Terahertz phase contrast imaging of sorption kinetics in porous coordination polymer nanocrystals using differential optical resonator.

The enhancement of light-matter coupling when light is confined to wavelength scale volumes is useful both for studying small sample volumes and increasing the overall sensing ability. At these length scales, nonradiative interactions are of key interest to which near-field optical techniques may reveal new phenomena facilitating next-generation material functionalities and applications. Efforts to develop novel chemical or biological sensors using metamaterials have yielded innovative ideas in the optical and terahertz frequency range whereby the spatially integrated response over a resonator structure is monitored via the re-radiated or leaked light. But although terahertz waves generally exhibit distinctive response in chemical molecules or biological tissue, there is little absorption for subwavelength size sample and therefore poor image contrast. Here, we introduce a method that spatially resolves the differential near-field phase response of the entire resonator as a spectral fingerprint. By simultaneously probing two metallic ring resonators, where one loaded with the sample of interest, the differential phase response is able to resolve the presence of guest molecules (e.g. methanol) as they are adsorbed or released within the pores of a prototypical porous coordination polymer.

Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry.

BACKGROUND: Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. METHODS AND RESULTS: Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. CONCLUSIONS: In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.

Arrhythmogenic hereditary syndromes: Brugada Syndrome, long QT syndrome, short QT syndrome and CPVT.

In approximately 10-20% of all sudden deaths no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. Each of these cardiac channelopathies is charaterized by unique genetic and clinical features. The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli or increased vagal tone. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The success of medical therapy remains modest for prevention of sudden cardiac death and may necessitate the insertion of an implantable cardioverter. However, side effects with inappropriate therapies in this patient group with often young and active individuals have to be encountered. More insights into the arrhythmogenesis is critical for future development of effective medical treatment strategies.

Evaluation and management of syncope.

Syncope is a common symptom and accounts for approximately 1% of all emergency visits. There are four main causes of syncope: reflex, neurally mediated syncope, orthostatic hypotension and cardiac syncope. The prognosis of patients with reflex syncopes is good, whereas patients with cardiac syncope are at increased risk for sudden cardiac death. The first diagnosic step after transient loss of consciousness the diagnosis syncope has to be established. It has to be differentiated from other forms of loss of consciousness according to current definition. Careful evaluation of the patient with syncope is mandatory. If the underlying cause of syncope can be diagnosed during initial evaluation, the patient should be treated accordingly. If the cause of syncope remains unclear, the patient has to be stratified with respect to the risk of a cardiovascular event and sudden cardiac death and further evaluation initiated. This review gives a comprehensive summary of definition, work-up and treatment of syncope based on the current guidelines for the evaluation of syncope.

[Long and short QT syndromes : Emergency treatment and secondary prophylaxis]. / Long- und Short-QT-Syndrome : Notfalltherapie und Sekundärprophylaxe.

Long QT syndrome (LQTS) is a rare inherited or acquired channelopathy associated with a relevant mortality if left untreated. Therapy can reduce the sudden cardiac death (SCD) rate significantly. Of 17 subtypes, LQTS1-3 are the most common. Clinical presentation ranges from asymptomatic patients to torsade de pointes (TdP) and SCD. Emergency therapy includes defibrillation, administration of magnesium, betablockers and temporary pacing and sedation. Secondary prevention is based on betablocker therapy and implantation of an implantable cardioverter-defibrillator (ICD), if appropriate. Short QT syndrome (SQTS) is a rare channelopathy that manifests as SCD in 34%. So far 250 cases with mutations in 8 genes have been reported. ICDs are the only reliable protection against SCD. Drug therapy is based on hydroquinidine. Further therapeutic options exist for certain subtypes of both diseases. Patients should be referred to specialized centers.

Unique and shared functions of different connexins in mice.

