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Biomedical subjects

E S Roach

Publications and source records attributed to E S Roach.

At least 19 recordsLinked to original sources
PubMed2000

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.

OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Adolescent↗
PubMed2000

A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16.

OBJECTIVE: To use genetic linkage analysis to localize a gene for paroxysmal kinesigenic dyskinesia (PKD) in a three generation African-American kindred. BACKGROUND: PKD is a rare autosomal dominant disorder characterized by episodic choreiform or dystonic movements that are brought on or exacerbated by voluntary movement. There are individuals with the clinical features of PKD but with no family history of the disease, but whether these sporadic cases represent spontaneous mutations of PKD or have a distinct condition is unknown. METHODS: A genome-wide linkage scan of polymorphic microsatellites at 25 cM resolution was performed to localize a gene for PKD in one African-American kindred. Pairwise multipoint linkage analyses were performed at different penetrance estimates. RESULTS: Evidence for linkage of the kinesigenic form of paroxysmal dyskinesia to chromosome 16 was obtained. A maximum lod score of 4.40 at theta = 0 was obtained with D16S419. Critical recombinants place the PKD gene between D16S3100 and D16S771. CONCLUSIONS: A paroxysmal kinesigenic dyskinesia (PKD) locus lies within an 18 cM interval on 16p11.2-q11.2, between D16S3100 and D16S771. A gene for infantile convulsions with paroxysmal choreoathetosis has also been mapped to this region. These two regions overlap by approximately 6 cM. These two diseases could be caused by different mutations in the same gene or two distinct genes may lie within this region.

Black People↗
PubMed2000

Stroke in children: recognition, treatment, and future directions.

Childhood stoke is increasingly recognized, but studies remain largely descriptive. Important differences from adult stroke include the following: (1) frequently delayed or missed diagnosis, (2) heterogenous and overlapping risk factors, and (3) developmental differences in the cerebrovascular, neurologic, and coagulation systems. These aspects limit the extrapolation of the results of adult stroke research and present challenges in caring for children with stroke. The incidence of childhood ischemic stroke exceeds 3.3 in 100,000 children per year, more than double the estimates from past decades. The increased incidence reflects, in part, increased survival in previously fatal conditions predisposing to stroke, including congenital heart disease, sickle cell anemia, and leukemia. Risk factors for stroke are recognized in more than 75% of children. Common risk factors include congenital heart disease and sickle cell disease. Progressive arteriopathies, including vasculitis and moyamoya syndrome, are rare in children with stroke; however, transient arteriopathies including post-varicella angiopathy are increasingly recognized. Prothrombotic abnormalities are frequently present but of unclear significance. Adverse outcomes after childhood stroke, including death in 10%, recurrence in 20%, and neurologic deficits in two thirds of survivors could be reduced with available stroke treatments. Aggressive prehospital emergency care and transfer could improve access to hyperacute stroke therapies including tPA. Currently, the diagnosis is delayed by more than 24 hours from onset in most children. As in adults, tPA will likely produce unacceptable rates of intracerebral hemmorrhage unless given within 3 hours of stroke symptom onset. The appropriate choices for in hospital treatment and secondary preventative strategies, including aspirin and anticoagulants, are controversial. Empiric recommendations are published; however, age-appropriate clinical trials are urgently needed. The large multinational networks of investigators necessary for designing and conducting these future trials are now being formed.

Adult↗
PubMed2000

Etiology of stroke in children.

Although the risk factors for stroke in children are numerous and differ greatly from the causes of stroke in adults, a thorough diagnostic evaluation can identify one or more risk factors in most patients. Cardiac disorders and hemoglobinopathy are the most common causes of ischemic infarction, whereas various congenital anomalies of the blood vessels or defects in coagulation or platelet function are often found in children with intraparenchymal hemorrhage. More than one risk factor is commonly identified, especially in children with dural venous thrombosis. Identification of the underlying risk factors for cerebrovascular disorders in children is important because many of the risk factors can be treated, reducing the risk of subsequent strokes.

Brain Neoplasms↗
PubMed2000

Tuberous sclerosis complex.

Tuberous sclerosis complex is an autosomal dominant disorder that causes significant complications in multiple organ systems. Both basic science and clinical research on tuberous sclerosis complex have flourished in recent years, improving our understanding of its molecular genetics and pathophysiology. Two tuberous sclerosis complex genes cause nearly identical phenotypes, and great progress has been made towards understanding how each of these genes functions. The recognition of tuberous sclerosis complex improved with revised diagnostic criteria, and the management of many of the complications of tuberous sclerosis complex has improved.

Epilepsy↗
PubMed2000

Nontraumatic brain hemorrhage in children: etiology and presentation.

