Down Syndrome and Musculoskeletal Concerns

Down Syndrome and the Human Genome

Down syndrome (DS) was first described in 1866 by John Langdon Down. Nearly 100 years later, Jerome Lejeune and his associates showed that it is due to the presence of an extra copy of chromosome 21, and today the syndrome is the single most common genetic cause of moderate mental retardation. Exciting new information is rapidly becoming available about DS with the development of modern molecular technologies and the mapping of the human genome. These are reviewed herein. Illustrations are also provided of: (a) a trisomy 21 karyotype; (b) a chromosome 21 relocation (translocation) to another chromosome employing relatively new color fluorescence technology (FISH or flouroscence in situ hybridization); (c) a partial map of chromosome 21; (d) reverse transcription polymerase chain reaction technology; and (e) Northern blotting to measure gene expression. Two classes of hypotheses regarding the mechanism causing DS are described, one focusing on the gene dosage effects and the second on amplified developmental instability. Evidence supporting each is reviewed, leading to the suggestion that gene dosage effect alone cannot be the sole mechanism leading to DS. Currently, it seems most likely that other mechanisms, such as epigenetic effects (functional alterations of distantly located genes), feedback mechanisms, tissue degeneration leading to decreased gene expression, and gene-gene interactions may be involved. It is concluded that they may be non-specific effects of the presence of extra chromosomal material, and that this is an issue that need further explicit study. As we learn more about the genes on chromosome 21, their protein products, and the impact of the presence of an extra copy of chromosome 21 on the rest of the genome/proteome, we shall achieve a better understanding of the underlying causes of specific features currently associated with DS. Invariably, this will lead to an expanded array of treatment options and have a significant positive impact on the lives of affected individuals.

Down Syndrome and Celiac Disease: A Review

The article provides an extensive literature review of celiac disease in Down syndrome, including the prevalence, screening tests, common clinical manifestations, biopsy findings and treatment approaches. Studies from Europe and the United States have documented a high prevalence of celiac disease in Down syndrome. Screening with IgA-antiendomysium antibodies or IgA-anti tissue transglutaminase and total IgA for all children with Down syndrome is therefore recommended. The early identification of celiac disease may improve gastrointestinal symptoms, growth and behavior while reducing the incidence of intestinal lymphoma.

Developmental apraxia of speech and intelligibility in children with Down syndrome

This study investigated whether characteristics of developmental apraxia of speech (DAS) are found in children with Down syndrome who are experiencing difficulty with speech intelligibility. DAS is the inability of a child to voluntarily program, combine, organize, and sequence movements necessary for speech. Seven participants with Down syndrome participated in the study. An analysis of a parent questionnaire, a conversational connected speech sample, and the The Apraxia Profile, a descriptive measure of speech characteristics, were used to determine whether the participants showed the characteristics of DAS. Results revealed that all participants showed characteristics of developmental apraxia of speech. The most common characteristics of developmental apraxia of speech displayed by the participants included decreased intelligibility with increased length of utterance, inconsistency of speech errors, decreased ability to perform voluntary tasks as compared to automatic tasks, difficulty sequencing oral movements and sounds, and a pattern of receptive language superior to expressive language. There is a large body of research on assessment and treatment of DAS that can be used to help children who show these characteristics. Implications for clinical practice and future research needs are discussed.

Patterns of feeding, eating and drinking in young children with Down syndrome with oral motor concerns

Evaluated oral motor skills related to feeding, eating, and drinking in 30 children with Down syndrome, aged 8 mo to 4 yrs 11 mo of age. Observational data on postural stability, position of the oral structures at rest, spoon-feeding, chewing, bolus formation, and drinking were analyzed. Approximately half of the children demonstrated some postural concerns. The children were generally found to have symmetrical patterns in the areas of posture and jaw movements. Hypotonia was present in most of the children, but different degrees of hypotonia were evidenced in different oral structures. Low muscle tone was observed more frequently in the tongue than the lips. Decreased sensory awareness and feedback, jaw instability, reduced upper lip mobility, open mouth posture, and tongue protrusion were some of the observed factors that affected feeding, eating, and drinking. The results support many of the anatomical and physiological findings that have been reported as associated characteristics for children with Down syndrome. The discussion considers compensatory and developmental patterns observed.

Living with Down Syndrome: The Family Experience

Our current understanding of well-being in families of children with Down syndrome is rather limited. What we do know is that these family experience increased stress, increased time demands, and changes in roles. It remains unclear why some families recover or adapt in the face of stressful circumstances, while others remain vulnerable, and some deteriorate. Future research needs to shift the focus from assessing stress and distress, to assessing resilience and adaptation. We have growing evidence that many families of children with Down syndrome are doing very well. What we need now is an understanding of the factors that contribute to resilience and successful adaptation.

