De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

The nature of cationic adsorption sites in alkaline zeolites--single, dual and multiple cation sites.

Gas adsorption on zeolites constitutes the base of many technological applications of these versatile porous materials. Quite often, especially when dealing with small molecules, individual extra-framework (exchangeable) cations are considered to be the adsorption site on which molecules coming from a gas phase form the corresponding adsorption complex. Nonetheless, while that can be the case in some instances, recent research work that combines variable temperature infrared spectroscopy with periodic DFT calculations showed that some types of adsorption sites involve two or more cations, which constitute dual and multiple cation sites, respectively. Adsorption complexes formed on these cationic adsorption sites differ in both structure and stability from those formed on a single cation alone. Examples concerning CO, CO(2) and H(2) adsorption on alkali and alkaline-earth metal exchanged zeolites are reviewed, with the double purpose of clarifying concepts and highlighting their relevance to practical use of zeolites in such fields as gas separation and purification, gas storage and heterogeneous catalysis.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

Perceptions of moral character modulate the neural systems of reward during the trust game.

Studies of reward learning have implicated the striatum as part of a neural circuit that guides and adjusts future behavior on the basis of reward feedback. Here we investigate whether prior social and moral information about potential trading partners affects this neural circuitry. Participants made risky choices about whether to trust hypothetical trading partners after having read vivid descriptions of life events indicating praiseworthy, neutral or suspect moral character. Despite equivalent reinforcement rates for all partners, participants were persistently more likely to make risky choices with the 'good' partner. As expected from previous studies, activation of the caudate nucleus differentiated between positive and negative feedback, but only for the 'neutral' partner. Notably, it did not do so for the 'good' partner and did so only weakly for the 'bad' partner, suggesting that prior social and moral perceptions can diminish reliance on feedback mechanisms in the neural circuitry of trial-and-error reward learning.

Extending animal models of fear conditioning to humans.

A goal of fear and anxiety research is to understand how to treat the potentially devastating effects of anxiety disorders in humans. Much of this research utilizes classical fear conditioning, a simple paradigm that has been extensively investigated in animals, helping outline a brain circuitry thought to be responsible for the acquisition, expression and extinction of fear. The findings from non-human animal research have more recently been substantiated and extended in humans, using neuropsychological and neuroimaging methodologies. Research across species concur that the neural correlates of fear conditioning include involvement of the amygdala during all stages of fear learning, and prefrontal areas during the extinction phase. This manuscript reviews how animal models of fear are translated to human behavior, and how some fears are more easily acquired in humans (i.e., social-cultural). Finally, using the knowledge provided by a rich animal literature, we attempt to extend these findings to human models targeted to helping facilitate extinction or abolishment of fears, a trademark of anxiety disorders, by discussing efficacy in modulating the brain circuitry involved in fear conditioning via pharmacological treatments or emotion regulation cognitive strategies.

Schizencephaly: correlations of clinical and radiologic features.

Schizencephaly is an uncommon congenital disorder of cerebral cortical development. Although a well-recognized cause of seizures and developmental deficits in children, previous reports describe the range of neurodevelopmental outcome in only 47 patients. We report the clinical and cranial imaging features of 47 children with unilateral open-lip (17), unilateral closed-lip (12), bilateral open-lip (12), and bilateral closed-lip (6) schizencephaly, as defined radiologically. The schizencephalic cleft occurred more often in the anterior than in the posterior neocortex. Children with closed-lip schizencephaly presented with hemiparesis or motor delay whereas patients with open-lip schizencephaly presented with hydrocephalus or seizures. Forty-three patients (91%) had associated cerebral developmental anomalies, most commonly absence of the septum pellucidum (45%) and focal cortical dysplasia (40%). There was a history of seizures in 57% of cases, a third of which were classified as difficult to control. Neurodevelopmental outcome was generally poor, with 51% of patients (24/47) having severe deficits, 32% of patients (15/47) having moderate impairment, and 17% of patients (8/47) having mild or no problems. Patients with closed-lip schizencephaly were more likely to have a mild to moderate outcome than those with open-lip type (78% versus 31%; p < 0.05). Children with unilateral schizencephaly had a mild or moderate outcome more frequently than those with bilateral lesions (62% versus 28%; p < 0.05). Children who had involvement of a single lobe accounted for 88% of those with mild outcomes and 53% of those with moderate outcomes. Unilateral closed-lip schizencephaly was associated with the best neurodevelopmental outcome; in contrast, 11 of 12 children with bilateral open-lip clefts had severe disabilities. Language development was significantly more likely to be normal in those children with unilateral schizencephaly than in those with bilateral clefts (48% versus 6%; p < 0.002). Thus, the presentation and outcome of children with schizencephaly are quite variable but are related to the extent of cortex involved in the schizencephalic defect.

Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype.

BACKGROUND: The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. OBJECTIVE: To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. METHODS: The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. RESULTS: The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. CONCLUSION: MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.

Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain.

BACKGROUND: Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. OBJECTIVE: To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. METHODS: The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. RESULTS: In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). CONCLUSIONS: Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Discontinuation of antiepileptic drug treatment after two seizure-free years in children with cerebral palsy.

OBJECTIVE: The risk of seizure relapse after antiepileptic drug (AED) discontinuation in children has been reported to vary between 6% and 40%. It has been suggested that neurologic deficit and mental retardation are poor prognostic factors for seizure relapse after AED discontinuation. Because epileptic children with cerebral palsy (CP) have neurologic deficits, and many have mental retardation, it is important to know their risk for seizure relapse. METHODS: AED treatment was discontinued in 65 children with CP and histories of epilepsy after 2 seizure-free years. All of the patients were followed until they had seizure relapses or for at least 2 years without seizures after AEDs were stopped. Multiple factors were analyzed for possible association with seizure relapse. RESULTS: Twenty-seven patients (41.5%) had seizure relapses. Patients with spastic hemiparesis had the highest relapse rate (61.5%), and those with spastic diplegia had the lowest rate (14.3%). No other factor correlated significantly with the risk of seizure relapse. CONCLUSIONS: Discontinuation of AEDs in children with CP can, and should, be practiced when possible after patients have been seizure-free for at least 2 years. AED discontinuation in patients with spastic hemiparesis is significantly more likely to lead to seizure relapse than in patients with other CP types, but no other factor is yet known to increase the chance of relapse.

Therapeutic drug concentration monitoring using saliva samples. Focus on anticonvulsants.

In the last 30 years there has been great interest in the use of saliva in therapeutic drug monitoring. Numerous investigators have suggested that saliva be used as an alternative body fluid for the therapeutic drug monitoring of anticonvulsant drugs. Not only can saliva be obtained easily on multiple occasions with minimal discomfort to the patient but, more importantly, useful relationships exist between the saliva and blood concentrations of the most commonly used anticonvulsant drugs. The measurement of anticonvulsant drug concentrations in saliva has been applied to pharmacokinetic and pharmacodynamic studies, and for therapeutic drug monitoring in a variety of seizure disorders. However, this simple and non-invasive method is not widely accepted in clinical practice. Several recent developments in sample collection and analytical methods, and the growing interest in free drug concentrations, provide a renewed impetus for saliva sampling for therapeutic drug monitoring of anticonvulsant drugs. Salivary flow rates vary significantly both between individuals and under different conditions. The use of stimulated saliva has several advantages over resting saliva. The salivary flow rate and pH, sampling conditions, contamination and many other pathophysiological factors may influence the concentrations of the medication in saliva. However, under standardised and well-controlled sampling condition, therapeutic drug monitoring of anticonvulsant drugs in saliva can be useful for determining compliance with medication in paediatric patients, for analysing the concentration of free drug and in situations where repeated sampling is necessary. Saliva is an alternative matrix for the therapeutic drug monitoring of carbamazepine, phenytoin, primidone and ethosuximide because the concentrations of these medications in saliva reflect the concentrations of the drug in serum. This is not the case for valproic acid (valproate sodium) and some controversy exists for phenobarbital. Further studies are required to assess the clinical value of monitoring anticonvulsant drugs and their metabolites in saliva, to examine the influence of pathophysiological factors on salivary drug concentrations, to improve the design of special devices to reproducibly and conveniently collect saliva samples, and to develop and use new analytical methods to achieve more sensitive and accurate results.