BACKGROUND: Connexins are the protein subunits of intercellular gap junction channels. In mammals, they are encoded by a family of at least 15 genes, which show cell-type-specific but overlapping patterns of expression. Mice lacking connexin43 (Cx43) die postnatally from obstruction of the right ventricular outflow tract of the heart. To discriminate between the unique and shared functions of Cx43, Cx40 and Cx32, we generated two 'knock-in' mouse lines, Cx43KI32 and Cx43KI40, in which the coding region of the Cx43 gene was replaced, respectively, by the coding regions of Cx32 or Cx40. RESULTS: Heterozygous mutants were fertile and co-expressed the wild-type and the corresponding recombinant allele in all tissues analyzed. Heterozygous Cx43KI32, but not Cx43KI40, mutant mothers were unable to nourish their pups to weaning age, possibly reflecting a defect in milk ejection. Homozygous mutant males were sterile because of extensive germ-cell deficiency. The ovaries of homozygous Cx43KI32 neonates exhibited all stages of follicular development and ovulation. The hearts of homozygous Cx43KI32 neonates showed mild morphological defects, but the cardiac morphology of homozygous Cx43KI40 neonates was relatively normal. Spontaneous ventricular arrhythmias were observed in most Cx43KI40 and some Cx43KI32 mutant mice, suggesting increased ventricular vulnerability in these mice. CONCLUSIONS: The postnatal lethality of Cx43-deficient mice was rescued in Cx43KI32 or Cx43KI40 mice, indicating that Cx43, Cx40 and Cx32 share at least some vital functions. On the other hand, Cx43KI32 and Cx43KI40 mice differed functionally and morphologically from each other and from wild-type mice. Thus, these connexins also have unique functions.

[Magnetic navigation in invasive electrophysiological diagnostic and therapy]. / Magnetische Navigation in der elektrophysiologischen Diagnostik und Therapie.

Electrophysiological stimulation and ablation is currently performed with manually deflectable catheters of different lengths and curves. Disadvantages of conventional therapy are catheter stiffness, limited local stability, risk of dislocation or perforation, and reduced tissue contact in regions with difficult access. Fluoroscopy to control catheter movement and position may require substantial radiation times. Magnetic navigation was first applied for right heart catherization in congenital heart disease in 1991; the first electrophysiological application took place in 2003. Today, an ablation electrode with small magnets is aligned in the patient's heart by two external magnets positioned at both sides of the thorax. Antegrade and retrograde movement of the distal catheter tip are performed via an external device on the patient's thigh. Three-dimensional MRI scans acquired before intervention can be merged with electroanatomical reconstruction, leading to further reductions of radiation burden. During treatment of supraventricular tachyarrhythmias high local precision of magnetically guided catheters, good local stability, and a substantially reduced radiation time have been reported. First applications in ventricular tachyarrhythmias and complex congenital cardiac defects indicate a comparable effect. Limitations of this therapy are the application in left atrial procedures (open irrigated ablation catheters not yet available), difficult transaortic retrograde approach (high lead flexibility), and the considerable costs. Magnet-assisted navigation is feasible during percutaneous coronary interventions of tortuous coronary arteries and in positioning guidewires in coronary sinus side branches for resynchronisation therapy. Future applications will be complex left atrial procedures, magnetically guided cardiac stem cell therapy, local drug application, and extracardiac vessel therapy.

Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene.

Mutations in the cardiac sodium channel gene SCN5A may result in various arrhythmia syndromes such as long QT syndrome type 3 (LQTS), Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction diseases (CCD) and possibly dilated cardiomyopathy (DCM). In most of these inherited cardiac arrhythmia syndromes the phenotypical expression may range from asymptomatic phenotypes to sudden cardiac death (SCD). A 16-year-old female died during sleep. Autopsy did not reveal any explanation for her death and a genetic analysis was performed. A variant in the SCN5A gene (E1053K) that was previously described as disease causing was detected. Family members are carriers of the same E1053K variant, some even in a homozygous state, but surprisingly did not exhibit any pathological cardiac phenotype. Due to the lack of genotype-phenotype correlation further genetic studies were performed. A novel deletion in the promoter region of SCN5A was identified in the sudden death victim but was absent in other family members. These findings demonstrate the difficulties in interpreting the results of a family-based genetic screening and underline the phenotypic variability of SCN5A mutations.

Efficacy of pacing therapies for treating atrial tachyarrhythmias in patients with ventricular arrhythmias receiving a dual-chamber implantable cardioverter defibrillator.

