Review: Central nervous system involvement in mitochondrial disease

Mitochondrial respiratory chain defects are an important cause of inherited disorders affecting approximately 1 in 5000 people in the UK population. Collectively these disorders are termed ‘mitochondrial diseases’ and they result from either mitochondrial DNA mutations or defects in nuclear DNA. Although they are frequently multisystem disorders, neurological deficits are particularly common, wide‐ranging and disabling for patients. This review details the manifold neurological impairments associated with mitochondrial disease, and describes the efforts to understand how they arise and progressively worsen in patients with mitochondrial disease. We describe advances in our understanding of disease pathogenesis through detailed neuropathological studies and how this has spurred the development of cellular and animal models of disease. We underscore the importance of continued clinical, molecular genetic, neuropathological and animal model studies to fully characterize mitochondrial diseases and understand mechanisms of neurodegeneration. These studies are instrumental for the next phase of mitochondrial research that has a particular emphasis on finding novel ways to treat mitochondrial disease to improve patient care and quality of life.     

The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national,prospective, population‐based study

Aim Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND). Method Since April 1997, we have identified patients aged 16 years or younger with suspected PIND through the monthly notification card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. Clinical details obtained from reporting paediatricians are classified by an Expert Group. Results By July 2008, 2493 cases of PIND had been reported, among which there were 112 children (69 males, 43 females) with mitochondrial diseases presenting between birth and 14 years 7 months (median 12mo), divided into 13 subgroups. In some instances, clinical features were characteristic of mitochondrial disease, but many children presented non‐specifically with combinations of developmental delay, hypotonia, failure to thrive, and seizures; 16 children had multisystem disease at presentation. Mortality was high: 40 children had died. Blood and/or cerebrospinal fluid lactate measurements were abnormal in 87 children, and 47 of 78 brain magnetic resonance images showed increased basal ganglia signal. Definite diagnoses were usually made by muscle enzyme or genetic studies. Interpretation This is a unique population‐based study of the mitochondrial disorders that cause childhood neurodegenerative disease. It provides detailed information about the clinical presentation and investigation of these complex cases.     

Mitochondrial dysfunction and neuromuscular disease

Mitochondrial diseases are a heterogeneous group of disorders with widely varying clinical features, due to defects in mitochondrial function. Involvement of both muscle and nerve is common in mitochondrial disease. In some cases, this involvement is subclinical or a minor part of a multisystem disorder, but myopathy and neuropathy are a major, often presenting, feature of a number of mitochondrial syndromes. In addition, mitochondrial dysfunction may play a role in a number of classic neuromuscular diseases. This article reviews the role of mitochondrial dysfunction in neuromuscular disease and discusses a rational approach to diagnosis and treatment of patients presenting with a neuromuscular syndrome due to mitochondrial disease.     

Child neurology services in Africa

The first African Child Neurology Association meeting identified key challenges that the continent faces to improve the health of children with neurology disorders. The capacity to diagnose common neurologic conditions and rare disorders is lacking. The burden of neurologic disease on the continent is not known, and this lack of knowledge limits the ability to lobby for better health care provision. Inability to practice in resource-limited settings has led to the migration of skilled professionals away from Africa. Referral systems from primary to tertiary are often unpredictable and chaotic. There is a lack of access to reliable supplies of basic neurology treatments such as antiepileptic drugs. Few countries have nationally accepted guidelines either for the management of epilepsy or status epilepticus. There is a great need to develop better training capacity across Africa in the recognition and management of neurologic conditions in children, from primary health care to the subspecialist level.     

中国线粒体脑肌病伴高乳酸血症和卒中样发作的诊治专家共识

线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)是一种由线粒体基因或核基因突变导致的,以卒中样发作、癫痫发作、认知与精神障碍、高乳酸血症、肌肉疲劳无力为主要临床特点的多系统代谢性疾病,其临床、病理特点和治疗策略具有一定的特殊性。为规范该病的诊治,结合国内外对该病的研究进展,专家组经反复讨论、修订,撰写了中国MELAS的诊治专家共识,从临床表现、家族史、辅助检查、诊断和鉴别诊断、治疗和护理、遗传咨询几大方面总结了该病的特点,供广大临床和科研工作者参考。     

Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis

One of the hardest challenges in medical genetics is to reach a molecular diagnosis in the presence of rare brain disorders. Hereditary spinocerebellar ataxia (HA), characterized by high clinical and genetic heterogeneity, is among the diseases that present this challenge. HA can have features overlapping with those of other neurological diseases, especially hereditary spastic paraplegia (HSP), as routine clinical application of next generation sequencing (NGS) has confirmed. This article reviews different NGS methods applied in heterogeneous cohorts of patients with suspected HA and suggests that exome sequencing should be considered the first-tier genetic approach in this setting. Its application lends support to the hypothesis of HA and HSP as two extremes of a continuous spectrum.     