Identification and molecular confirmation of a small chromosome 10q duplication [dir dup(10)(q24.2-->q24.3)] inherited from a mother mosaic for the abnormality.

We describe a family in which two siblings exhibited developmental delay, reduced muscle tone and mild muscle weakness. Cytogenetic evaluation demonstrated that both children had a tandem duplication of a small portion of the long arm of chromosome 10 [46,XX or XY,dir dup(10)(q24.2-->q24.3)], inherited from their clinically normal mother, who was found to be mosaic for the duplicated chromosome 10. Fluorescence in situ hybridization approaches, including total chromosome painting and the use of regional specific cosmid probes, were used to confirm the chromosome 10q origin of the duplicated material. This is the smallest confirmed duplication of this portion of chromosome 10 reported to date.

The influence of polytherapy on the relationships between serum carbamazepine and its metabolites in epileptic children.

The influence of polytherapy on the relationships between the age, weight, carbamazepine (CBZ) dose, total clearance, and intrinsic clearance, with concentrations, concentration ratios, and level/dose ratios of CBZ, carbamazepine-10,11-epoxide (CBZ-E) and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) are investigated. Three groups of patients with CBZ monotherapy, or receiving CBZ polytherapy by taking CBZ and valproic acid (VPA) or CBZ plus other antiepileptic drugs (AEDs) were studied. The significant correlations between serum CBZ concentrations and CBZ dose in patients taking CBZ alone were no longer significant in patients with polytherapy, and the positive associations between serum CBZ-E concentrations and CBZ dose were lost in patients with CBZ + VPA. Only the concentrations of CBZ-H had significant correlations with CBZ dose in all three groups of patients. Results from this relationship study indicate a heteroinduction effect of other AEDs on CBZ metabolism, and a relatively weak influence on CBZ-E elimination. Data also suggest that there is a block in the biotransformation from CBZ-E to CBZ-H in patients taking CBZ + VPA, presumably caused by the inhibition effect of VPA on epoxide hydrolase. Therapeutic drug monitoring of CBZ will benefit from the knowledge obtained from the relationship study.

Predicting the probability of meningioma recurrence based on the quantity of peritumoral brain edema on computerized tomography scanning.

OBJECT: The goal of this study was to determine whether the quantity of peritumoral brain edema displayed on computerized tomography (CT) scanning could be correlated with brain invasion and subsequent recurrence of meningiomas. METHODS: One hundred thirty-five patients who underwent resection of intracranial meningiomas at the Ottawa Civic Hospital were followed during the period 1980 to 1998. A complete resection was defined as one in which tumor, invaded bone, and involved dura were removed. Tumors were examined microscopically for evidence of brain invasion. The mean follow-up period was 9 +/- 4 years (standard deviation [SD]) and the mean time to recurrence was 5 +/- 4 years (SD). The authors used a simple grading system based on the average thickness (in centimeters) of edema seen on an axial CT slice showing the most tumor. Edema grade was linearly related to edema volume determined by digitizing the scans (r = 0.96; 29 cases). The chance of brain invasion increased by 20% for each centimeter of edema (r(s) = 1, p < 0.0001; 124 cases). The presence of brain invasion was predictive of recurrence after complete resection with an accuracy of 83%, a sensitivity of 89%, and a specificity of 82%. The chance of recurrence within 10 years after complete resection was given by the equation: percentage chance of recurrence = (centimeter of edema)3 x 0.7, which can be used to predict the chance of recurrence based on findings on CT scans (r(s) = 1, p < 0.0001; 86 patients). Statistical significance was confirmed using Kaplan-Meier and univariate and multivariate analyses. Completeness of resection was the most powerful predictor of recurrence (p < 0.00001, r = 0.6), followed by edema grade and brain invasion (both p = 0.02, r = 0.1). Patient age and gender and tumor location, size, and histological subtype were nonsignificant factors. CONCLUSIONS: Brain invasion causes peritumoral edema. Invaded brain tissue is also the source of residual cells in cases of tumor recurrence after gross-total resection.

