McLeod syndrome: Five new pedigrees with novel mutations.

OBJECTIVE: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations. METHODS: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center. RESULTS: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity. CONCLUSIONS: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS.

Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive degeneration of the central nervous system and high basal ganglia iron deposition. The list of identified causative genes for NBIA syndromes continues to expand and includes one autosomal dominant, one X-linked, and a number of recessive forms. Mitochondrial membrane protein-associated neurodegeneration is a recently described NBIA syndrome caused by C19orf12 mutations. In this study, we report two consanguineous families with a homozygous C19orf12 p.Thr11Met mutation. Our patients presented at a later age and had more rapid disease progression, leading to early death in two, than those previously reported. We conclude that C19orf12 mutation is associated with wide phenotypic heterogeneity, and that further research is needed to examine the role of C19orf12 in NBIA and related diseases and to elucidate its protein function as well as other factors that may affect disease progression and expression.

Increased expression of receptor phosphotyrosine phosphatase-ß/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes.

Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-ß/ζ (RPTP ß/ζ) and that the gene encoding RPTPß/ζ (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPß/ζ in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPß/ζ (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTPß/ζ signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPß/ζ as a therapeutic target in schizophrenia.

Neurologic phenotypes associated with acanthocytosis.

The term "neuroacanthocytosis" is normally used to refer to autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome, but there are other movement disorders in which erythrocyte acanthocytosis may also be seen, such as Huntington disease-like 2 and pantothenate kinase-associated neurodegeneration. Disorders of serum lipoproteins such as Bassen-Kornzweig disease form a distinct group of neuroacanthocytosis syndromes in which ataxia is observed, but movement disorders are not seen. Genetic testing has enabled us to distinguish between these disorders, even when there are considerable similarities between phenotypes. Improved detection is important for accurate genetic counseling, for monitoring for complications, and, it is hoped, for implementing causal treatments, once these become available. As in other neurodegenerative conditions, animal models are a promising strategy for the development of such therapies.

Cost effectiveness of a community based research project to help women quit smoking.

OBJECTIVE: To estimate the cost effectiveness of a four year, multifaceted, community based research project shown previously to help women quit smoking. DESIGN: A quasi-experimental matched control design. SETTING: Two counties in Vermont and two in New Hampshire, USA. SUBJECTS: Women aged 18-64 years. METHODS: Costs were the grant related expenditures converted to 2002 US dollars. Survey results at the end of the intervention were used to estimate the numbers of never smokers, former smokers, light smokers, and heavy smokers in the intervention and comparison counties, and 1986 life tables for populations of US women categorised by smoking status to estimate the gain in life expectancy. MAIN OUTCOME MEASURES: Cost effectiveness ratios, as dollars per life-year saved, for the intervention only and for total grant costs (intervention, evaluation and indirect costs). RESULTS: The cost effectiveness ratio for the intervention, in 2002 US dollars per life-year saved, discounted at 3%, was 1156 dollars (90% confidence interval (CI) 567 dollars to infinity), and for the total grant, 4022 dollars (90% CI 1973 dollars to infinity). When discounted at 5%, these ratios were 1922 dollars (90% CI 1024 dollars to 15,647 dollars), and 6683 dollars (90% CI 3555 dollars to 54,422 dollars), respectively. CONCLUSION: The cost effectiveness ratios of this research project are economically attractive, and are comparable with other smoking cessation interventions for women. These observations should encourage further research and dissemination of community based interventions to reduce smoking.

Transgenic mouse model of early-onset DYT1 dystonia.

Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice, although levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.

Factors associated with arm swelling after breast cancer surgery.

PURPOSE: As life expectancy improves for women with breast cancer, more women will be living with symptoms of lymphedema. This study reports the incidence of arm or hand swelling and associated risk factors in women with invasive breast cancer following surgery. METHODS: Data were obtained from baseline and follow-up interviews of women with invasive breast cancer (n = 145), and mammography and pathology records. The Kaplan-Meier method was used to estimate the probability of developing arm or hand swelling over time. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for arm or hand swelling. RESULTS: Of women in this study, 38% self-reported arm or hand swelling. There was a significantly increased risk of arm swelling if women were under 50 years of age, had axillary node dissection, received chemotherapy, worked outside the home, and had a high household income. There was no association of body weight with swelling. A significantly decreased risk of arm swelling was found in women who were on treatment for high blood pressure. After adjustment for nodal dissection, only age had a significant independent effect. CONCLUSIONS: Our study highlights two important areas of future research that could reduce the incidence of lymphedema. There is a need to better understand the role that treatment for high blood pressure may play in protecting women from arm edema. Second, the potential effect of weight as a modifiable lymphedema risk factor needs to be studied in more detail in light of the conflicting results of different studies.