Current concepts of mitochondrial disorders in childhood

Respiratory chain deficiencies have long been regarded as rare neuromuscular diseases mostly originating from mutations in the mitochondrial genome. Research in the last years has created quite a different picture. The clinical spectrum has expanded to multiorgan disease manifestation, with an estimated minimum incidence in children of 1:11,000. Mutations in the nuclear genome have been discovered in recent years, thereby adding mendelian genetics to the broadened spectrum of mitochondrial disease. This review summarizes recent advances in mitochondrial disorders with a special focus on childhood presentation and therapeutic approaches that may prove useful in the future.     

The protean manifestations of childhood narcolepsy and their misinterpretation

Narcolepsy often begins in childhood but is infrequently recognized, partly because of its many manifestations that can be confused with other conditions. The clinical presentations of excessive sleepiness, cataplexy, hallucinatory phenomena, and sleep paralysis (not always occurring together) are very varied. The picture may be further complicated by the occurrence of automatic behaviour, memory and visual problems, and associated sleep disorders, as well as the psychological and social consequences of having narcolepsy. Not surprisingly, therefore, misinterpretation of the symptoms as primarily psychological, or otherwise physical, may well occur leading to inappropriate management including initial referral to psychiatric or educational rather than neurological or sleep disorder services. The wide-ranging and special features of childhood narcolepsy need to be appreciated by health care and other professionals as well as by parents.     

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces.

The aim of an EFNS neurological management guideline is to provide guidance for clinical neurologists, other health care professionals and health care providers about important aspects of management of neurological disease. It represents the view of an expert task force appointed by the chairperson of the scientific committee with the agreement of the chairperson of a Scientist Panel. It will be a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.     

Neuropsychological Advances in Child and Adolescent Mental Health: The Decade of the Brain

As the 'decade of the brain' comes to a close, it is clear that the field of neuropsychology has made many vital contributions to evaluation, treatment, and research issues in child and adolescent health care. In the study of brain-behaviour relationships, the neuropsychologist plays a unique role. The practice of child neuropsychology is differentiated from adult work because developmental and environmental influences have a significant impact on practice. The various goals of the child neuropsychologist may include psychoeducational and neuropsychological assessment, the exploration of brain-behaviour relationships, consultation with a variety of professionals ranging from teachers to neurologists, and rehabilitation training. Advances in medical treatment have contributed to an expanding population of children and adolescents with neurological and/or neuropsychiatric concerns. New research in this field has also provided evidence of disordered or dysfunctional neurological systems in a number of childhood disorders and psychiatric conditions. This paper reviews some contributions that neuropsychology has made to the health care of children and adolescents in the past decade.     

MELAS--mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome--two cases confirmed by biochemical and molecular investigations. Differential diagnosis of stroke causes

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a maternally inherited multisystem disease caused by mutations of the mitochondrial DNA. The characteristic clinical features are: encephalopathy manifesting as dementia and seizures, stroke-like episodes at young age (usually < 40), lactic acidosis and myopathy with ragged-red fibres. Other frequent manifestations include: sensorineural deafness, diabetes, hypoparathyroidism, peripheral neuropathy and cardiomyopathy. We present two patients with MELAS who were diagnosed 4 and 9 years respectively following the onset of the disease despite the characteristic clinical pictures. The differential diagnostics of inborn and acquired disorders causing stroke is included. We regard that mitochondrial diseases are still insufficiently known and are frequently misdiagnosed. The knowledge is indispensable for establishing diagnosis and accurate genetic counselling. Although there is no specific therapy for mitochondrial diseases to date, coenzyme Q and various vitamins as well as moderate degree exercise might be recommended.     

