Development of clinical practice guidelines for allied health and nursing assessment and management of Duchenne muscular dystrophy.

PURPOSE: To provide evidence-based guidance specific to allied health and nursing practice for the assessment and management of individuals with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: Thirteen key focus areas were identified in consultation with health professionals and consumer advocacy groups. A series of systematic literature reviews were conducted to identify assessment and management strategies for each key focus area. A consensus process using modified Delphi methodology, including an Australia-New Zealand expert consensus meeting, was conducted. Recommendations underwent consultative review with key groups before being finalised and prepared for dissemination. RESULTS: This clinical practice guideline (CPG) generated 19 evidence-based recommendations, 117 consensus-based recommendations and five research recommendations across the 13 focus areas to inform allied health assessment and management of individuals with DMD. CONCLUSIONS: The resulting recommendations can be used in conjunction with existing medical CPGs to improve, standardise and advocate for allied health and rehabilitation care in DMD. The process used here may be useful for the development of CPGs in other rare diseases.Implications for rehabilitationImplementation-ready evidence-based statements to guide clinical care of individuals with DMD are provided with the potential to improve participation, function in the community and quality of life.A model for developing best practice statements for other rare neurological diseases is described.Allied health and nursing health professionals should focus research efforts to generate quality evidence to support rehabilitation practice.

Reliability and validity of the FSHD-composite outcome measure in childhood facioscapulohumeral dystrophy.

This study aims to investigate intra-rater reliability and construct validity of the Facioscapulohumeral Dystrophy Composite Outcome Measure (FSHD-COM), in childhood FSHD. Participants included eighteen children with FSHD, and matched healthy controls. Reliability data were collected from 15 participants with FSHD over two testing sessions. Validity data were collected from all participants. Participants with FSHD completed; the FSHD-COM (and modified pediatric version), Motor Function Measure-32 (MFM-32), FSHD Severity Scales, Performance of the Upper Limb 2.0, Pediatric Quality of Life™ Neuromuscular Module and pediatric FSHD Health-Index Questionnaire. Both versions of the FSHD-COM showed excellent intra-rater reliability (ICC1,2 > 0.99, lower 95%CI > 0.98) with a Minimal Detectable Change (MDC95%) of ≤14.5%. The FSHD-COM had robust and widespread correlations with other related outcome measures. The FSHD-COM versions and 6 min walk test effectively discriminated between children with and without FSHD; the MFM-32 and 10 m walk/run test did not. Ceiling effects were not observed on either version of the FSHD-COM. Reliability and validity findings in this childhood FSHD study concord with estimates in adults. Both versions of the FSHD-COM were effective in discriminating disease in children with mild FSHD symptoms. The FSHD-COM has the potential to be a useful measure of function across the life span.

Is Reluctance to Share Alzheimer's Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?

BACKGROUND: Preclinical Alzheimer's disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed. OBJECTIVE: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment. DESIGN: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure. SETTING: We conducted interviews on campus at the University of California, Irvine. PARTICIPANTS: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study. MEASUREMENTS: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment. RESULTS: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results. CONCLUSIONS: This is one of the first studies to explore how potential preclinical Alzheimer's disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.

Measurement properties and utility of performance-based outcome measures of physical functioning in individuals with facioscapulohumeral dystrophy - A systematic review and evidence synthesis.

Access to reliable, valid, accurate and responsive outcome measures is essential to ensure standards of care and clinical trial readiness in facioscapulohumeral dystrophy. Review aims: 1. identify and provide a descriptive summary of all outcome measures used to measure physical function. 2. systematically appraise the evidence on measurement properties (reliability, construct validity, measurement error and responsiveness) of performance-based outcome measures of physical function in individuals diagnosed with facioscapulohumeral dystrophy. Selected electronic health-related databases were searched from inception - Feb 2019. Two authors independently screened studies for eligibility and extracted data for psychometric evidence. The methodological quality of outcome measure studies was appraised using the consensus-based standards for the selection of health measurement instruments (COSMIN) checklist. Of 12 identified outcome measures, four required high-technology equipment. Only three were FSHD specific. The FSH-clinical score had 'moderate' quality positive evidence for reliability. The remaining measures had 'low' to 'very low' quality evidence supporting properties of reliability, validity, responsiveness and measurement error. Identified studies tended towards low recruitment in middle-aged, ambulant individuals making results hard to generalise across lifespan and levels of severity. There is a paucity of measurement evidence supporting the use of outcome measures in people with facioscapulohumeral dystrophy.

