The longitudinal effects of a physical activity programme on the physical fitness and disability of back pain patients: Service evaluation.

OBJECTIVE: To evaluate the longitudinal effect of a group physical activity service to help patients self-manage un-resolving back pain. BACKGROUND: Back pain is one of the most common and costly conditions. Large scale trials have demonstrated a role for less traditional treatment including exercise, yet the long term effects of patient centred, group physical activity programmes remains unclear. METHODS: One hundred and eighty-one un-resolving back pain patients (aged 53 ± 17 years) completed a 6 × 2 h physical activity programme. All activities were relevant to activities of daily living and incorporated activities to develop aerobic fitness, flexibility, core activation, and muscular strength and endurance. Dietary advice, home diaries and pedometers were provided. RESULTS: Measures of back pain, aerobic fitness, muscular endurance and body composition showed significant (p< 0.05) pre-post intervention improvements. Disability rating decreased by 19% alongside improvements in aerobic fitness (15%), back extension (36%) back flexion (16%) and grip strength (5%). Six month follow up identified (p< 0.05) reductions in body fat (6.5%) whilst aerobic fitness, disability rating and muscular strength and endurance remained stable. CONCLUSION: Group physical activity programmes could contribute to the self-management of back pain, enabling sustained improvements in fitness, physical activity and body fatness.

Survey of family history taking and genetic testing in pediatric practice.

Family health history collection and genetic testing are core elements for the successful translation of genomics into primary care practice. Yet, little is known about how pediatric providers implement these elements in practice. We surveyed the membership of the American Academy of Pediatrics regarding family health history (FHH) collection and genetic testing in the primary care setting. Three hundred forty-nine (349) responses were analyzed with the initial response rate of 43.3%. Four principal findings were noted-(1) family health history is still recognized as a critical part of the medical evaluation; (2) perceived obstacles for FHH are time in obtaining the FHH and concerns about the family's knowledge of their FHH; (3) a 3-generation family history is out of the scope of routine care and alternate methods should be considered; (4) most primary care providers (PCPs) do not feel comfortable ordering, interpreting, and counseling regarding current genetic testing. Expanded genetic/genomic education at multiple levels (undergraduate medical education, graduate medical education, and maintenance of certification) is clearly indicated to allow PCPs to integrate these vital elements into a current evaluation (acute care or health maintenance) in the primary care setting.

Beyond the Genetic Diagnosis: Providing Parents What They Want to Know.

Clinicians need to provide accurate, up-to-date, and balanced information to parents following a prenatal or postnatal diagnosis of Down syndrome and other genetic conditions. Families want information about the genomic outcomes and medical issues, but they also want information about life outcomes and social supports. Because the anticipated outcomes of a condition can change significantly based on available social support, health care, and services, it is important for clinicians to stay up-to-date about new developments and credible, medically reviewed information about Down syndrome and other genetic conditions to access resources for clinical care.

The SSV Evaluation System: A Tool to Prioritize Short Structural Variants for Studies of Possible Regulatory and Causal Variants.

Short structural variants (SSVs) are short genomic variants (<50 bp) other than SNPs. It has been suggested that SSVs contribute to many human complex traits. However, high-throughput analysis of SSVs presents numerous technical challenges. In order to facilitate the discovery and assessment of SSVs, we have developed a prototype bioinformatics tool, "SSV evaluation system," which is a searchable, annotated database of SSVs in the human genome, with associated customizable scoring software that is used to evaluate and prioritize SSVs that are most likely to have significant biological effects and impact on disease risk. This new bioinformatics tool is a component in a larger strategy that we have been using to discover potentially important SSVs within candidate genomic regions that have been identified in genome-wide association studies, with the goal to prioritize potential functional/causal SSVs and focus the follow-up experiments on a relatively small list of strong candidate SSVs. We describe our strategy and discuss how we have used the SSV evaluation system to discover candidate causal variants related to complex neurodegenerative diseases. We present the SSV evaluation system as a powerful tool to guide genetic investigations aiming to uncover SSVs that underlie human complex diseases including neurodegenerative diseases in aging.