Bromocriptine: problems with low-dose de novo therapy in Parkinson's disease.

Twenty Parkinson's disease patients, who had not yet received levodopa, were treated with low-dose bromocriptine. At a mean daily bromocriptine dose of 13.2 mg, 13 patients (65%) improved and had a 32% reduction in the combined score for tremor rigidity and bradykinesia. Adverse effects were frequent, and 25% of the patients were taken off the drug because of nausea or vomiting. After 30 months follow-up, only three patients continued on bromocriptine alone. Ten patients were eventually maintained on low-dose bromocriptine and levodopa-carbidopa, and a clear synergistic effect of bromocriptine in this drug combination was documented in eight patients. Low-dose bromocriptine does not replace levodopa as initial therapy for Parkinson's disease. The potential long-term benefit of the early use of combined low-dose levodopa-dopamine agonist therapy needs to be further studied.

Interactions of valproic acid with carbamazepine and its metabolites' concentrations, concentrations ratios, and level/dose ratios in epileptic children.

In two groups of epileptic children receiving carbamazepine (CBZ) therapy with or without valproic acid (VPA) comedication, we investigate the drug interactions of VPA on serum CBZ and its metabolites' concentrations, concentration ratios, and level/dose ratios. Serum total and free CBZ-10, 11-epoxide (CBZ-E) concentrations are significantly increased in patients taking CBZ plus VPA, together with higher CBZ-E/CBZ concentration ratios and CBZ-E level/dose ratios. These results reflect the accumulation of CBZ-E. The decreased concentration ratios of trans-10, 11-dihydroxy-10, 11-dihydro-CBZ (CBZ-H)/CBZ-E observed in patients taking CBZ plus VPA suggest an inhibition in the biotransformation from CBZ-E to CBZ-H. Significant negative correlations are found between serum VPA level and CBZ-H/CBZ-E concentration ratios, indicating that the inhibition of CBZ-E hydrolysis by VPA may depend on the concentration of VPA (total or free CBZ-H/CBZ-E concentration ratio = [formula: see text], respectively). VPA concentration also shows significant positive correlations with CBZ-E and CBZ level/dose ratios. Patients taking CBZ plus VPA have significant higher free fractions of CBZ and CBZ-E than do patients on CBZ alone, suggesting a protein-binding displacement by VPA.

Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review.

Over the last several years, botulinum toxin type A has gained widespread use for the management of focal spasticity in children with cerebral palsy. To assess the current patterns of botulinum toxin type A use in the clinical setting, the dose, muscles injected, age at injection, and interval between injections of botulinum toxin type A treatments were examined in a retrospective chart review of children with cerebral palsy (N = 270) over a 2-year period at three major treatment centers. The average dose of botulinum toxin type A across the three centers ranged from 7.7 to 10.8 U/kg body weight, and the average total amount of botulinum toxin type A injected at a single visit ranged from 154 to 205 U. The majority of botulinum toxin type A injections were to the muscles to the lower limbs. The average age at first injection was 6.2 years, and the average interval between injections ranged from 134 to 199 days.

Thrombocytopenia secondary to high valproate levels in children with epilepsy.