The clinical and radiographic findings of 68 children and adolescents with nontraumatic intraparenchymal brain hemorrhage were analyzed retrospectively. There were 43 boys and 25 girls, and the average age was 7.1 years (range, 3 months to 18 years). The most common presenting symptom was a combination of headache or vomiting (40 cases, or 58.8%). Hemiparesis was the major presenting sign in 11 (16.2%) of the children, seizures occurred in 25 (36.8%) patients, and 6 (8.8%) children were irritable. Only 2 (2.9%) children were comatose at presentation. One or more risk factors for hemorrhage were found in 61 (89.7%) of 68 children. A third (23 cases, or 33.8%) had an arteriovenous malformation or fistula; altogether 29 (42.6%) children had some type of congenital vascular anomaly. Hematologic or coagulation disorders were present in 22 (32.4%) patients, and 9 (13.2%) patients had brain tumors. Hemorrhage could not be attributed to systemic hypertension in any child. The likelihood of establishing the cause of bleeding was greater when evaluation included cerebral angiography (97.3% versus 80.4% without angiography). Half (34 cases, or 50.0%) of the patients regained normal neurologic function. Six (8.8%) patients died, either directly or partly as a consequence of the hemorrhage. The remaining patients had various neurologic sequelae, including 17 (25.0%) with hemiparesis, 5 (7.4%) with aphasia, 7 (10.3%) with epileptic seizures, and 3 (4.4%) with hydrocephalus. More detailed follow-up studies are needed to obtain more information about the frequency of cognitive sequelae.

Adolescent↗
PubMed2000

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.

Adolescent↗
PubMed1999

Germ-line mosaicism in tuberous sclerosis: how common?

Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.

Adult↗
PubMed1999

Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.

At the recent Tuberous Sclerosis Consensus Conference, a subcommittee proposed recommendations to guide the rational use of diagnostic studies in patients with tuberous sclerosis complex. Recommendations were made for diagnostic evaluation at the time of diagnosis, when testing helps both to establish the diagnosis and to identify potential complications. Additional guidelines were proposed for the ongoing surveillance of established patients to detect later complications of tuberous sclerosis complex. In the absence of comprehensive population studies to govern the use of diagnostic studies in individuals with tuberous sclerosis complex, the panel developed guidelines based on the disorder's natural history, concentrating on complications that are common, clinically significant, and more easily managed when found early. Finally, the group made suggestions for the use of diagnostic tests to identify family members who have tuberous sclerosis complex. Although these recommendations should standardize and improve our use of diagnostic studies in individuals with tuberous sclerosis complex, the clinical approach in a given patient must remain flexible enough to meet the needs of individual patients and families.

Adult↗
PubMed1998

Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex.

BACKGROUND: The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the brain, heart, skin, and kidney. Malignant tumors also can occur in patients with tuberous sclerosis, particularly in the kidney, although they occur less frequently than benign tumors. The types of malignancy that occur in TSC have not been characterized fully. METHODS: Clinical and pathologic features of 8 malignant tumors from 6 TSC patients ranging in age from 22 months to 21 years are reviewed. Six tumors were renal, one was from the inguinal region, and one was from the brain. The tumors were analyzed for loss of heterozygosity (LOH) in the chromosomal regions of the TSC1, TSC2, and VHL genes. RESULTS: Three patients (ages 7, 8, and 20 years) had renal cell carcinomas (RCCs). Two of these patients had multifocal RCCs. All three patients with RCC also had prominent multifocal dysplasia of renal cyst epithelium. Two patients (ages 20 and 21 years) had malignant angiomyolipomas (1 renal and 1 inguinal). One patient (age 22 months) had a Grade 4 giant cell astrocytoma (glioblastoma multiforme). LOH in the region of the TSC2 gene was found, either in the malignant tumor or in benign tumors, in all five patients whose DNA could be analyzed. CONCLUSIONS: Children with TSC, as well as adults with the disease, are at risk for developing malignant tumors. Two types of renal malignancy occur in TSC: RCC, which appears to arise from dysplastic renal cyst epithelial cells, and malignant angiomyolipoma. Tumors cytologically similar to malignant angiomyolipomas also may occur at extrarenal sites. LOH analyses suggest that the majority of patients with TSC who develop malignant tumors have germline TSC2, rather than TSC1, gene mutations.

Adult↗
PubMed1998

Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients.

Ninety patients with tuberous-sclerosis complex (TSC) were tested for subtle mutations in the TSC2 gene, by means of single-strand conformational analysis (SSCA) of genomic DNA. Patients included 56 sporadic cases and 34 familial probands. For all patients, SSCA was performed for each of the 41 exons of the TSC2 gene. We identified 32 SSCA changes, 22 disease-causing mutations, and 10 polymorphic variants. Interestingly, we detected mutations at a much higher frequency in the sporadic cases (32%) than in the multiplex families (9%). Among the eight families for which linkage to the TSC2 region had been determined, only one mutation was found. Mutations were distributed equally across the gene; they included 5 deletions, 3 insertions, 10 missense mutations, 2 nonsense mutations, and 2 tandem duplications. We did not detect an increase in mutations either in the GTPase-activating protein (GAP)-related domains of TSC2 or in the activating domains that have been identified in rat tuberin. We did not detect any mutations in the exons (25 and 31) that are spliced out in the isoforms. There was no evidence for correspondence between variability of phenotype and type of mutation (missense versus early termination). Diagnostic testing will be difficult because of the genetic heterogeneity of TSC (which has at least two causative genes: TSC1 and TSC2), the large size of the TSC2 gene, and the variety of mutations. More than half of the mutations that we identified (missense, small in-frame deletion, and tandem duplication) are not amenable to the mutation-detection methods, such as protein-truncation testing, that are commonly employed for genes that encode proteins with tumor-suppressor function.

Adolescent↗
PubMed1998

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.

Adolescent↗
PubMed1998

Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.

At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.

Angiofibroma↗