BACKGROUND: Although overdrive pacing for treating atrial flutter is well established, the efficacy of device-based atrial pacing for treating spontaneous atrial tachyarrhythmias in patients with implantable cardioverter defibrillators (ICD) is unknown. This study evaluated the efficacy of novel pacing therapies for treating atrial tachyarrhythmias in patients receiving a dual-chamber ICD to treat ventricular tachyarrhythmias. METHODS AND RESULTS: A Jewel AF ICD was implanted in 537 patients with ventricular arrhythmia who were followed for 11.4+/-8.2 months (74% had a documented history of atrial tachyarrhythmias). The device discriminated atrial tachycardia (AT) from atrial fibrillation (AF) on the basis of cycle length and regularity, and it used 3 different methods of overdrive atrial pacing (Ramp, Burst+, and 50-Hz burst) to treat AT episodes and one method (50-Hz burst) to treat AF episodes. Pacing successfully terminated 59% of 1500 spontaneous AT episodes in 127 patients and 30% of 880 AF episodes in 101 patients (P<0.001). With AT and AF episodes combined, pacing efficacy was 48%. Pacing efficacy was significantly reduced at AT cycle lengths

Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study.

OBJECTIVES: The purpose of this prospective study was to assess left atrial chamber and appendage function after internal atrial defibrillation of atrial fibrillation and to evaluate the time course of recovery. BACKGROUND: External cardioversion of atrial fibrillation may result in left atrial appendage dysfunction ("stunning") and may promote thrombus formation. In contrast to external cardioversion, internal atrial defibrillation utilizes lower energies; however, it is unknown whether the use of lower energies may avoid stunning of the left atrial appendage. METHODS: Transesophageal and transthoracic echocardiography were performed in 20 patients 24 h before and 1 and 7 days after internal atrial defibrillation to assess both left atrial chamber and appendage function. Transthoracic echocardiography was again performed 28 days after internal atrial defibrillation to assess left atrial function. The incidence and degree of spontaneous echo contrast accumulation (range 1+ to 4+) was noted, and peak emptying velocities of the left atrial appendage were measured before and after internal atrial defibrillation. To determine left atrial mechanical function, peak A wave velocities were obtained from transmitral flow velocity profiles. RESULTS: Sinus rhythm was restored in all patients. The mean +/- SD peak A wave velocities increased gradually after cardioversion, from 0.47 +/- 0.16 m/s at 24 h to 0.61 +/- 0.13 m/s after 7 days (p < 0.05) and 0.63 +/- 0.13 m/s after 4 weeks. Peak emptying velocities of the left atrial appendage were 0.37 +/- 0.16 m/s before internal atrial defibrillation, decreased significantly after internal atrial defibrillation to 0.23 +/- 0.1 m/s at 24 h (p < 0.01) and then recovered to 0.49 +/- 0.23 m/s (p < 0.01) after 7 days. The corresponding values for the degree of spontaneous echo contrast were 1.2 +/- 1.2 before internal atrial defibrillation versus 2.0 +/- 1.0 (p < 0.01) and 1.1 +/- 1.3 (p < 0.01) 1 and 7 days after cardioversion, respectively. One patient developed a new thrombus in the left atrial appendage, and another had a thromboembolic event after internal atrial defibrillation. CONCLUSIONS: Internal atrial defibrillation causes depressed left atrial chamber and appendage function and may result in the subacute accumulation of spontaneous echo contrast and development of new thrombi after cardioversion. These findings have important clinical implications for anticoagulation therapy before and after low energy internal atrial defibrillation in patients with atrial fibrillation.

Transverse conduction capabilities of the crista terminalis in patients with atrial flutter and atrial fibrillation.