L’autisme à l’âge adulte : aspects cliniques

Studies relating to autism spectrum disorders have mainly been carried out in children. However, when children with autism become adult, their handicap continues to put a strain on their everyday life. It is important that health professionals in charge of adult patients consider the possibility of autistic syndrome in patients whose behavior is atypical. Mental disorders may present in a special way in patients with autism spectrum disorders. For instance, depression may produce irritability, aggressive behavior, and change of rituals. Autism spectrum disorders have common features with many other mental disorders, such as schizophrenia and obsessive-compulsive disorders. Our article offers a review of clinical and historical particularities that may help clinicians establish appropriate diagnosis. In this article we focus on clinical features, differential diagnosis, and comorbidity in adult people with autism spectrum disorders. A subsequent article will deal with diagnostic work-up and therapeutic aspects of autism in adult patients.     

Problems with botulinum toxin treatment in mitochondrial cytopathy: case report and review of the literature

Botulinum toxin type A (BTXA) is widely used in neurological therapeutics for a variety of indications such as dystonia, spasticity, hyperhidrosis, and hypersalivation. It is relatively contraindicated in disorders of neuromuscular transmission, in individuals with known hypersensitivity or bleeding disorders, and during pregnancy. Two patients are presented with initially undetermined multisystem neurological disorders and excessive sialorrhoea, later diagnosed as mitochondrial cytopathy, who had side effects after treatment with ultrasound guided BTXA injections. Published reports on the use of BTXA injections in hypersalivation of various causes are reviewed, along with the proposed mechanisms of hypersensitivity to BTXA in patients with mitochondrial cytopathies. Clinicians should be cautious when using BTXA injections in such patients because of the significant risk of side effects.     

Mehr als Anfälle und Antiepileptika

Severe disabilities and multiple comorbidities in patients are frequently encountered problems for neuropediatricians. Mental retardation, cognitive problems and intellectual disability of varying degrees are frequent comorbidities in various epilepsy syndromes. Patients with epilepsy and behavioral problems, such as attention deficits and hyperactivity as well as children with autism and autistic features are difficult to treat. Movement disorders, such as cerebral palsy can occur together with epilepsy. Epilepsy and movement disorders can be symptoms of a common underlying disorder. The investigation of syndromal disorders and metabolic diseases with epilepsy as one of multiple symptoms requires specific diagnostic procedures. Patients and their families need specific support once these mostly incurable diseases have been diagnosed. Children with progressive neurological diseases and severe disabilities often need specialized palliative care. In all these situations a multidisciplinary team, including physicians, nurses and specialists from various therapeutic disciplines is necessary to provide the specialized care the patients and families need to attain a good quality of life.     

Late diagnosis of neurodegenerative disease in children: anosognosia by proxy

Anosognosia is a term now generally defined as a failure to recognize the existence of disease processes, particularly those with a neurological basis. Denial of illness has been recognized in a large number of disorders, and is generally thought to have not only a central nervous system basis, but to also be influenced by the psychological processes of denial. This disorder has been reported in the adult population, and there are initial suggestions that it exists in children/adolescents. We propose to extend the concept of anosognosia to the caregivers of children who suffer significant dementia, and extended degeneration in neuropsychological and neurological functioning. We term this syndrome anosognosia by proxy. Three case examples are presented in which parents, teachers, and health care professionals observed extended deterioration in a child/adolescent's level of functioning prior to seeking appropriate diagnostic evaluations. Possible explanations for this process are advanced, including a combination of insidious onset coupled with the intimate nature of the child/parent relationship. The need for professional, teacher, and parent education on the nature of childhood degenerative neurological disorders is emphasized.     

How good are we at diagnosing seizures based on semiology?

The accuracy of visual diagnosis of seizures based on semiologic features among different health care professionals is largely unknown. We evaluated the ability of health care professionals to correctly diagnose epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) from a random selection of 10 ES and 10 PNES videos. The 20 videos (without accompanying electroencephalography) were shown only once, in a random mix to different groups of health care professionals. These individuals, blinded to the diagnosis, were asked to classify the seizure as ES or PNES. We used summary receiver operating characteristic (SROC) curves to determine the accuracy for each group. Next we calculated the difference between the area under the curve (AUC) of SROC between neurologists (as the reference) and the other groups of health care professionals. Neurologists achieved significantly higher AUC results compared to other health care professionals. These results indicate a wide range of diagnostic accuracy among different health care professionals and have practical implications for the evaluation of patients with seizure disorders in acute settings.     

