Relation between inheritance of cyanotic congenital heart disease and persistent foramen ovale.

Cyanotic congenital heart disease (CCHD) usually occurs sporadically, but occasionally it is familial without evidence of Mendelian inheritance. The investigators previously reported an association between dominant inheritance of clinically significant atrial shunts (large persistent foramina ovale and small atrial septal defects) and migraine with aura in some families. In 1 family, 4 patients with CCHD were linked by relatives with atrial shunts. The presence of atrial shunts and migraine symptoms was investigated in another family in which 3 members had CCHD. Contrast echocardiography was used to detect whether atrial right-to-left shunts were present in family members. A consultant neurologist, who was blinded to cardiac findings, diagnosed and categorized migraine symptoms. In this family, relatives with atrial right-to-left shunts linked 3 members who had CCHD. There appears to be dominant inheritance of atrial shunts, which is linked to inheritance of CCHD in some families. In conclusion, it is possible that the gene responsible most often causes an atrial shunt but sometimes causes more complex heart disease.

Prevalence of migraine in adults with cyanotic congenital heart disease.

OBJECTIVE: There is an increased prevalence of patent foramen ovale in patients with migraine, leading to the suggestion that migraine is more common in patients with potential right-to-left shunts. The aim of this study was to investigate the prevalence of migraine in adults with large right-to-left shunts because of cyanotic congenital heart disease. DESIGN AND PATIENTS: In total, 29 cyanotic adult patients with congenital heart disease answered a questionnaire to determine the prevalence of migraine with or without aura. A total of 38 matched acyanotic patients with congenital heart disease served as controls. A subgroup of 18 acyanotic patients also underwent bubble contrast echocardiography to look for patent foramen ovale. RESULTS: Twenty (69%) of the cyanotic patients had migraine, the majority 17 (59%) having migraine with aura. Twenty-two (58%) of the 38 acyanotic patients had migraine, of whom 16 (42%) had migraine with aura. Nine (50%) of the 18 acyanotic patients who consented to an echocardiogram had patent foramen ovale. Of those with patent foramen ovale, 8 (89%) had migraine and 6 (67%) had migraine with aura. CONCLUSION: There is an increased prevalence of migraine with aura in both cyanotic and acyanotic patients with congenital heart disease. The high prevalence of migraine in acyanotic patients with congenital heart disease may be due to an increased prevalence of patent foramen ovale.

Relation of atrial shunts to migraine in patients with ischemic stroke and peripheral emboli.

This study investigated whether the increased incidence of stroke in young subjects with migraine is because they have an increased prevalence of atrial right-to-left shunts. The investigators report the prevalence of clinically relevant atrial shunts in those with stroke and migraine compared with those with stroke but without migraine and also in historic control groups of subjects who had migraine with aura but no stroke and in population controls. Of 60 consecutive stroke patients, 42 (70%) had large- or medium-sized atrial shunts. Transcatheter shunt closure was performed in 39 patients, of whom 35 had patent foramen ovales (mean diameter 9.8 +/- 4.1 mm) and 4 had atrial septal defects. If atrial shunts were unrelated to stroke in patients with migraines, shunt prevalence in those with migraine and stroke would be the same as in those with migraine but without stroke. However, a much greater shunt prevalence was found in those with stroke and migraine with aura (84%) than in those with migraine with aura but no stroke (38.1%, p <0.001), population controls (12.2%, p <0.001), and those with stroke but no migraine (55.6%, p <0.05). Shunt prevalence was also significantly greater in patients who had stroke and migraine without aura (75%) than in population controls (p <0.001) and in those with migraine with aura but no stroke (p <0.05). In conclusion, the increased incidence of stroke in subjects with migraine compared with the general population is because they have a higher prevalence of large atrial shunts and hence an increased risk for paradoxic embolism.

Recurrent dystonia in homocystinuria: a metabolic pathogenesis.

Dystonia complicating homocystinuria is extremely rare in the absence of thromboembolic disease. We report a unique case of recurrent dystonia in a patient with homocystinuria secondary to pyridoxine-unresponsive cystathionine beta-synthase deficiency. Brain MRI was normal. Two biochemical markers for homocystinuria, homocystine and methionine, were markedly elevated during periods when our patient manifested dystonia. These findings suggest that accumulation of sulfur-containing amino acids may contribute to the pathophysiology of dystonia in patients with homocystinuria.

Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia.

DNA polymerase gamma (pol gamma ) is required to maintain the genetic integrity of the 16,569-bp human mitochondrial genome (mtDNA). Mutation of the nuclear gene for the catalytic subunit of pol gamma (POLG) has been linked to a wide range of mitochondrial diseases involving mutation, deletion, and depletion of mtDNA. We describe a heterozygous dominant mutation (c.1352G-->A/p.G451E) in POLG2, the gene encoding the p55 accessory subunit of pol gamma , that causes progressive external ophthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase (COX)-deficient muscle fibers. Biochemical characterization of purified, recombinant G451E-substituted p55 protein in vitro revealed incomplete stimulation of the catalytic subunit due to compromised subunit interaction. Although G451E p55 retains a wild-type ability to bind DNA, it fails to enhance the DNA-binding strength of the p140-p55 complex. In vivo, the disease most likely arises through haplotype insufficiency or heterodimerization of the mutated and wild-type proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibers and results in the clinical phenotype.