The potential of gene therapy for Down syndrome

As the father of a 7-year-old boy with Down syndrome (DS), I was intrigued to read in the recent book Altered Fates: Gene Therapy and the Retooling of Human Life, by Lyon and Gorner (NY: WW Norton & Co., 1996 and 1995) that the 1990s gene-therapy revolution—besides well-publicized forays into treatments for a variety of illnesses—even holds forth the potential of treatment for DS.
Historically, DS genetics research began with early-80s mouse studies—by Dr. Charles J. Epstein of UC San Francisco and his colleague Dr. Yoram Groner of Israel's Weizmann Institute of Science—focusing on the destruction caused by 50 percent too much (corresponding to the third human chromosome 21, or HC21, in people with DS) of the enzyme copper/zinc-containing superoxide dismutase.
A major milestone in DS-genetics research was reached in 1992: completion of a physical mapping of HC21 by Daniel Cohen, Ilya Chumakov, and colleagues at the Paris-based Centre d'Etude du Polymorphisme Human (CEPH, now known as GenSet), in conjunction with many researchers and institutes in other countries. This milestone, announced in October 1992, represented the first fruits of the Human Genome Project, well ahead of its original goal of completing physical maps of all human chromosomes by 2005, and now aiming for this goal by 2002-03.
Several milestone genetic maps of the DS chromosome region of HC21 were published by American, Canadian, Australian, Israeli, Japanese, and Italian researchers in 1994 on. These findings, achieved via the yeast artificial chromosome (YAC) technique, often targeted the neurotransmitters glutamate and acetylcholine. Specific genes studied included the beta-amyloid precursor protein (APP) gene, apolipoprotein E (apoE) gene, Ets2 proto-oncogene (mutant gene promoting cancer), DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) gene, "minibrain" gene, TPRD (tetratricopeptide repeat D) gene, and several others. [For the latest list of the many genes now linked to DS, go to the Research section of the following web site: http://www.dsresearch.org].
A major breakthrough for potential gene therapy in general was the development of the first human artificial chromosomes (HACs) by a Case Western Reserve University (CWRU)/University Hospitals of Cleveland/Athersys, Inc. partnership. This development, announced in April 1997 in the journal Nature Genetics, will have important applications in the repeatable construction of delivery vehicles for genetically engineered substances.
Some of the 50-75 DS-genetics papers published very recently—between June 1997 and December 1998—are highlighted. The researchers writing these papers come from the U.S., Spain, Japan, France, and the U.K. Recent advances in molecular neurogenetics, including the transplantation of fetal neurons, are covered from a Scientific American article published in June 1997. Also highlighted is a recent review—written by gene-therapy patriarch Dr. W. French Anderson and published in the 30 April 1998 issue of Nature—of the progress of gene therapy in general.
The final sections focus on the June 1998 announcement of the National Institutes of Child Health and Human Development's $10 million grant to Denver-based Eleanor Roosevelt Institute (ERI) for a genetics-based 5-year study of learning in people with DS. The particular interests of ERI President/Senior Fellow (and study leader) Dr. David Patterson are covered in depth, via major quotations from an article he published in the NDSS Conference: The Future Is Ours (July 9-11, 1998) proceedings. This article is entitled "New Opportunities in Research for Down Syndrome and Their Ethical and Social Implications."
It is noted that—with the geometric progress in the pace of genetic-engineering and gene-therapy developments—it is reasonable to conclude that Americans will see gene-based treatments for certain characteristics of DS and its associated Alzheimer's disease within the foreseeable future, possibly even within a few years.

Reaction times verify nondemented status of adults with Down syndrome

17 nondemented adults with Down syndrome (DS; aged 40-55 yrs) were compared to 49 adults of comparable ages and IQs, employing three 2-choice reaction time (RT) tasks. Recent prospective studies have documented the frequent absence of dementia in adults with DS despite the presumed presence of substantial neuropathology consistent with Alzheimer's disease (AD), but indications of dementia might be detectable by tasks not included in the assessment batteries. Because measures of processing speed are sensitive to "early" AD in people without retardation, target search and speeded matching tasks were employed to determine whether DS patients process information more slowly than their peers. Results indicated that no such effects were present, adding to the accumulating evidence that: (a) dementia in DS patients in their 40s and early 50s will not necessarily be present, even in its subtlest forms, and (b) factors must exist that determine risk within this clearly vulnerable population.

A population survey of suicide attempts in persons with and without Down syndrome

This study is a population survey of suicidal behavior in persons with Down syndrome compared to a control population of persons whose mental retardation had other etiologies. The survey was based on the Client Development Evaluation Report, a standardized instrument used by California Department of Developmental Services involving a sample of individuals with Down syndrome. Individuals with Down syndrome had significantly fewer incidences of suicidal behavior as compared to the control group. Of the 11,277 persons with Down syndrome four had suicidal behavior in the previous year compared to 1,142 of 143,143 individuals in the control group. Somewhat unexpectedly, the study also found significantly less depression in persons with Down syndrome compared to the control group. Given a case report of an individual with Down syndrome and suicide behavior who also had epilepsy, the data were analyzed for the relationship of epilepsy and suicidal behavior epilepsy, but not Down syndrome proved to be a significant predictor for suicide behavior.

Comprehensive speech and language intervention for school-aged children with Down syndrome

This article describes a comprehensive speech and language assessment and treatment program for school-aged children with Down syndrome, targeting receptive and expressive language skills, speech skills, oromotor skills, pragmatics skills, and general behavioral performance, including levels of attention and play. The whole language approach, collaborative consultation, and family participation and education are discussed. Specific resources (books and therapy materials) are provided.