A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression.

INTRODUCTION: We recently showed that tagging single-nucleotide polymorphisms across the SNCA locus were significantly associated with increased risk for Lewy body (LB) pathology in Alzheimer's disease (AD) cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive. METHODS: We used a bioinformatics algorithm to catalog structural variants in a region of SNCA intron 4, followed by phased sequencing. We performed a genetic association analysis in autopsy series of LB variant of Alzheimer's disease (LBV/AD) cases compared with AD-only controls. We investigated the biological functions by expression analysis using temporal-cortex samples. RESULTS: We identified four distinct haplotypes within a highly polymorphic low-complexity cytosine-thymine (CT)-rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT-rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA messenger RNA. DISCUSSION: We have discovered a novel haplotype in a CT-rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis-regulation of the gene expression.

Surveying the current landscape of clinical genetics residency training.

PURPOSE: Further knowledge about medical genetics residency training structure and function could help advance this educational process. METHODS: Medical genetics residency program directors were surveyed about their trainees' backgrounds and skills as well as the recruitment and matching process. RESULTS: Previous resident training was predominantly in pediatrics (49%). Average ratings of residents' beginning clinical knowledge (scale of 1-10, minimal to superior) were: dysmorphology - 3.5, inborn errors of metabolism - 2.5, prenatal genetics - 2.6, and cancer genetics - 2.8. On average, four months of research were required for categorical residency and fifteen months for combined residency. For the 2011 transition to ERAS/NRMP, 69% of program directors were extremely or somewhat prepared; however, 21% felt unprepared. The number of trainees at most institutions remained unchanged. 36% of respondents reported that ERAS/NRMP has had no impact on recruitment of trainees, and 26% felt it has had a slightly positive impact. Continued utilization was recommended by 71% while 5% disagreed. CONCLUSION: Genetics residents come from diverse training backgrounds. Their education can be directed toward specific areas of perceived initial weakness. ERAS/NRMP has not drastically increased entrance into the field. Further discussions are merited regarding enhancement of medical genetics residency recruitment and training.

African-American TOMM40'523-APOE haplotypes are admixture of West African and Caucasian alleles.

BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40'523-APOE haplotypes. METHODS: We have compared the APOE and TOMM40'523 phased haplotype frequencies of a 9.5 kb TOMM40/APOE genomic region in West African, Caucasian, and African-American cohorts. RESULTS: African-American haplotype frequency scans of poly-T lengths connected in phase with either APOE ε4 or APOE ε3 differ from both West Africans and Caucasians and represent admixture of several distinct West African and Caucasian haplotypes. A new West African TOMM40'523 haplotype, with APOE ε4 connected to a short TOMM40'523 allele, is observed in African-Americans but not Caucasians. CONCLUSION: These data have therapeutic implications for the age of onset risk algorithm estimates and the design of a prevention trial for African-Americans or other mixed ethnic populations.

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations.

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.

Genetic services and attitudes in primary care pediatrics.

Given the integral role primary care pediatricians (PCPs) play in caring for children with genetic conditions, we aimed to identify current practices of PCPs regarding genetic patients, their attitudes toward genetic medical care and their choices regarding family history taking. We conducted an on-line survey of a national convenience sample of PCPs associated with the American Academy of Pediatrics' Quality Improvement Innovation Networks. Eighty-eight respondents (29% response rate) were included in the analysis. Seventy-four (86%) reported ordering genetic based tests three or less times annually. Eleven (13%) strongly agreed that they discuss with patients the potential risks, benefits, and limitations of genetic tests. Forty-three (49%) agreed or strongly agreed that they feel competent in providing healthcare to patients related to genetics and genomics. Perceived competence was not associated with more recent training (P = 0.29), number of genetic tests ordered annually (P = 0.84) or mean number of weekly patient encounters (P = 0.15). 100% of participants stated that taking a family history is important. 27 (31%) agreed or strongly agreed that they gather a minimum of a three-generation family history. Forty-one of the 63 participants with an electronic health record (65%) reported their system was fair or poor in its ability to easily capture a three-generation family history. PCPs interested in quality improvement reported variation in care practices for children with genetic diseases and a majority did not feel competent to provide genetic related healthcare. Research should focus on improving the care and diagnosis of children with genetic disorders and enhanced integration of genetic medicine into routine primary preventative care.