Acute flaccid myelitis in childhood: a retrospective cohort study.

BACKGROUND AND PURPOSE: Clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM. METHODS: This was a retrospective cohort study. RESULTS: Eight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total). CONCLUSIONS: Acute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness.

Observations of body mass index in Duchenne muscular dystrophy: a longitudinal study.

BACKGROUND/OBJECTIVES: Nutritional issues that are associated with Duchenne muscular dystrophy (DMD) remain poorly understood. The aim of this analysis was to describe and explore longitudinal observations of body mass index (BMI) in a cohort of children with DMD. SUBJECTS/METHODS: Anthropometric and clinical characteristics were collected retrospectively and longitudinally for boys with DMD seen in two large neuromuscular clinics. BMI Z-scores were determined using the Centers for Disease Control and Prevention reference values for children (2000). RESULTS: Medical records (n=193) were examined from which 75% were included for analysis. The mean age of the cohort at the time of data collection was 11.9 years, with 72% of patients currently or previously using steroids. The highest prevalence of obesity based on the BMI Z-score was 50% at the age of 10 years. Longitudinally, BMI Z-scores from the age of 2 to 12 years plot approximately one s.d. above the mean, after which there is a marked and progressive decline. BMI gainers were identified for whom BMI Z-score increased by 1.65 units compared with the 0.09 units in non-gainers. BMI gainers were younger when they had their first BMI measurement (5.9 vs 7.2 years), and this measure was significantly lower compared with the non-gainers (BMI Z-score: 0.04 vs 1.17). In this cohort, BMI was associated with age, ambulatory status and lung function. CONCLUSIONS: This study demonstrates that boys with DMD using steroid therapy experience shifts in BMI. A declining BMI appears to be associated with increasing age. Interpretation of growth patterns is limited here by a lack of normative growth references in DMD.

Binaural speech processing in individuals with auditory neuropathy.

Auditory neuropathy disrupts the neural representation of sound and may therefore impair processes contingent upon inter-aural integration. The aims of this study were to investigate binaural auditory processing in individuals with axonal (Friedreich ataxia) and demyelinating (Charcot-Marie-Tooth disease type 1A) auditory neuropathy and to evaluate the relationship between the degree of auditory deficit and overall clinical severity in patients with neuropathic disorders. Twenty-three subjects with genetically confirmed Friedreich ataxia and 12 subjects with Charcot-Marie-Tooth disease type 1A underwent psychophysical evaluation of basic auditory processing (intensity discrimination/temporal resolution) and binaural speech perception assessment using the Listening in Spatialized Noise test. Age, gender and hearing-level-matched controls were also tested. Speech perception in noise for individuals with auditory neuropathy was abnormal for each listening condition, but was particularly affected in circumstances where binaural processing might have improved perception through spatial segregation. Ability to use spatial cues was correlated with temporal resolution suggesting that the binaural-processing deficit was the result of disordered representation of timing cues in the left and right auditory nerves. Spatial processing was also related to overall disease severity (as measured by the Friedreich Ataxia Rating Scale and Charcot-Marie-Tooth Neuropathy Score) suggesting that the degree of neural dysfunction in the auditory system accurately reflects generalized neuropathic changes. Measures of binaural speech processing show promise for application in the neurology clinic. In individuals with auditory neuropathy due to both axonal and demyelinating mechanisms the assessment provides a measure of functional hearing ability, a biomarker capable of tracking the natural history of progressive disease and a potential means of evaluating the effectiveness of interventions.

Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.

