A shifting view of neurodevelopmental disability

Abstract

The challenges that lie ahead in identifying the causes and pathogenic mechanisms of neurodevelopmental disabilities have been brought into focus by heated debates surrounding the development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). DSM-5 is scheduled for release in May, 2013, and the eleventh revision of the International Classification of Diseases (ICD-11), which is expected to harmonise with DSM-5, is underway.Growing recognition of shared genetic causes among so-called neurodevelopmental disorders—a broad definition of which includes intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, and disorders outside the purview of DSM-5 such as cerebral palsy and epilepsy—is challenging the validity of current diagnostic boundaries. In this issue, David Ledbetter and colleagues argue that these clinically heterogeneous disorders, which have overlapping symptoms and frequently co-occur, should be thought of not as causally and pathophysiologically distinct, but as the manifestations of “developmental brain dysfunction”, a common denominator.Also in this issue, Dan Doherty and colleagues review developmental disorders of the midbrain and hindbrain, which have emerged as causes of neurodevelopmental dysfunction. Advances in the imaging and genetics of these disorders have helped clinicians to make reliable diagnoses to predict outcome and guide medical management. Because different mutations in a single gene can result in different disorders, knowing how each gene mutation affects the structure of its protein and how the affected protein interacts with other components in specific molecular pathways will be key to making the leap from genetic causes to targets for treatment.These articles highlight the emergence of two different approaches to disease classification. In the case of genetic malformations of brain development, researchers are moving towards a classification system based on genotype and disrupted embryological processes—cause and mechanism. The development of DSM-5 and ICD-11 has seen calls for fundamental reform of the diagnostic classification of complex neurodevelopmental disorders to reflect comorbidities and shared genetic risk factors and to integrate dimensional and categorical views of these conditions. The US National Institute of Mental Health is taking steps to address the problem with its Research Domain Criteria (RDoC) project, which will use data from neuroscience and genetics to cut across traditional diagnostic categories. Many of the clarifications and refinements in DSM-5, including the use of dimensional approaches (levels of severity), will be broadly welcomed by clinicians and researchers. But the fact that the manual must, for the time being, retain the largely descriptive criteria of old, without reference to cause or pathogenic process, should give fresh impetus to efforts to identify the genetic, environmental, and developmental underpinnings of complex neurodevelopmental disorders.Making sense of the vast amounts of genetic data that are being generated for autism, intellectual disability, and other neurodevelopmental disorders is a daunting but vital step in understanding the causes of dysfunction and in developing effective treatments. Models of rare monogenic disorders—such as the autism-related disorders Rett syndrome, fragile X syndrome, tuberous sclerosis, and Timothy syndrome—are providing clues to molecular and cellular disease mechanisms and have shown that a reversal of some features of human neurodevelopmental disorders might be feasible.As researchers strive to link genetic variations and environmental exposures to cellular mechanisms of neurodevelopment and disease, a better understanding of the complex programmes of human brain development will be needed. Among the resources available to aid discovery are recently published maps of the human brain transcriptome across the course of development. The stage is set for large-scale, integrated studies that run the gamut from basic genetic, molecular, and circuit-level analyses to clinical translational research.As the evidence from these studies accumulates, we anticipate further, perhaps more radical, reform of the systems of classification for neurodevelopmental disorders. Regardless of the limitations of current and future incarnations of DSM and ICD, a clear aim of diagnostic classification must be to gain an accurate view of the strengths and needs of people with neurodevelopmental disabilites so that they can benefit from appropriate treatments and receive the support necessary to allow them to play their part in society. The challenges that lie ahead in identifying the causes and pathogenic mechanisms of neurodevelopmental disabilities have been brought into focus by heated debates surrounding the development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). DSM-5 is scheduled for release in May, 2013, and the eleventh revision of the International Classification of Diseases (ICD-11), which is expected to harmonise with DSM-5, is underway. Growing recognition of shared genetic causes among so-called neurodevelopmental disorders—a broad definition of which includes intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, and disorders outside the purview of DSM-5 such as cerebral palsy and epilepsy—is challenging the validity of current diagnostic boundaries. In this issue, David Ledbetter and colleagues argue that these clinically heterogeneous disorders, which have overlapping symptoms and frequently co-occur, should be thought of not as causally and pathophysiologically distinct, but as the manifestations of “developmental brain dysfunction”, a common denominator. Also in this issue, Dan Doherty and colleagues review developmental disorders of the midbrain and hindbrain, which have emerged as causes of neurodevelopmental dysfunction. Advances in the imaging and genetics of these disorders have helped clinicians to make reliable diagnoses to predict outcome and guide medical management. Because different mutations in a single gene can result in different disorders, knowing how each gene mutation affects the structure of its protein and how the affected protein interacts with other components in specific molecular pathways will be key to making the leap from genetic causes to targets for treatment. These articles highlight the emergence of two different approaches to disease classification. In the case of genetic malformations of brain development, researchers are moving towards a classification system based on genotype and disrupted embryological processes—cause and mechanism. The development of DSM-5 and ICD-11 has seen calls for fundamental reform of the diagnostic classification of complex neurodevelopmental disorders to reflect comorbidities and shared genetic risk factors and to integrate dimensional and categorical views of these conditions. The US National Institute of Mental Health is taking steps to address the problem with its Research Domain Criteria (RDoC) project, which will use data from neuroscience and genetics to cut across traditional diagnostic categories. Many of the clarifications and refinements in DSM-5, including the use of dimensional approaches (levels of severity), will be broadly welcomed by clinicians and researchers. But the fact that the manual must, for the time being, retain the largely descriptive criteria of old, without reference to cause or pathogenic process, should give fresh impetus to efforts to identify the genetic, environmental, and developmental underpinnings of complex neurodevelopmental disorders. Making sense of the vast amounts of genetic data that are being generated for autism, intellectual disability, and other neurodevelopmental disorders is a daunting but vital step in understanding the causes of dysfunction and in developing effective treatments. Models of rare monogenic disorders—such as the autism-related disorders Rett syndrome, fragile X syndrome, tuberous sclerosis, and Timothy syndrome—are providing clues to molecular and cellular disease mechanisms and have shown that a reversal of some features of human neurodevelopmental disorders might be feasible. As researchers strive to link genetic variations and environmental exposures to cellular mechanisms of neurodevelopment and disease, a better understanding of the complex programmes of human brain development will be needed. Among the resources available to aid discovery are recently published maps of the human brain transcriptome across the course of development. The stage is set for large-scale, integrated studies that run the gamut from basic genetic, molecular, and circuit-level analyses to clinical translational research. As the evidence from these studies accumulates, we anticipate further, perhaps more radical, reform of the systems of classification for neurodevelopmental disorders. Regardless of the limitations of current and future incarnations of DSM and ICD, a clear aim of diagnostic classification must be to gain an accurate view of the strengths and needs of people with neurodevelopmental disabilites so that they can benefit from appropriate treatments and receive the support necessary to allow them to play their part in society. Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and geneticsHistorically, the midbrain and hindbrain have been considered of secondary importance to the cerebrum, which has typically been acknowledged as the most important part of the brain. In the past, radiologists and pathologists did not regularly examine these structures—also known as the brainstem and cerebellum—because they are small and difficult to remove without damage. With recent developments in neuroimaging, neuropathology, and neurogenetics, many developmental disorders of the midbrain and hindbrain have emerged as causes of neurodevelopmental dysfunction. Full-Text PDF Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidenceNeurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Full-Text PDF