Summary Epileptic encephalopathies of infancy and childhood comprise a large, heterogeneous group of severe epilepsies characterised by several seizure types, frequent epileptiform activity on EEG, ...and developmental slowing or regression. The encephalopathies include many age-related electroclinical syndromes with specific seizure types and EEG features. With the molecular revolution, the number of known monogenic determinants underlying the epileptic encephalopathies has grown rapidly. De-novo dominant mutations are frequently identified; somatic mosaicism and recessive disorders are also seen. Several genes can cause one electroclinical syndrome, and, conversely, one gene might be associated with phenotypic pleiotropy. Diverse genetic causes and molecular pathways have been implicated, involving ion channels, and proteins needed for synaptic, regulatory, and developmental functions. Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways. These findings underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
The monoamine neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders ...result in aberrant monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, monoamine neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of monoamine neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of monoamine neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.
Movement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive ...diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a critical postsynaptic signaling pathway in medium spiny neurons. Here, we review the clinical presentation, genetic findings, and disease mechanisms that characterize these genetic postsynaptic movement disorders.
Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological ...processes. Historically, the observation of acquired manganism in miners and people who misuse drugs provided early evidence of brain toxicity related to manganese exposure. The identification of inherited manganese transportopathies, which cause neurodevelopmental and neurodegenerative syndromes, further corroborates the neurotoxic potential of this element. Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders.
Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first ...suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A
-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.
Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, ...characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.
An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are ...clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control.
What this paper adds
Implicated genes encode proteins with very diverse functions.
Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear.
Early diagnosis of treatable disorders is essential and next generation sequencing may be required.
What this paper adds
Implicated genes encode proteins with very diverse functions.
Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear.
Early diagnosis of treatable disorders is essential and next generation sequencing may be required.
Editor's Choice
Technological improvement in genetic diagnosis has radically changed paediatric neurology. We have seen the expansion of the phenotype and understanding of previously known disorders, recognition of novel ones, and the development of new treatments. These changes place a new emphasis on clinical diagnosis. My Editor’s Choice for the February 2020 issue is a much needed narrative review describing the phenotype of a number of genetic conditions presenting with movement disorders and epilepsy. It will help clinicians recognize typical but rarely described presentations, better understand the conditions, and provide them with a rational diagnostic approach in order to improve management
Summary The monoamine neurotransmitter disorders consist of a rapidly expanding heterogeneous group of neurological syndromes characterised by primary and secondary defects in the biosynthesis ...degradation, or transport of dopamine, norepinephrine, epinephrine, and serotonin. Disease onset can occur any time from infancy onwards. Clinical presentation depends on the pattern and severity of neurotransmitter abnormalities, and is predominated by neurological features (encephalopathy, epilepsy, and pyramidal and extrapyramidal motor disorders) that are primarily attributed to deficiency of cerebral dopamine, serotonin, or both. Many neurotransmitter disorders mimic the phenotype of other neurological disorders (eg, cerebral palsy, hypoxic ischaemic encephalopathy, paroxysmal disorders, inherited metabolic diseases, and genetic dystonic or parkinsonian syndromes) and are, therefore, frequently misdiagnosed. Early clinical suspicion and appropriate investigations, including analysis of neurotransmitters in CSF, are essential for accurate clinical diagnosis. Treatment strategies focus on the correction of monoamine deficiency by replacement of monoamine precursors, the use of monoamine analogues, inhibition of monoamine degradation, and addition of enzyme cofactors to promote monoamine production.
The homotypic fusion and protein sorting (HOPS) complex is the structural bridge necessary for the fusion of late endosomes and autophagosomes with lysosomes. Recent publications linked mutations in ...genes encoding HOPS complex proteins with the aetiopathogenesis of inherited dystonias (i.e. VPS16, VPS41, and VPS11). Functional and microstructural studies conducted on patient-derived fibroblasts carrying mutations of HOPS complex subunits displayed clear abnormalities of the lysosomal and autophagic compartments. We propose to name this group of diseases HOPS-associated neurological disorders (HOPSANDs), which are mainly characterized by dystonic presentations. The delineation of HOPSANDs further confirms the connection of lysosomal and autophagic dysfunction with the pathogenesis of dystonia, prompting researchers to find innovative therapies targeting this pathway.
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