Noonan and Cardio-facio-cutaneous (CFC) syndromes are characterized by typical dysmorphic features, cardiac defects, short stature, variable ectodermal anomalies, and intellectual disability. Both belong to the Ras/mitogen-activated protein kinase pathway group of disorders and clinical features overlap other related conditions, notably LEOPARD and Costello syndromes. KRAS mutations account for about 2% of reported Noonan and <5% of reported CFC cases. The mutation spectrum includes recurrent missense changes clustering in particular domains of the KRAS protein and conferring gain-of-function. We report three patients from two unrelated families with novel missense KRAS mutations, p.K147E and p.Y71H. Both mutations affect a residue which is highly conserved in KRAS and other RAS isoforms. One of the families includes a mother and son pair who represent the first report of a vertically transmitted KRAS mutation. In addition, the mother and son pair had peripheral neuropathy, complicated by Charcot arthropathy in the mother. An unusual phenotypic effect of the specific KRAS mutation or a coincidence of two independent disorders may be considered. KRAS mutation-associated phenotypes appear to be subject to considerable clinical heterogeneity. All three cases highlight the challenges of clinical assessment in KRAS mutation-positive patients, and the utility of molecular testing as an adjunct to diagnosis.

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

Pediatric sciatic neuropathies: a 30-year prospective study.

OBJECTIVE: The incidence, cause, and prognosis of sciatic neuropathy in children is not well understood. We report our 30-year experience of 53 patients with pediatric sciatic neuropathies (SN). METHODS: Prospective review of the history, physical examination, electrophysiologic findings, and clinical course of children with SN. RESULTS: The etiology of SN injury was varied and included trauma (13), iatrogenic causes (13) (8 orthopedic surgeries and 5 miscellaneous surgeries), prolonged extrinsic compression and immobilization (6), tumors (7), vascular (5), idiopathic and progressive (4), infantile and nonprogressive (2), and unknown, presumed postviral (3). Electrophysiologic studies demonstrated abnormalities in motor conduction studies of the peroneal nerve in 44/53 (83%) or tibial nerve in 35/51 (67%). Sensory conduction studies were abnormal in sural nerve in 34 of 43 cases (79%), and superficial peroneal nerves in 15/25 (60%). Needle EMG was abnormal in peroneal innervated muscles in all subjects, in tibial nerve innervated muscles in 43/51 (84%), and in the hamstrings in 18/29 (62%). Prognosis for recovery was variable and depended on the etiology and the severity of the nerve injury. CONCLUSIONS: SN is an uncommon mononeuropathy in children. The causes of SN are varied in children compared to adults. Electrophysiologic studies in children may be limited by poor tolerance but play an important role in establishing the diagnosis.

A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood.

OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMTX) is infrequently diagnosed in childhood, and its clinical and neurophysiologic features are not well-described. We reviewed clinical, neurophysiologic, and pathologic findings in 17 children with CMTX. METHODS: This was a retrospective review of children with CMTX from 2 tertiary pediatric hospitals. The diagnosis of CMTX was based on an identifiable connexin 32 mutation (CMTX1) or a consistent pedigree and neurophysiologic features in children without a connexin 32 mutation (CMTX-other). RESULTS: Six boys and 2 girls from 8 kindreds had CMTX1, and 8 boys and 1 girl from 5 kindreds had other forms of CMTX (CMTX-other). Fifteen children, including males and carrier females, were symptomatic from infancy or early childhood (younger than 5 years). In addition to the typical Charcot-Marie-Tooth disease clinical phenotype, some patients had delayed motor development, sensorineural hearing loss, tremor, pathologic fractures, or transient CNS disturbances. Eleven children underwent nerve conduction studies. Median nerve motor nerve conduction velocities were in the intermediate to normal range (30-54 m/s) in all children older than 2 years. Axon loss, reflected by low-amplitude compound muscle action potentials, was present in all patients. A pattern of X-linked dominant inheritance, with carrier females showing an abnormal neurologic or neurophysiologic examination, correlated with the presence of a connexin 32 mutation in all but 2 pedigrees. CONCLUSIONS: The clinical phenotype of CMTX is broader than previously reported. Onset in males and carrier females is most often in early childhood. Families with an X-linked dominant inheritance pattern are likely to have CMTX1.