Late Diagnosis of Neurodegenerative Disease in Children: Anosognosia by Proxy

Anosognosia is a term now generally defined as a failure to recognize the existence of disease processes, particularly those with a neurological basis. Denial of illness has been recognized in a large number of disorders, and is generally thought to have not only a central nervous system basis, but to also be influenced by the psychological processes of denial. This disorder has been reported in the adult population, and there are initial suggestions that it exists in children/adolescents.We propose to extend the concept of anosognosia to the caregivers of children who suffer significant dementia, and extended degeneration in neuro-psychological and neurological functioning. We term this syndrome anosognosia by proxy. Three case examples are presented in which parents, teachers, and health care professionals observed extended deterioration in a child/adolescent’s level of functioning prior to seeking appropriate diagnostic evaluations. Possible explanations for this process are advanced, including a combination of insidious onset coupled with the intimate nature of the child/parent relationship. The need for professional, teacher, and parent education on the nature of childhood degenerative neurological disorders is emphasized.     

Pathogenic mitochondrial DNA mutations in protein-coding genes

More than 200 disease-related mitochondrial DNA (mtDNA) point mutations have been reported in the Mitomap (http://www.mitomap.org) database. These mutations can be divided into two groups: mutations affecting mitochondrial protein synthesis, including mutations in tRNA and rRNA genes; and mutations in protein-encoding genes (mRNAs). This review focuses on mutations in mitochondrial genes that encode proteins. These mutations are involved in a broad spectrum of human diseases, including a variety of multisystem disorders as well as more tissue-specific diseases such as isolated myopathy and Leber hereditary optic neuropathy (LHON). Because the mitochondrial genome contains a large number of apparently neutral polymorphisms that have little pathogenic significance, along with secondary homoplasmic mutations that do not have primary disease-causing effect, the pathogenic role of all newly discovered mutations must be rigorously established. A scoring system has been applied to evaluate the pathogenicity of the mutations in mtDNA protein-encoding genes and to review the predominant clinical features and the molecular characteristics of mutations in each mtDNA-encoded respiratory chain complex.     

The relationship between psychiatry and neurology

Neurology and psychiatry deal with diseases of the (central) nervous system. Historically neurological disorders are related to a proven organic basis, whereas psychiatric disorders are mainly defined by the phenomenology and course of the symptoms. Neuroscientific research methods such as molecular genetics, neurochemistry, neurophysiology, neuropathology, functional (SPECT, PET, fMRI) or structural (MRI) imaging have dramatically increased our knowledge of psychiatric and neurological disorders in the last 20 years. Accordingly diagnostic and therapeutic procedures and the long-term prognosis of numerous diseases in both disciplines have substantially improved (i.e. pharmacotherapy, psychotherapy, functional neurosurgery). For major brain disorders - such as dementia of the Alzheimer type - close collaboration between both disciplines is developing in diagnosis, therapy and care. Due to common neurobiological research topics, educational programs, medical training and the challenges of assuring appropriate care to patients with brain disorders, further cooperation between neurology and psychiatry is expected and necessary.     

Rare neurological diseases: A Pandora's box for neurology (an European and Italian perspective)

Rare neurological diseases are a heterogeneous group of disorders mainly affecting the central and peripheral nervous systems and muscle, representing almost 50% of all rare diseases; this means that neurologists are among the main specialists involved in their diagnosis and research. However, the classical interest of neurologists is primarily directed towards the more common diseases such as dementia, multiple sclerosis, headache, epilepsy and stroke, while avoiding the follow-up of rare neurological diseases that have, taken altogether, had such a major impact on health systems in Europe as well as in other countries around the world. Rare diseases are also considered ‘orphan’ diseases, as only a few of them have treatments. In Europe as in the USA in recent years, considerable interest has been generated by these disorders, thereby stimulating more specific programs of care and management. In fact, the difficulty of diagnosis and the need for super-specialization in this field has led to the organization of dedicated centers in different countries to collect patients’ data within a network for diagnosis, treatment and research. The present report describes our experience in Siena with such a reference center for these disorders and their diagnosis and treatment, and also includes a discussion of the organization of care for rare neurological diseases in Europe and Italy. Finally, this report also covers the new initiative of the Italian Neurological Society to promote an information center for rare neurological diseases to disseminate information and knowledge to all neurologists working in this field.