Huntington's disease--like 2 can present as chorea-acanthocytosis.

Three patients from a previously described family with autosomal dominant chorea-acanthocytosis were found to have the CTG trinucleotide repeat expansion mutation of the junctophilin-3 gene associated with Huntington's disease-like 2 (HDL2). One of six previously identified patients with HDL2 had acanthocytosis on peripheral blood smear, suggesting that HDL2 should be considered in the differential of chorea-acanthocytosis.

Phenotypic features of myoclonus-dystonia in three kindreds.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the epsilon-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2)gene (one family). OBJECTIVE: To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. METHODS: Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. RESULTS: Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. CONCLUSIONS: Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.

Community interventions for reducing smoking among adults.

BACKGROUND: Since smoking behaviour is determined by social context, the best way to reduce the prevalence of smoking may be to use community-wide programmes which use multiple channels to provide reinforcement, support and norms for not smoking. OBJECTIVES: To assess the effectiveness of community interventions for reducing the prevalence of smoking. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group specialised register, MEDLINE (1966-August 2001) and EMBASE (1980-August 2001) and reference lists of articles. SELECTION CRITERIA: Controlled trials of community interventions for reducing smoking prevalence in adult smokers. The primary outcome was smoking behaviour. DATA COLLECTION AND ANALYSIS: Data were extracted by one person and checked by a second. MAIN RESULTS: Thirty two studies were included, of which seventeen included only one intervention and one comparison community. Only four studies used random assignment of communities to either the intervention or comparison group. The population size of the communities ranged from a few thousand to over 100,000 people. Change in smoking prevalence was measured using cross-sectional follow-up data in 27 studies. The estimated net decline ranged from -1.0% to 3.0% for men and women combined (10 studies). For women, the decline ranged from -0.2% to + 3.5% per year (n=11), and for men the decline ranged from -0.4% to +1.6% per year (n=12). Cigarette consumption and quit rates were only reported in a small number of studies. The two most rigorous studies showed limited evidence of an effect on prevalence. In the US COMMIT study there was no differential decline in prevalence between intervention and control communities, and there was no significant difference in the quit rates of heavier smokers who were the target intervention group. In the Australian CART study there was a significantly greater quit rate for men but not women. REVIEWER'S CONCLUSIONS: The failure of the largest and best conducted studies to detect an effect on prevalence of smoking is disappointing. A community approach will remain an important part of health promotion activities, but designers of future programmes will need to take account of this limited effect in determining the scale of projects and the resources devoted to them.

Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions.

BACKGROUND: The term chorea-acanthocytosis describes a heterogeneous group of neurodegenerative disorders with variable clinical features and modes of inheritance. The characteristic acanthocytic appearance of red blood cells is attributed to abnormalities of a membrane protein, band 3, although the relationship between this and the neurodegenerative process has yet to be determined. OBJECTIVE: To describe features of phenotype, inheritance, and neuropathological findings in a family with this disorder. METHODS: Clinical and hematologic evaluations were performed on all available family members and neuropathological examination was performed on one case. RESULTS: Autosomal dominant inheritance was evident, with variable clinical features of chorea or parkinsonism, marked cognitive changes, but no seizures or peripheral neurologic abnormalities. Abnormalities of band 3 were demonstrated on gel electrophoresis of red blood cell membranes. Neuropathological examination revealed severe neuronal loss of the caudate-putamen and intranuclear inclusion bodies in many areas of the cerebral cortex. These inclusion bodies were immunoreactive for ubiquitin, expanded polyglutamine repeats, and torsinA. CONCLUSIONS: This family extends the genetic spectrum of chorea-acanthocytosis to include autosomal dominant inheritance, possibly due to expanded trinucleotide repeats. Intraneuronal inclusion bodies have recently been associated with a wide range of inherited neurodegenerative disorders and may provide a clue to etiopathogenesis, in addition to potentially indicating a function of torsinA.

TorsinA immunoreactivity in brains of patients with DYT1 and non-DYT1 dystonia.