OBJECTIVES: In this study, the transverse conduction capabilities of the crista terminalis (CT) were determined during pacing in sinus rhythm in patients with atrial flutter and atrial fibrillation. BACKGROUND: It has been demonstrated that the CT is a barrier to transverse conduction during typical atrial flutter. Mapping studies in animal models provide evidence that this is functional. The influence of transverse conduction capabilities of the CT on the development of atrial flutter remains unclear. METHODS: The CT was identified by intracardiac echocardiography. The atrial activation at the CT was determined during programmed stimulation with one extrastimulus at five pacing sites anteriorly to the CT in 10 patients with atrial flutter and 10 patients with atrial fibrillation before and after intravenous administration of 2 mg/kg disopyramide. Subsequently, atrial arrhythmias were reinduced. RESULTS: At baseline, pacing with longer coupling intervals resulted in a transverse pulse propagation across the CT. During shorter coupling intervals, split electrograms and a marked alteration of the activation sequence of its second component were found, indicating a functional conduction block. In patients with atrial flutter, the longest coupling interval that resulted in a complete transverse conduction block at the CT was significantly longer than that in patients with atrial fibrillation (285 +/- 49 ms vs. 221 +/- 28 ms; p < 0.05). After disopyramide administration, a transverse conduction block occurred at longer coupling intervals as compared with baseline (287 +/- 68 ms vs. 250 +/- 52 ms; p < 0.05). Subsequently, a sustained atrial arrhythmia was inducible in 15 of 20 patients. This was atrial flutter in three patients with previously documented atrial fibrillation and in eight patients with history of atrial flutter. Mapping revealed a conduction block at the CT in all of these patients. CONCLUSIONS: It was found that the CT provides transverse conduction capabilities and that the conduction block during atrial flutter is functional. Limited transverse conduction capabilities of the CT seem to contribute to the development of atrial flutter.

Prevalence of left atrial chamber and appendage thrombi in patients with atrial flutter and its clinical significance.

OBJECTIVES: The study was done to assess the prevalence of left atrial (LA) chamber and appendage thrombi in patients with atrial flutter (AFl) scheduled for electrophysiologic study (EPS), to evaluate the prevalence of thromboembolic complications after transesophageal echocardiographic (TEE)-guided restoration of sinus rhythm and to evaluate clinical risk factors for a thrombogenic milieu. BACKGROUND: Recent studies showed controversial results on the prevalence of atrial thrombi and the risk of thromboembolism after restoring sinus rhythm in patients with AFl. METHODS: Between 1995 and 1999, patients with AFl who were scheduled for EPS were included in the study. After transesophageal assessment of the left atrial appendage and exclusion of thrombi, an effective anticoagulation was initiated and patients underwent EPS within 24 h. RESULTS: We performed 202 EPSs (radiofrequency catheter ablation, n = 122; overdrive stimulation, n = 64; electrical cardioversion, n = 16) in 139 consecutive patients with AFl. Fifteen patients with a thrombogenic milieu were identified. All of them had paroxysmal atrial fibrillation (AF). Transesophageal echocardiography revealed LA thrombi in two cases (1%). After EPS no thromboembolic complications were observed. Diabetes mellitus, arterial hypertension and a decreased left ventricular ejection fraction were found to be independent risk factors associated with a thrombogenic milieu. CONCLUSIONS: The findings of a low prevalence of LA appendage thrombi (1%) in patients with AFl and a close correlation between a history of previous embolism and paroxysmal AF support the current guidelines that patients with pure AFl do not require anticoagulation therapy, whereas patients with AFl and paroxysmal AF should receive anticoagulation therapy. In addition, the presence of clinical risk factors should alert the physician to an increased likelihood for a thrombogenic milieu.

[Primary electrical heart disease in adulthood--electrophysiological findings and therapy]. / Primär elektrische Herzerkrankungen im Erwachsenenalter--Elektrophysiologische Befunde und Therapie.

Sudden cardiac death accounts for 100,000 victims in Germany per year. Predominantly, patients with structural heart disease such as coronary artery disease or dilated cardiomyopathy are affected. However, approximately 5-10% of sudden deaths hit patients without structural disease of the heart. The proportion of young patients (< 40 years of age) in this group is even higher (10-20%). In younger patients significantly more diseases like hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and primary electrical diseases of the heart could be observed such as long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The primary electrical diseases are different concerning their electrocardiographical pattern, clinical triggers of arrhythmias, results of invasive diagnostics and therapy. Meanwhile, molecular genetic screening can reveal specific mutations of ion channels and can identify consecutive functional defects. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The implantable cardioverter defibrillator is the therapy of choice in most symptomatic patients. With increasing knowledge as a result of sophisticated molecular genetic screening, identification of underlying ion channel defects and new details of the mechanisms of arrhythmogenesis, a potential genotype-guided therapy will gain more importance in the future.

Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation.