The role of cardiac and pulmonary pathology in migraine: a hypothesis.

From observation of recent data linking migraine with right-to-left shunts and by analogy with the etiologies of decompression illness, we postulate that cardiac and pulmonary pathology can have an important effect on the cranial final common pathway that generates attacks of migraine. One possible mechanism is associated with a significant right-to-left shunt, which is usually through a persistent foramen ovale, but is sometime through a pulmonary shunt. This allows a venous agent, possibly 5-hydroxytryptamine, to bypass the lung filter. Migraine can occur when there is no shunt if similar agents are liberated in the left heart beyond the lung filter, possibly by platelet activation. Migraine could also occur if the venous agents are produced in such large amounts that they overwhelm the pulmonary filter or are unaffected by passage through the lungs. In some individuals migraine may be unrelated to blood-borne triggers.

The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma.

Von Hippel-Lindau (VHL) disease is a heritable tumor susceptibility syndrome caused by germline mutations in the VHL gene. The types of tumor that can occur in affected individuals include retinal and central nervous system hemangioblastoma, renal cell carcinoma, pheochromocytoma, and others. The pattern of tumor types that develops in a VHL-affected family defines the clinical subtype (1, 2A, 2B, 2C). Generally, it is difficult to accurately predict an individual's clinical phenotype based on their VHL mutation. However, in a few specific VHL mutations, a strong genotype-phenotype correlation has been established. We report here on the clinical findings in individuals from three unrelated families with a V84L VHL germline mutation, and present follow-up information regarding the only other reported family with this missense mutation. In each of these four families, the major clinical manifestation of VHL disease is multiple early-onset pheochromocytomas (VHL type 2C). This series of eight patients strengthens the correlation between the V84L mutation and the VHL type 2C phenotype, and improves our ability to provide prognostic and management recommendations for similarly affected individuals.

Widening the sphere of influence: using a tool to extend extrapersonal visual space in a patient with severe neglect.

We report evidence that visual representations of space close to the body can be extended when a patient uses a tool to explore the environment. HB had severe neglect of left and far spatial regions which was determined more by how locations were visually perceived than by how they were represented tactilely or through proprioception. His ability to detect visual targets in left and far space was improved, however, when he held a tool. He also had limited tactile/proprioceptive knowledge about the location of his hand. These data suggest that by holding a tool, HB's more intact representation of near, visual space could be extended to include stimuli presented at a distance from his body. This extension of space improved his detection of visual stimuli. We discuss the implications of the results for the nature of our internal representation of space.

An investigation of HLA-encoded genetic susceptibility to multiple sclerosis in subjects of Asian Indian and Afro-Caribbean ethnic origin

The association of multiple sclerosis (MS) with the HLA class 11 loci DR and DQ was investigated in populations of Asian Indian and Afro-Caribbean ethnic origin, resident in the United Kingdom. The putative haplotype, DRB1*1501.DQA1*0102.DQBI*0602, was weakly positively associated with MS in both races. The overall contribution to disease susceptibility of this marker was small. Over 80 percent of MS patients in both racial groups did not possess this haplotype. The data suggest that other genetic and/or environmental factors may be more important in predisposing to MS in these two races. Our study also raises the possibility that genetically distinct forms of the disease may be expressed in white Caucasian and non-Caucasian populations (AU)

Epidemiology of human T-cell leukemia/lymphoma virus type 1 (HTLV-I) infections in a subpopulation of Afro-Caribbean origin in England

Epidemiological studies on neurological diseases in residents of Afro-Caribbean origin in the West Midlands region of England have identified eight patients with tropical spastic paraparesis (TSP), all of whom were found to be infected with human T-cell leukemia/lymphoma virus type 1 (HTLV-1). The husband of one of the patients with TSP was also infected with HTLV-1 and had a T-cell lymphoma. In addition, six asymptomatic HTLV-1-infected first-degree relatives of the TSP patients have been found. By anonymous testing of over 700 sera obtained from individuals of Afro-Caribbean, African, or Asian ethnic origin, seven HTLV-1-infected individuals were detected, who were all immigrants from the Caribbean. Overall, these numbers yielded a seroprevalence of HTLV-1 infections of 3.4 percent among the immigrant population of Afro-Caribbean origin, which is comparable with the prevalence of HTLV-1 in Jamaica in an equivalent age and sex cohort. Sera were tested for HTLV-1 antibody by means of three different procedures: passive particle agglutination test (Serodia), indirect enzyme-labeled immunosorbent assay (ELISA; Dupont), and indirect immunoflourescence test (in-house, using HTLV-1-infected MT2 cells). The results of all three tests correlated very well with each other. HTLV-1 antibody titres in TSP patients were on the whole significantly higher than those of asymptomatic carriers, but some of the apparently healthy first-degree relatives and one anonymously tested individual had titres as high as most of the TSP patients. (AU)