Determinants of reduced health-related quality of life in pediatric inherited neuropathies.

OBJECTIVE: We have shown that health-related quality of life (QOL) in children with inherited neuropathies (Charcot-Marie-Tooth disease [CMT]) is significantly reduced compared to population norms, thus establishing its utility as an outcome measure in therapeutic trials. However, the Australian ascorbic acid trial in children with CMT type 1A (CMT1A) identified no change in QOL scores despite a trend toward improvement in nerve conduction velocities in the treated group. The objective of this study was to identify clinical, electrophysiologic, and functional correlates of QOL in children with CMT1A, to guide future investigations of strategies to improve QOL and reduce disability in these patients. METHODS: In this cross-sectional study, a series of multivariate regression models were developed to determine whether QOL scores could be explained by demographic and symptom data, standardized measures of gross motor function, foot/ankle and hand/finger involvement, electrophysiology, and gait characteristics in 70 children aged 5-16 years with CMT1A. RESULTS: Independent determinants of reduced QOL in children with CMT1A, from strongest to weakest, were leg cramps, hand tremor, short step length, reduced long jump distance, ankle inflexibility, poor agility and endurance, advancing age, and foot drop. Many of the standardized clinical and electrophysiologic measures used as endpoints in clinical trials of CMT correlated poorly with QOL. CONCLUSION: QOL is negatively affected by CMT1A in children. Multivariate modeling suggests that interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility might have a substantial effect on QOL in children with CMT1A.

Autosomal dominant congenital spinal muscular atrophy--a possible developmental deficiency of motor neurones?

We describe a kindred with an unusual congenital lower motor neuron disorder with significant but static muscle weakness predominantly affecting the lower limbs. The proband had talipes equinovarus and congenital hip contractures and did not walk until 19 months of age. Lower-extremity predominant, primarily proximal weakness was identified on assessment at three years. Over a 20 year follow-up there has been no clinical progression. The proband has a four-year-old daughter with very similar clinical findings. Electromyography and muscle biopsy suggest reduced numbers of giant normal duration motor units with little evidence of denervation or reinnervation. Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described. It is possible that the disorder is due to a congenital deficiency of motor neurons.

Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.

OBJECTIVE: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations. METHODS: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined. RESULTS: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations. CONCLUSION: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Interventions for the prevention and treatment of pes cavus.

BACKGROUND: People with pes cavus frequently suffer foot pain, which can lead to significant disability. Despite anecdotal reports, rigorous scientific investigation of this condition and how best to manage it is lacking. OBJECTIVES: To assess the effects of interventions for the prevention and treatment of pes cavus. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (April 2007), MEDLINE (January 1966 to April 2007), EMBASE (January 1980 to April 2007), CINAHL (January 1982 to April 2007), AMED (January 1985 to April 2007), all EBM Reviews (January 1991 to April 2007), SPORTdiscuss (January 1830 to April 2007) and reference lists of articles. We also contacted known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials of interventions for the treatment of pes cavus. We also included trials aimed at preventing or correcting the cavus foot deformity. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Only one trial (custom-made foot orthoses) fully met the inclusion criteria. Two additional cross-over trials (off-the-shelf foot orthoses and footwear) were also included. Both studies assessed secondary biomechanical outcomes less than three-months after randomisation. Data used in the three studies could not be pooled due to heterogeneity of diagnostic groups and outcome measures. The one trial that fully met the inclusion criteria investigated the treatment of cavus foot pain in 154 adults over a three month period. The trial showed a significant reduction in the level of foot pain, measured using the validated 100-point Foot Health Status Questionnaire, with custom-made foot orthoses versus sham orthoses (WMD 10.90; 95% CI 3.21 to 18.59). Furthermore, a significant improvement in foot function measured with the same questionnaire was reported with custom-made foot orthoses (WMD 11.00; 95% CI 3.35 to 18.65). There was also an increase in physical functioning of the Medical Outcomes Short Form - 36 (WMD 9.50; 95% CI 4.07 to 14.93). There was no difference in reported adverse events following the allocation of custom-made (9%) or sham foot orthoses (15%) (RR 0.61; 95% CI 0.26 to 1.48). AUTHORS' CONCLUSIONS: In one randomised controlled trial, custom-made foot orthoses were significantly more beneficial than sham orthoses for treating chronic musculoskeletal foot pain associated with pes cavus in a variety of clinical populations. There is no evidence for any other type of intervention for the treatment or prevention of foot pain in people with a cavus foot type.

