Lipid storage diseases, also known as the lipidoses, are a group of inherited metabolic disorders in which there is lipid accumulation in various cell types, including the central nervous system, because of the deficiency of a variety of enzymes. Over time, excessive storage can cause permanent cellular and tissue damage. The brain is particularly sensitive to lipid storage as the contents of the central nervous system must occupy uniform volume, and any increases in fluids or deposits will lead to pressure changes and interference with normal neurological function. In addition to primary lipid storage diseases, lysosomal storage diseases include the mucolipidoses (in which excessive amounts of lipids and carbohydrates are stored in the cells and tissues) and the mucopolysaccharidoses (in which abnormal glycosylated proteins cannot be broken down because of enzyme deficiency). Neurological dysfunction can be a manifestation of these conditions due to substrate deposition as well. This review will explore the modalities of neuroimaging that may have particular relevance to the study of the lipid storage disorder and their impact on elucidating aspects of brain function. First, the techniques will be reviewed. Next, the neuropathology of a few selected lipid storage disorders will be reviewed and the use of neuroimaging to define disease characteristics discussed in further detail. Examples of studies using these techniques will be discussed in the text. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;17:269–282.
Newborn screening (NBS) is a public health program aimed at identifying treatable conditions in presymptomatic newborns to avoid premature mortality, morbidity, and disabilities. Currently, every newborn in the Unites States is screened for at least 29 conditions where evidence suggests that early detection is possible and beneficial. With new or improved treatment options and development of high-throughput screening tests, additional conditions have been proposed for inclusion into NBS programs. Among those are several conditions with a strong neuronopathic component. Some of these conditions have already been added to a few national and international screening programs, whereas others are undergoing pilot studies to determine the test performance metrics. Here, we review the current state of NBS for 13 lysosomal storage disorders, X-adrenoleukodystrophy, Wilson disease, and Friedreich ataxia.
The congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60 disorders, affecting approximately 800 individuals, have been identified, many in the last 5 years. CDG should be considered in any multi-system syndrome or single tissue disorder not explained by the identification of another disorder. The initial clinical presentation varies significantly among individuals, even between affected siblings. However, two thirds of the known CDGs are associated with intellectual disabilities and most affected individuals need support services throughout their lives. Additional disorders of glycosylation are likely to be characterized over time.
Frailty is increasingly being recognized as a relevant health measure in older populations, associated with an increased risk of adverse health outcomes and care dependency. Because it is generally perceived that people with intellectual disabilities are "old" from age 50 onwards, frailty research in this group might lead to an understanding of factors, contributing to this perception. The development since the 1990s of conceptual and operational definitions of frailty has resulted in different approaches: biological (phenotype), multidimensional, and non-specific deficit accumulation. All approaches consider disability a consequence rather than a cause of frailty. This may be different for long-disabled populations, which would have consequences for validity of frailty measures. First research shows that the different approaches are applicable to study populations with intellectual disabilities as well. Frailty as defined by both the phenotypic and deficit accumulation approach appears to develop considerably earlier and is more severe in people with intellectual disabilities than in the general older population, supporting the notion of early aging. Before any clinical implications can be outlined, health outcomes (validity), causes, and prevention of frailty should be investigated.
This review highlights several methodological challenges involved in research on aging, health, and mortality in adults with rare intellectual disability syndromes. Few studies have been performed in this area, with research obstacles that include: the ascertainment of older adults with genetic versus clinical diagnoses; likelihood that adults will not receive adequate health care and referrals to genetic specialists; cohort differences related to generational and treatment effects; and increased mortality and selective survival biases. Even so, aging in Prader-Willi and Williams syndromes are reviewed as they reveal new insights into the phenotypic expression and treatment options for older adults with these disorders. The review ends with recommendations for future research that takes better advantage of genetic advances, changes in adult phenotypes, and ties across syndrome-specific research silos. Although aging in rare neurodevelopmental disorders is barely on the research landscape, the field stands to learn much from these older adults.
© 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013; 17:185–186.
Individuals with intellectual disability (ID) are now living longer with the majority of individuals reaching middle and even “old age.” As a consequence of this extended longevity they are vulnerable to the same age‐associated health problems as elderly adults in the general population without ID. This includes dementia, a general term referring to a variety of diseases and conditions causing substantial loss of cognitive ability and functional declines; adults with Down syndrome are at especially high risk. A great deal of recent effort has focused on the very earliest detectable indicators of decline (and even prodromal stages of dementia‐causing diseases). A condition called mild cognitive impairment (MCI) has been conceptually defined as a decline in functioning that is more severe than expected with typical brain aging but not severe enough to meet criteria for a diagnosis of dementia. Consensus criteria for both dementia and MCI have been developed for typically developing adults but are of limited applicability for adults with ID, given their pre‐existing cognitive impairments. Early diagnosis will continue to be of growing importance, both to support symptomatic treatment and to prevent irreversible neuropathology when interventions are developed to slow or halt the progression of underlying disease. While the intellectual and developmental disabilities field has for some time recognized the need to develop best‐practices for the diagnosis of MCI and dementia, there remains a pressing need for empirically based assessment methods and classification criteria. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;18:31–42.