A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.

'Salt & Pepper' syndrome is an autosomal recessive condition characterized by severe intellectual disability, epilepsy, scoliosis, choreoathetosis, dysmorphic facial features and altered dermal pigmentation. High-density SNP array analysis performed on siblings first described with this syndrome detected four shared regions of loss of heterozygosity (LOH). Whole-exome sequencing narrowed the candidate region to chromosome 2p11.2. Sanger sequencing confirmed a homozygous c.994G>A transition (p.E332K) in the ST3GAL5 gene, which encodes for a sialyltransferase also known as GM3 synthase. A different homozygous mutation of this gene has been previously associated with infantile-onset epilepsy syndromes in two other cohorts. The ST3GAL5 enzyme synthesizes ganglioside GM3, a glycosophingolipid enriched in neural tissue, by adding sialic acid to lactosylceramide. Unlike disorders of glycosphingolipid (GSL) degradation, very little is known regarding the molecular and pathophysiologic consequences of altered GSL biosynthesis. Glycolipid analysis confirmed a complete lack of GM3 ganglioside in patient fibroblasts, while microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other GSL biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked and GSL glycans revealed collateral alterations in response to loss of complex gangliosides in patient fibroblasts and in zebrafish embryos injected with antisense morpholinos that targeted zebrafish st3gal5 expression. Morphant zebrafish embryos also exhibited increased apoptotic cell death in multiple brain regions, emphasizing the importance of GSL expression in normal neural development and function.

Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder.

PURPOSE: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. METHODS: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. RESULTS: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. CONCLUSION: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.

Genetic and genomic literacy in pediatric primary care.

A colloquium on genetic literacy in pediatric primary care sponsored by the Health Resources and Services Administration Maternal and Child Health Bureau was held at the American Academy of Pediatrics headquarters on October 2-3, 2012. The overarching goal of the colloquium was to provide context for delivery of genetics-related services in day-to-day pediatric primary care practice, encompassing 3 dimensions of medicine: prevention, diagnosis, and management. Participants considered the whole spectrum of disease, from rare disorders to common disorders, the genetics-related components of which are often overlooked. Specific topics included family history, genomics, genetic literacy and competency, epigenetics, and a focused view of primary care and genetics. A consensus statement was developed to provide recommendations for integration of genetics into pediatric primary care.

Epigenetics and primary care.

Epigenetics, the study of functionally relevant chemical modifications to DNA that do not involve a change in the DNA nucleotide sequence, is at the interface between research and clinical medicine. Research on epigenetic marks, which regulate gene expression independently of the underlying genetic code, has dramatically changed our understanding of the interplay between genes and the environment. This interplay alters human biology and developmental trajectories, and can lead to programmed human disease years after the environmental exposure. In addition, epigenetic marks are potentially heritable. In this article, we discuss the underlying concepts of epigenetics and address its current and potential applicability for primary care providers.

Clinical utility of the X-chromosome array.