In selected patients, atrial fibrillation (AF) converts to atrial flutter (AFI) due to treatment with class IC antiarrhythmic drugs. In this study, we prospectively investigated the effects of AFI ablation and continuation of drug therapy in patients with AF who developed AFI due to long-term administration of class IC antiarrhythmic drugs. The study population consisted of 187 patients from an AF registry with paroxysmal AF who were orally treated with flecainide (n = 96) or propafenone (n = 91). Twenty-four patients (12.8%) developed AFI during the course of treatment. In 20 of these patients (10.7%), electrophysiologic study revealed typical AFI. These patients underwent radiofrequency ablation of AFI. Ablation failed in 1 patient. All patients continued preexisting drug treatment. Recurrence of AF was assessed by ambulatory Holter monitoring and serial questionnaires. During a mean follow-up of 11 +/- 4 months, the incidence of AF episodes was significantly lower in patients with a combined therapy (2.7 +/- 3.6 per year) than in control subjects with a sole drug treatment (7.8 +/- 9.2 per year, p <0.05) and than before therapy (10.2 +/- 5.4 per year, p <0.001). Subgroup analysis revealed that 7 patients (36.8%) remained symptom free with no evidence of atrial tachyarrhythmia. Eight additional patients (42.1%) had ongoing paroxysmal AF, however, with a significantly lower incidence of AF episodes than before therapy (2.3 +/- 1.6 per year vs 11.5 +/- 5.0 per year, p <0.001). In the remaining 4 patients (14.7%), no beneficial effect of AFI ablation was found. It is concluded that in patients with AF who develop typical AFI due to administration of class IC antiarrhythmic agents, a combined therapy with catheter ablation of AFI and continuation of drug treatment is highly effective in reducing occurrence and duration of atrial tachyarrhythmias.

Echocardiographic parameters for predicting maintenance of sinus rhythm after internal atrial defibrillation.

Chronic atrial fibrillation (AF), which is refractory to external electrical direct current shock and/or pharmacologic cardioversion, may be successfully cardioverted using internal atrial defibrillation. To avoid unnecessary procedures, it is important to be able to predict which patients will revert to AF. Thirty-eight patients with chronic AF underwent successful internal atrial defibrillation and were followed for 6 months after restoration of sinus rhythm. Left atrial (LA) diameter, left ventricular ejection fraction, maximum LA appendage area, and peak emptying velocities of the LA appendage were analyzed to determine which of these factors were associated with recurrence of AF. Forty-nine percent of patients had a recurrence of AF within 6 months following internal atrial defibrillation. The preprocedural ejection fraction (mean +/- SD 59 + 14% vs 57 + 13%, p = 0.63), LA diameter (4.2 +/- 0.6 cm vs 4.5 +/- 0.6 cm, p = 0.16), and LA appendage area (5.0 +/- 1.5 cm2 vs 5.8 +/- 1.5 cm2, p = 0.13) did not differ significantly between patients who maintained sinus rhythm and those who had recurrence of AF. Peak emptying velocities of the LA appendage before cardioversion were significantly lower in patients with recurrence of AF compared with patients who maintained sinus rhythm (0.26 +/- 0.1 m/s vs 0.49 +/- 0.17 m/s, p = 0.001). A peak emptying velocity <0.36 had a sensitivity of 82% and a specificity of 83% for predicting recurrence of AF.

Hemodynamic and cardiorespiratory function following internal atrial defibrillation for chronic atrial fibrillation.

Internal atrial defibrillation (IAD) is able to restore sinus rhythm in patients with chronic atrial fibrillation (AF) and failed external electrical and/or pharmacologic cardioversion. To assess whether cardiorespiratory and hemodynamic function improve after IAD, 35 patients were prospectively investigated during constant workload exercise by spiroergometry and Doppler echocardiography before IAD, and 1 day and 1 month after IAD. Oxygen uptake kinetics, ventilation, left atrial mechanical function, and pulmonary artery pressure were determined simultaneously at rest and during steady state. During the serial follow-up, 20 patients maintained sinus rhythm. The time interval for achieving the steady state (146 +/- 53 vs 132 +/- 42 seconds; p = 0.5) and the oxygen deficit (645 +/- 190 vs 670 +/- 174 ml; p = 0.7) were not different before and 1 day after IAD, but decreased significantly after 1 month (98 +/- 16 seconds, p = 0.01 and 487 +/- 72 ml, p = 0.02). Exercise pulmonary artery systolic pressures were 38 +/- 13 mm Hg before IAD, increased significantly to 46 +/- 11 mm Hg on day 1 (p = 0.03), and decreased below baseline values at 1 month to 31 +/- 12 mm Hg (p = 0.07). Peak A-wave velocities increased from 0.51 +/- 0.1 m/s after 1 day to 0.67 +/- 0.2 m/s after 1 month (p = 0.03). Restoration of sinus rhythm in patients with AF resistant to external electrical and/or pharmacologic cardioversion improves hemodynamic and cardiorespiratory function at daily activity exercise levels.

Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome.

We have ascertained and examined a patient with autistic disorder (AD) and monosomy X (Turner syndrome). The patient met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)/International Classification of Diseases (ICD-10) criteria for AD verified by the Autism Diagnostic Interview-Revised. The patient exhibited both social and verbal deficits and manifested the classical physical features associated with monosomy X. Skuse et al. [1997: Nature 387:705-708] reported three such cases of AD and monosomy X in their study of Turner syndrome and social cognition. They observed that monosomy X females with a maternally inherited X chromosome had reduced social cognition when compared with monosomy X females with a paternally inherited X chromosome. All three cases of AD and monosomy X were maternally inherited. Based on their data, they suggested that there was a gene for social cognition on the X chromosome that is imprinted and not expressed when the X chromosome is of maternal origin. Thus, we conducted parent-of-origin studies in our AD/monosomy X patient by genotyping X chromosome markers in the patient and her family. We found that the patient's X chromosome was of maternal origin. These findings represent the fourth documented case of maternal inheritance of AD and monosomy X and provide further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition.

De novo partial duplication of chromosome 7p in a male with autistic disorder.

We describe a de novo partial duplication of 7p in a 25-year-old male with autistic disorder (AD). High-resolution chromosome analysis revealed an extra segment added to the proximal short arm of chromosome 7. The G-band pattern was consistent with an inverted duplication of 7p11.2-p14.1. Fluorescent in situ hybridization (FISH), using a whole chromosome 7 DNA probe (Cytocell, Inc., UK), confirmed that the extra chromosome material is derived from chromosome 7, indicating that the patient is partially trisomic for a region of the short arm of chromosome 7. Partial duplication of the short arm of chromosome 7 is uncommon with little more than 30 cases in the literature. This is the first report of an individual with a 7p duplication who also has AD.

Confirmation of locus heterogeneity in the pure form of familial spastic paraplegia.

Familial spastic paraplegia (FSP), characterized by progressive spasticity of the lower extremities, is in its "pure" form generally of autosomal dominant inheritance pattern. Hazan et al. [Nat Genet 5:163-167, 1993] reported tight linkage of a large FSP family to the highly polymorphic microsatellite marker D14S269 with z (theta) = 8.49 at theta = 0.00 They further demonstrated evidence for locus heterogeneity when they showed that 2 FSP families were unlinked to this region. We have subsequently studied 4 FSP families (3 American, one British) and excluded the disease locus in these families for approximately 30 cM on either side of D14S269, thereby confirming evidence for locus heterogeneity within the spastic paraplegia diagnostic classification.

Three probands with autistic disorder and isodicentric chromosome 15.

We have identified three unrelated probands with autistic disorder (AD) and isodicentric chromosomes that encompass the proximal region of 15q11.2. All three probands met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV; American Psychiatric Association, 1994], and International Classification of Diseases ( ICD-10) diagnostic criteria for AD, confirmed with the Autism Diagnostic Interview -Revised (ADI-R). Chromosome analysis revealed the following karyotypes: 47,XX,+idic(15)(q11.2), 47,XX, +idic(15) (q11.2), and 47,XY,+idic(15)(q11.2). Haplotype analysis of genotypic maker data in the probands and their parents showed that marker chromosomes in all three instances were of maternal origin. Comparison of the clinical findings of the three AD probands with case reports in the published literature (N = 20) reveals a clustering of physical and developmental features. Specifically, these three probands and the majority of reported probands in the literature exhibited hypotonia (n = 13), seizures (n = 13), and delayed gross motor development (n = 13). In addition, clustering of the following clinical signs was seen with respect to exhibited speech delay (n = 13), lack of social reciprocity (n = 11), and stereotyped behaviors (n = 12). Collectively, these data provide further evidence for the involvement of chromosome 15 in AD as well as present preliminary data suggesting a clustering of clinical features in AD probands with proximal 15q anomalies.