The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;17:187–196.
Mitochondrial fatty acid oxidation disorders include conditions in which the transport of activated acyl-Coenzyme A (CoA) into the mitochondria or utilization of these substrates is disrupted or blocked. This results in a deficit in the conversion of fat into energy. Most patients with fatty acid oxidation defects are now identified through newborn screening by tandem mass spectrometry. With earlier identification and preventative treatments, mortality and morbidity rates have improved. However, in the absence of severe health and neurological effects from these disorders, subtle developmental delays or neuropsychological deficits have been noted. Medical records were reviewed to identify outcomes in 85 children with FAOD's diagnosed through newborn screening and followed at one metabolic center. Overall, 54% of these children identified through newborn screening experienced developmental challenges. Speech delay or relative weakness in language was noted in 26 children (31%) and motor delays were noted in 24 children (29%). The majority of the 46 children receiving psychological evaluations performed well within the average range, with only 11% scoring <85 on developmental or intelligence tests. These results highlight the importance of screening children with fatty acid oxidation disorders to identify those with language, motor, or cognitive delay. Although expanded newborn screening dramatically changes the health and developmental outcomes in many children with fatty acid oxidation disorders, it also complicates the interpretation of biochemical and molecular findings and raises questions about the effectiveness or necessity of treatment in a large number of cases. Only by systematically evaluating developmental and neuropsychological outcomes using standardized methods will the true implications of newborn screening, laboratory results, and treatments for neurocognitive outcome in these disorders become clear.
BACKGROUND The lysosomal-autophagocytic system diseases (LASDs) affect multiple body systems including the central nervous system (CNS). The progressive CNS pathology has its onset at different ages, leading to neurodegeneration and early death. METHODS Literature review provided insight into the current clinical neurological findings, phenotypic spectrum, and pathogenic mechanisms of LASDs with primary neurological involvement. CONCLUSIONS CNS signs and symptoms are variable and related to the disease-specific underlying pathogenesis. LAS dysfunction leads to diverse global cellular consequences in the CNS ranging from specific axonal and dendritic abnormalities to neuronal death. Pathogenic mechanisms for disease progression vary from impaired autophagy, massive storage, regional involvement, to end-stage inflammation. Some of these features are also found in adult neurodegenerative disorders, for example, Parkinson's and Alzheimer's diseases. Lack of effective therapies is a significant unmet medical need.
At present, there may be over 210,000 people with Down syndrome (DS) over the age of 55 in the United States (US) who have significant needs for augmented services due to circumstances related to ordinary and/or pathological aging. From 1979 through 2003, the birth prevalence of DS rose from 9.0 to 11.8 (31.1%) per 10,000 live births in 10 representative US regions. This increase, largely due to women conceiving after age 35, portends an ever-growing population of people with DS who may be subject to pathogenic aging. Whereas Trisomy 21 is one of the most widespread genetic causes of intellectual disability (ID), it still is one of the least understood of all genetic ID syndromes. While longevity in people with DS has improved appreciably in as modest a period as 30 years, age-specific risk for mortality still is considerably increased compared both with other people with ID or with the typically developing population. The penetrance of the phenotype is widely distributed, even though a consistent genotype is assumed in 95% of the cases. Some, but not all body systems, exhibit signs of premature or accelerated aging. This may be due to both genetic and epigenetic inheritance. We now know that the long-term outcome for people with DS is not as ominous as once contemplated; a number of people with DS are living into their late 60s and 70s with few if any major signs of pathogenic aging. Alzheimer's disease (AD), a devastating disease that robs a person of their memory, abilities and personality, is particularly common in elder adults with DS, but is not a certainty as originally thought, some 20% to 30% of elder adults with DS might never show any, or at most mild signs of AD. DS has been called a mature well-understood syndrome, not in need of further research or science funding. We are only beginning to understand how epigenetics affects the phenotype and it may be feasible in the future to alter the phenotype through epigenetic interventions. This chapter is divided into two sections. The first section will review typical and atypical aging patterns in somatic issues in elder adults with DS; the second section will review the multifaceted relationship between AD and DS.
Cognitive and behavioral correlates of molecular variations related to the FMR1 gene have been studied rather extensively, but research about the long-term outcome in individuals with fragile X spectrum disorders remains sparse. In this review, we present an overview of aging research and recent findings in regard to cellular and clinical manifestations of aging in fragile X syndrome, and the FMR1 premutation.
