a duplication on chromosome 17p11.2 was identified as the causative genetic defect of CMT1A. Since then causative mutations in 17 genes have been identified. This review summarises the clinical and molecular genetic features of primary inherited neuropathies. It is aimed primarily at clinicians and geneticists. Therefore less emphasis is placed on the pathology and the (often unknown) underlying biological disease mechanisms.     

MELAS型线粒体脑肌病的临床、影像学和肌肉病理分析

目的 探讨MELAS型线粒体脑肌病的临床表现、影像学特点和肌肉组织病理学改变,提高人们对本病的认识.方法 回顾性分析5例MELAS型线粒体脑肌病的临床表现、脑影像学改变(MRI和CT),以及骨骼肌活检的组织病理学特点.结果 MELAS型线粒体脑肌病的主要临床表现为局灶性或全身性癫NFDCC发作、听觉和视觉障碍、运动不能耐受、认知功能障碍、脑卒中样发作、血乳酸水平升高等.脑影像学检查可见病灶多位于颞、枕、顶叶皮层脑回处,脑MRI表现为长T1、长T2信号,部分患者头颅CT可见基底节钙化.骨骼肌活检5例患者肌肉组织中均可见破碎红边纤维(RRF),2例行电镜检查均可见异常线粒体聚集.结论 MELAS型线粒体脑肌病是一种以高乳酸血症和卒中样发作为特征的脑和肌肉能量代谢障碍综合征.患者临床表现复杂多样,容易造成误诊,其诊断需在临床表现和影像学特点的基础上,结合骨骼肌活检病理检查发现RRF或异常线粒体聚集,可获得临床确诊.     

Clinical features and molecular genetics of autosomal recessive cerebellar ataxias

Among the hereditary ataxias, autosomal recessive spinocerebellar ataxias comprise a diverse group of neurodegenerative disorders. Clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathy, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal anomalies, and cutaneous disorders, among others. Molecular pathogenesis also ranges from disorders of mitochondrial or cellular metabolism to impairments of DNA repair or RNA processing functions. Diagnosis can be improved by a systematic approach to the categorisation of these disorders, which is used to direct further, more specific, biochemical and genetic investigations. In this Review, we discuss the clinical characteristics and molecular genetics of the more common autosomal recessive ataxias and provide a framework for assessment and differential diagnosis of patients with these disorders.     

A cluster of disseminated small cortical lesions in MELAS: its distinctive clinical and neuroimaging features

Journal of Neurology - To investigate a diversity of stroke-like episodes (SLEs) in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and report a disseminated...     

Hereditary recurrent focal neuropathies: clinical and molecular features

The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies: hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22 gene resulting in altered expression of the PMP22 protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.     

The first decade of molecular genetics in neurology: changing clinical thought and practice.

Molecular genetics has had a powerful impact on clinical neurology. Definitions of disease are changing from clinical criteria to DNA analysis, resolving questions about the nature of clinically similar but not identical diseases. Genetic counseling is more reliable. Concepts of mendelian inheritance are being tested and new forms of mutation have been discovered to explain anticipation. Nonmendelian forms of inheritance have emerged; concepts of pathogenesis are on a more secure footing; and novel treatments are being explored.     

MELAS: clinical phenotype and morphological brain abnormalities

We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. In all three cases there was a reduced immunocytochemical staining for mtDNA-encoded subunits of the respiratory chain, confirming the presence of a defective mitochondrial protein synthesis in this disease. Mitochondrial abnormalities were mostly confined to multiple areas of different size and shape, in agreement with the focal character of the brain pathology in MELAS, and were most prominent in the cerebral cortex, providing a morphological contribution to the explanation of the cognitive regression of the patients. Immunoreactivity for mtDNA-encoded subunits was reduced in the walls of many pial and intracerebral arterioles of different brain regions but there was no clear correlation between territories of affected vessels and distribution of the histological and immunohistochemical lesions. Cerebral focal lesions in MELAS might have a metabolic nature and several pathogenetic mechanisms might be involved in the genesis of stroke-like episodes when there is a local increased ATP demand.     

Clinical features and molecular genetics of autosomal recessive spinocerebellar degenerations]

The number of patients with spinocerebellar degeneration (SCD) has recently exceeds 20,000 in Japan. Among them, sporadic form is the most common form (67.2%). Among the hereditary forms of SCD, autosomal dominant (AD) form comprises 27.0%, while autosomal recessive (AR) form is rare (1.8%). Because of the rare occurrence of AR-SCD, the molecular genetic studies have been difficult to conduct. Recent progresses in molecular genetics, however, have enabled identification of causative genes for the majority of AR-SCD. Although Friedreich's ataxia is the most representative form of AR-SCD, patients with molecular diagnosis of Friedreich's ataxia have not been described in the Japanese population. Among the various forms of AR-SCD, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) seems to be the most common form in the Japanese population. Aprataxin, the causative gene for EAOH, has been suggested to play a role in the single strand DNA break repair. Interestingly, abnormalities in DNA break repair processes have been implicated in several forms of AR-SCD including AOA2, SCAN1 and ataxia telangiectasia. In this group of AR-SCD, cerebellar atrophy is more marked compared to that observed in Friedreich's ataxia. Taken together, abnormalities in DNA break repair processes may play an essential role in cerebellar degeneration in this group of AR-SCD.     

Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia

Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T > A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9 + 2T > G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.     

MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission

Severe prolonged migrainous symptoms and prolonged partial status epilepticus are characteristic features of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Maternal transmission previously found in myoclonus epilepsy and ragged-red fibers (MERRF), another mitochondrial disease, is suggested in this disorder as well.