A mutation of the DYT1 gene, which codes for torsinA, has been identified as the cause of one form of autosomal dominantly inherited dystonia. TorsinA immunohistochemistry was used to examine a case of DYT1, and several cases of non-DYT1, dystonia. No evidence was found for alterations of immunoreactivity at the light microscopic level, specifically neither cytoplasmic aggregations nor colocalization of torsinA immunoreactivity with a marker for endoplasmic reticulum. These findings contrast with results of recent cell culture studies of torsinA.

The Harris-Galante Porous acetabular component at intermediate follow-up.

Outcome of the acetabular component in 90 consecutive primary noncemented total hip arthroplasties (THAs) was prospectively studied. The acetabular cup consisted of a hemispherical titanium alloy shell with a titanium fiber-mesh porous coating and a modular polyethylene liner (Harris-Galante Porous-1, Zimmer, Warsaw, Ind). The cup was implanted using line-to-line reaming with adjunctive dome screw fixation. The femoral component consisted of a titanium alloy stem with titanium fiber-mesh porous coating and a 28-mm cobalt-chrome modular head. Mean patient age was 53 years (range: 27-75 years); male:female ratio was 48:42; and mean follow-up was 6 years (range: 4.5-8 years). One acetabular component was revised for aseptic loosening. Of 81 unrevised hips available for follow-up, mean Harris hip score was 57 preoperatively and 96 at final follow-up (72% excellent, 15% good, 1 3% fair, and none poor). Of 61 unrevised hips with adequate radiographic follow-up, radiographic failure (complete periprosthetic radiolucency) was evident in 3 (4.9%) and periacetabular osteolysis in none. Radiographic failure did not correlate with poor clinical outcome. Linear polyethylene wear rate (mean: 0.13 mm/year) did not correlate with age, gender, weight, outcome, or cup abduction angle, but did correlate with the presence of femoral periprosthetic osteolysis (0.18 mm/year with femoral osteolysis versus 0.11 mm/year without; P= .01). This series of porous-coated hemispherical cups demonstrated excellent intermediate-term clinical and radiographic outcome, comparable with similarly favorable results reported by the prosthesis designers. A potentially adverse effect of polyethylene wear on the longevity of a THA was supported by a positive correlation between polyethylene wear rate and femoral osteolysis.

Distribution and immunohistochemical characterization of torsinA immunoreactivity in rat brain.

A mutation of the DYT1 gene on chromosome 9q34 has recently been identified as the cause of one form of autosomal-dominantly inherited dystonia. TorsinA, the protein product of this gene, has homology with the family of heat shock proteins, and is found in many peripheral tissues and brain regions. We used a polyclonal antibody to torsinA, developed in our laboratory, to systematically examine the regional distribution of torsinA in rat brain. We find that neurons in all examined structures are immunoreactive for this protein. There is intense immunoreactivity in most neuronal nuclei, with slightly less labeling of cytoplasm and proximal processes. Terminals also are labeled, especially in striatum, neocortex and hippocampus. Double-labeling fluorescence immunohistochemistry using antibodies to neurotransmitters and other neurochemical markers demonstrated that the majority of neurons of all studied neurochemical types are immunoreactive for torsinA. Our findings indicate that torsinA is widely distributed in the central nervous system implicating additional, localized factors, perhaps within the basal ganglia, in the development of dystonia. Many other proteins have a similar widespread distribution, including some which have been implicated in other movement disorders and neurodegenerative processes, such as parkin, alpha-synuclein, ubiquitin and huntingtin. The distribution of torsinA in rat brain as demonstrated by immunohistochemistry contrasts with the results of in situ hybridization studies of torsinA mRNA in human postmortem brain in which a more limited distribution was found.

McLeod neuroacanthocytosis: genotype and phenotype.

McLeod syndrome is caused by mutations of XK, an X-chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

Intrathecal baclofen for dystonia: benefits and complications during six years of experience.

Fourteen patients with primary or secondary dystonia received intrathecal baclofen (ITB) through an implanted pump following a trial dose. Patients were selected for ITB trial if they had clinically unsatisfactory responses to oral antidystonic medications, including oral baclofen. Patients were rated using the Burke-Fahn-Marsden rating scale by a blinded rater after the dose of ITB was optimized. Five patients experienced improvement in symptoms as determined by a change in rating scale scores, although only two had a clear clinical benefit. Etiology of dystonia did not determine the efficacy of ITB therapy, as benefit or failure was seen in both primary and secondary dystonia.