With medical advances, more individuals with cerebral palsy (CP) syndromes who reside in developed countries are surviving to adolescence and adulthood. However, there continues to be a paucity of research examining long-term health, functional activities, and participatory outcomes over their life-course. This article reviews the current literature assessing adult outcomes for individuals with CP within the framework of the International Classification of Functioning (ICF), Disability, and Health model of enablement. Preliminary data over the last decade indicate that among adults with cerebral palsy without intellectual disability, 60-80% completed high school, 14-25% completed college, up to 61% were living independently in the community, 25-55% were competitively employed, and 14-28% were involved in long term relationships with partners or had established families. These outcomes occurred with biomedical advances in the management of spasticity, deformity, and medical co-morbidities, as well as with concurrent policy initiatives to increase access to a continuum of habilitative and education services. Although we have incomplete population data to inform comprehensive life-course planning, there are opportunities to create clinical and translational community networks with improved measures of functioning and participation that can better inform us about the factors influencing lifespan development of people with CP.
This article reviews the research on health promotion for adults aging with developmental disabilities. First, it examines barriers to healthy aging, including health behaviors and access to health screenings and services. Second, it reviews the research on health promotion interventions, including physical activity interventions, health education interventions, and health care and screening preventive services. This review found evidence that the three types of health promotion interventions, physical activity and exercise, health education and mixed approaches, and health care and screening services can play a role in reducing health disparities for adults with developmental disabilities. Studies focusing primarily on physical activity and exercise tended to show improved fitness and some success in reducing obesity, reducing maladaptive behaviors, and improving alertness, though none of these studies showed longer term health benefits. The studies that took a more holistic approach by also including exercise and nutrition health education tended to show some evidence not only for changes in weight reduction but also for changes in health behavior attitudes (exercise self-efficacy, outcomes expectations, and barriers) and behaviors (e.g., dietary intake) and to a limited extent for improved life satisfaction. The literature on health screenings and services demonstrated the important role of health checks in identifying previously undetected conditions. These conditions include life threatening ones such as cancer and cardio-vascular disease, as well as less serious conditions that are often more common among adults with developmental disabilities and could be treated if caught early.
Developmental Disabilities Research ReviewsVolume 18, Issue 1 p. 1-5 Research Article Editorial: Special issue on adult development and aging with IDD Wayne Silverman, Corresponding Author Wayne Silverman Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Waisman Center, University of Wisconsin, MadisonCorrespondence to: Wayne Silverman, Kennedy Krieger Institute, 707 North Broadway, Suite 222s, Baltimore MD 21205. E-mail: [email protected]Search for more papers by this authorMarsha R. Mailick, Marsha R. Mailick Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Waisman Center, University of Wisconsin, MadisonSearch for more papers by this author Wayne Silverman, Corresponding Author Wayne Silverman Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Waisman Center, University of Wisconsin, MadisonCorrespondence to: Wayne Silverman, Kennedy Krieger Institute, 707 North Broadway, Suite 222s, Baltimore MD 21205. E-mail: [email protected]Search for more papers by this authorMarsha R. Mailick, Marsha R. Mailick Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Waisman Center, University of Wisconsin, MadisonSearch for more papers by this author First published: 16 August 2013 https://doi.org/10.1002/ddrr.1122Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES Bull C, Rigby ML, Shinebourne EA. 1985. Should management of complete atrioventricular canal defect be influenced by coexistent Down syndrome? Lancet 1: 1147- 1149. Coppus AMW. 2013. People with intellectual disability: what do we know about adulthood and life expectancy? Dev Disabil Res Rev. Dykens EM. 2013. Aging in rare intellectual disability syndromes. Dev Disabil Res Rev. Evenhuis H, Schoufour J, Echteld M. 2013. Frailty and intellectual disability: a different operationalization? Dev Disabil Res Rev. Fisch GS. 2012. Nosology and classification in autism: classification counts. Am J Med Genet 106C: 91- 103. Fraser M, Mitchell A. 1876. Kalmuc idiocy: report of a case with autopsy and notes on sixty-two cases. J Ment Sci 22: 169- 179. Frisch D, Msall ME. 2013. Health, functioning and participation of adolescents and adults with cerebral palsy: a review of outcomes research. Dev Disabil Res Rev. Grossman HJ. 1983. Classification in mental retardation. Washington |DC: American Association on Mental Deficiency, p. 5- 10. Guthrie R, Susi A. 1963. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32: 338- 343. Heller T, Sorensen A. 2013. Promoting healthy aging in adults with developmental disabilities. Dev Disabil Res Rev. Hermann B, Seidenberg M, Sager M, et al. 2008. Growing old with epilepsy: the neglected issue of cognitive and brain health in aging and elder persons with chronic epilepsy. Epilepsia 49: 731- 740. Krinsky-McHale SJ, Silverman W. 2013. Dementia and mild cognitive impairment in adults with intellectual disability: issues of diagnosis. Dev Disabil Res Rev. Liu JJ, Mula M, Hermann BP. 2012. Uncovering the neurobehavioral comorbidities of epilepsy over the lifespan. Lancet 380: 1180- 1192. Malamud N. 1972. Neuropathology of organic brain syndromes associated with aging. In: CM Gaitz, editor. Aging and the brain. New York: Plenum. p 63- 87. Perkins EA, Berkman KA. 2012. Into the unknown: aging with autism spectrum disorders. Am J Intellect Dev Disabil 117: 478- 486. Piven J, Rabins P, et al. 2011. Autism spectrum disorders in older adults: toward defining a research agenda. J Am Geriatr Soc 59: 2151- 2155. Raimondi AJ, Matsumoto S. 1967. A simplified technique for performing the venticulo-peritoneal shunt: technical note. J Neurosurg 26: 357- 360. Ruparelia A, Pearn M, Mobley WC. 2013. Aging and intellectual disability: insights from mouse models of Down syndrome. Dev Disabil Res Rev. Schneider A, Ligsay A, Hagerman RJ. 2013. Fragile X syndrome: an aging perspective. Dev Disabil Res Rev. Todres ID. 2006. History of pediatric care. In: BP Fuhrman, JJ Zimmerman, editors. Pediatric Critical Care. Philadelphia: Mosby Elsevier. pp 7- 14. Zigman WB. 2013. Atypical aging in Down syndrome. Dev Disabil Res Rev. Citing Literature Volume18, Issue1Special Issue: Special Issue on Adult Development and Aging with IDDAugust 2013Pages 1-5 ReferencesRelatedInformation
Increases in the life expectancy of people with Intellectual Disability have followed similar trends to those found in the general population. With the exception of people with severe and multiple disabilities or Down syndrome, the life expectancy of this group now closely approximates with that of the general population. Middle and old age, which until 30 years ago were not recognized in this population, are now important parts of the life course of these individuals. Older adults with Intellectual Disabilities form a small, but significant and growing proportion of older people in the community. How these persons grow older and how symptoms and complications of the underlying cause of the Intellectual Disability will influence their life expectancy is of the utmost importance. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;18:6–16.
Down syndrome (DS) is one of many causes of intellectual disability (ID), others including but not limited to, fetal alcohol syndrome, Fragile X syndrome, Rett syndrome, Williams syndrome, hypoxia, and infection. Down syndrome is characterized by a number of neurobiological problems resulting in learning and memory deficits and early onset Alzheimer's disease. The cognitive impairment in people with DS is virtually universal but varies considerably with respect to expressivity and severity. Significant advances in medical treatment and social inclusion have increased longevity in people with DS resulting in an increased aging population, thus highlighting the significance of early onset of dementia and the importance of identifying pharmacotherapies to treat DS-associated health complications in adults. Given its prevalence and established mouse models, this review will focus on ID in the DS population; specifically, the superimposed effect of aging on the complications already manifest in DS adults and the cognitive insights gained from studies on mouse models of DS.
Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field.
The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy. Ten genes have been identified so far that result in an NCL (CLN1-10). The most common forms are CLN1, CLN2, and CLN3, which were previously known as Infantile, Late-Infantile, and Juvenile NCL's, respectively. CLN1 and CLN2 result from mutations in soluble lysosomal enzymes palmitoyl-protein thioesterase (PPT) and tripeptidyl peptidase 1 (TPP1), which can be measured in white blood cells for clinical diagnosis. Molecular diagnostic testing is routinely available for CLN1, CLN2, and CLN3. Sequencing of other NCL genes may be required to establish a diagnosis when the common forms are ruled out. The pathogenesis of NCL neuronal loss resulting from loss of function of any of the NCL gene products remains unknown and no treatment options are presently available. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;17:254–259.
Individuals with intellectual disabilities experience health disparities and disparities in accessing health care services compared to individuals within the general population. In order to eliminate these disparities the contributors to them must be understood. In this article, we aim to describe a recent reconceptualization of health and disability (Krahn, et al. [ 2006 ] Mental. Retard. Dev. Disabilities Res. Rev. 12:70–82) to further understand the health disparities between individuals with Down syndrome, the most common identified cause of intellectual disability in the United States, and the general population. We also detail known health disparities between individuals with Down syndrome of different races and discuss the possible reasons for these disparities, as well as potential actions to address them. © 2012 Wiley Periodicals, Inc. Dev Disabil Res Rev 2011; 17:32–35.