Previous studies have limited the use of specific X-chromosome array designed platforms to the evaluation of patients with intellectual disability. In this retrospective analysis, we reviewed the clinical utility of an X-chromosome array in a variety of scenarios. We divided patients according to the indication for the test into four defined categories: (1) autism spectrum disorders and/or developmental delay and/or intellectual disability (ASDs/DD/ID) with known family history of neurocognitive disorders; (2) ASDs/DD/ID without known family history of neurocognitive disorders; (3) breakpoint definition of an abnormality detected by a different cytogenetic test; and (4) evaluation of suspected or known X-linked conditions. A total of 59 studies were ordered with 27 copy number variants detected in 25 patients (25/59 = 42%). The findings were deemed pathogenic/likely pathogenic (16/59 = 27%), benign (4/59 = 7%) or uncertain (7/59 = 12%). We place particular emphasis on the utility of this test for the diagnostic evaluation of families affected with X-linked conditions and how it compares to whole genome arrays in this setting. In conclusion, the X-chromosome array frequently detects genomic alterations of the X chromosome and it has advantages when evaluating some specific X-linked conditions. However, careful interpretation and correlation with clinical findings is needed to determine the significance of such changes. When the X-chromosome array was used to confirm a suspected X-linked condition, it had a yield of 63% (12/19) and was useful in the evaluation and risk assessment of patients and families.

Improving newborn screening follow-up in pediatric practices: quality improvement innovation network.

OBJECTIVE: To implement a 6-month quality improvement project in 15 primary care pediatric practices to improve short-term newborn screening (NBS) follow-up. METHODS: At the start of the project, each practice completed a survey to evaluate office systems related to NBS and completed a chart audit. Practice teams were provided information about NBS and trained in quality-improvement methods, and then implemented changes to improve care. Monthly chart audits over a 6-month period were completed to assess change. RESULTS: At baseline, almost half of practices completed assessment of infants for NBS; after 6 months, 80% of practices completed assessment of all infants. Only 2 practices documented all in-range results and shared them with parents at baseline; by completion, 10 of 15 practices documented and shared in-range results for ≥ 70% of infants. Use of the American College of Medical Genetics ACTion sheets, a decision support tool, increased from 1 of 15 practices at baseline to 7 of 15 at completion. CONCLUSIONS: Practices were successful in improving NBS processes, including assessment, documentation, and communication with families. Providers perceived no increase in provider time at first visit, 2- to 4-week visit, or during first contact with the family of an infant with an out-of-range result after implementation of improved processes. Primary care practices increased their use of decision support tools after the project.

Health supervision for children with fragile X syndrome.

Fragile X syndrome (an FMR1-related disorder) is the most commonly inherited form of mental retardation. Early physical recognition is difficult, so boys with developmental delay should be strongly considered for molecular testing. The characteristic adult phenotype usually does not develop until the second decade of life. Girls can also be affected with developmental delay. Because multiple family members can be affected with mental retardation and other conditions (premature ovarian failure and tremor/ataxia), family history information is of critical importance for the diagnosis and management of affected patients and their families. This report summarizes issues for fragile X syndrome regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and age-related health supervision guidelines. The diagnosis of fragile X syndrome not only involves the affected children but also potentially has significant health consequences for multiple generations in each family.

Neuro-ophthalmology and the Anti-GQ1b antibody syndromes.

The discovery of the association of the anti-GQ1b IgG antibody with the postinfectious clinical syndromes of ophthalmoplegia, ataxia, and areflexia helped house the phenotypes of the Miller Fisher syndrome (MFS), atypical MFS, Guillain-Barré syndrome with ophthalmoplegia, and Bickerstaff's brainstem encephalitis under one roof. The neuro-ophthalmologic signs classically predominate and may vary from case to case, but they maintain clinically recognizable patterns that assist with the diagnosis. The identification of a common lipopolysaccharide on the plasma membrane in human cranial and peripheral nerves at the GQ1b epitope and on infectious particles of bacteria and viruses (ie, Campylobacter jejuni) demonstrates molecular mimicry. The high frequency of oculomotor dysfunction is partially explained by the tissue ganglioside concentration and distribution and the attraction of antibody-stimulating complement activation. Current experimental treatment targets antibody removal and neutralization and prevents membrane attack complex formation through deactivation of complement. This article aims to bring together the historically disparate opinions on the origins of these syndromes as either a purely peripheral nervous system or central nervous system dysfunction, highlight the clinical neuro-ophthalmologic signs, discuss some of the biology of the anti-GQ1b antibody, and review imaging abnormalities and treatment of this fascinating disorder.