Oropharyngeal dysphagia in juvenile dermatomyositis (JDM): an evaluation of videofluoroscopy swallow study (VFSS) changes in relation to clinical symptoms and objective muscle scores.

OBJECTIVE: To determine if objective, validated scores of muscle weakness and function [manual muscle testing (MMT), childhood myositis assessment scale (CMAS)] or scores of general disease activity or function [childhood health assessment questionnaire and physician global assessment of disease activity visual analogue scale (VAS)], can predict children at risk of swallow abnormalities in juvenile dermatomyositis (JDM) measured by videofluoroscopic swallow studies (VFSS). METHODS: Patients were referred for speech and language dysphagia assessment upon diagnosis of JDM or flare of disease. VFSS was used to document a swallow score indicating severity of swallow dysfunction. Clinical symptoms, examination findings and objective scores of disease activity were analysed. Any correlation was looked for using chi-squared Fisher exact test and linear regression models. RESULTS: Fourteen patients with inflammatory myopathy (age 2-16 years) had clinical assessments and VFSS. VFSS was abnormal in 11 children (79%). Only two children were asymptomatic at assessment, but both had swallow dysfunction, including aspiration, on VFSS. In contrast, three of the symptomatic children had a normal VFSS. No relationship was found between objective disease severity scores and VFSS swallow score. CONCLUSIONS: This study failed to show any correlation between swallow score and objective measures of muscle strength and function (MMT/CMAS) or general disease activity and function [physician VAS/childhood health assessment questionnaire (CHAQ)]. In the absence of a more accurate assessment method to determine which children with active JDM are most at risk of swallow dysfunction and aspiration, all children with active dermatomyositis should be referred for speech and language assessment and VFSS.

Outcome of noninvasive ventilation in children with neuromuscular disease.

OBJECTIVE: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. METHODS: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. RESULTS: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. CONCLUSION: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.

Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes.

Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22,000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.

Sec14p-like proteins regulate phosphoinositide homoeostasis and intracellular protein and lipid trafficking in yeast.

The major PI (phosphatidylinositol)/PC (phosphatidylcholine)-transfer protein in yeast, Sec14p, co-ordinates lipid metabolism with protein transport from the Golgi complex. Yeast also express five additional gene products that share 24-65% primary sequence identity with Sec14p. These Sec14p-like proteins are termed SFH (Sec Fourteen Homologue) proteins, and overexpression of certain individual SFH gene products rescues sec14-1(ts)-associated growth and secretory defects. SFH proteins are atypical in that these stimulate the transfer of PI, but not PC, between distinct membrane bilayer systems in vitro. Further analysis reveals that SFH proteins functionally interact with the Stt4p phosphoinositide 4-kinase to stimulate PtdIns(4,5)P(2) synthesis which in turn activates phospholipase D. Finally, genetic analyses indicate that Sfh5p interfaces with the function of specific subunits of the exocyst complex as well as the yeast SNAP-25 (25 kDa synaptosome-associated protein) homologue, Sec9p. Our current view is that Sfh5p regulates PtdIns(4,5)P(2) homoeostasis at the plasma membrane, and that Sec9p responds to that regulation. Thus SFH proteins individually regulate specific aspects of lipid metabolism that couple, with exquisite specificity, with key cellular functions.