We reviewed the frequency of valproate-induced thrombocytopenia in children with epilepsy in our institution. Sixty-four (21%) of 306 children taking valproate developed thrombocytopenia. Thirty-two of these 64 patients had at least one platelet count lower than 100 x 10(3)/mm3. Eight patients developed signs of bleeding. Low platelet levels were typically noted in patients with serum valproate levels of over 140 micrograms/mL, and reduction of the medication dose usually resulted in a prompt increase in the number of platelets. Only one patient developed thrombocytopenia unrelated to high serum drug levels, and her platelet count did not improve until the drug was discontinued. Neither the age of the patient nor the use of additional antiepileptic medication correlated with the platelet count. However, duration of valproate use was related. These data suggest that, although valproate may cause thrombocytopenia via more than one mechanism, by far the most common factor is the presence of high valproate levels. Thus, the medication can be safely lowered in most patients with thrombocytopenia rather than discontinued altogether. Platelet counts should probably be monitored more carefully in patients known to have higher drug levels.

Abnormal sudomotor function in the hypomelanotic macules of tuberous sclerosis complex.

To investigate the integrity of sympathetic innervation in the hypomelanotic macules of tuberous sclerosis complex, we studied sudomotor function in nine patients with tuberous sclerosis complex. Postganglionic sudomotor function was assessed using the Silastic imprint test in nine patients with tuberous sclerosis complex who have at least one hypomelanotic macule greater than 2 cm in diameter. Sweating was induced by iontophoresis with 0.5% pilocarpine nitrate and sweat droplets were counted under a microscope using a 1 x 1 cm grid. Silastic imprint testing of an analogous skin area contralateral to the hypomelanotic macule was measured as a control. Sweat volume quantitation using sweat collectors was performed in five of the subjects. The sweat volume collected from the hypomelanotic macule was reduced compared to the control skin in four of the five subjects. Sweat droplet counts from the hypomelanotic macule were significantly reduced in only one of nine subjects. These data suggest that, although there is no difference in the number of functioning sweat glands in most hypomelanotic macules, the sweat glands produce less sweat (ie, decreased sweat volume) than in normal skin. We hypothesize that focal abnormalities of sympathetic innervation might be responsible for the hypomelanotic macules of tuberous sclerosis complex.

Early diagnosis of subependymal giant cell astrocytoma in patients with tuberous sclerosis.

We present 19 patients with tuberous sclerosis complex and subependymal giant cell astrocytoma. The mean age at the time of tumor diagnosis was 9.4 years (range, 1.5 to 21 years). Computed cranial tomography (CT) or cranial magnetic resonance imaging (MRI) identified the lesion which was resected in all cases. Seven patients had hydrocephalus and there was an interval increase in the tumor size or a large tumor without hydrocephalus in 12 patients. Surgical criteria included: (1) presence of hydrocephalus; (2) interval increase in tumor size; (3) new focal neurologic deficit attributable to the tumor; and/or (4) symptoms of increased intracranial pressure. Eight patients were identified through a surveillance program involving annual computed cranial tomography. All of these eight patients had their tumor removed prior to the development of symptoms, none had neurologic deficits which persisted after surgery, and none has so far developed recurrent subependymal giant cell astrocytoma. In contrast, of the 11 patients from the non-surveillance group 7 were symptomatic at tumor diagnosis, 1 had a complicated postoperative course, 2 developed recurrent giant cell astrocytoma, and 1 had an extensive lesion that could not be completely excised. Periodic cranial imaging may help to identify subependymal giant cell astrocytomas in tuberous sclerosis patients before they become symptomatic. Earlier diagnosis and treatment could reduce surgical morbidity and the risk of tumor recurrence.

Tuberous sclerosis.

Tuberous sclerosis complex is a disorder of cellular differentiation and proliferation that is inherited as an autosomal dominant trait with variable penetrance and a high spontaneous mutation rate. Lesions occur in the brain, skin, kidneys, heart, and other organs. Recent studies suggest genetic heterogeneity, with at least two gene loci on chromosomes 9, 16, and perhaps 11.