A structural basis for reading fluency: white matter defects in a genetic brain malformation.

BACKGROUND: Multiple lines of evidence have suggested that developmental dyslexia may be associated with abnormalities of neuronal migration or axonal connectivity. In patients with periventricular nodular heterotopia--a rare genetic brain malformation characterized by misplaced nodules of gray matter along the lateral ventricles--a specific and unexpected reading disability is present, despite normal intelligence. We sought to investigate the cognitive and structural brain bases of this phenomenon. METHODS: Ten adult subjects with heterotopia, 10 with dyslexia, and 10 normal controls were evaluated, using a battery of neuropsychometric measures. White matter integrity and fiber tract organization were examined in six heterotopia subjects, using diffusion tensor imaging methods. RESULTS: Subjects with heterotopia and those with developmental dyslexia shared a common behavioral profile, with specific deficits in reading fluency. Individuals with dyslexia seemed to have a more prominent phonological impairment than heterotopia subjects. Periventricular nodular heterotopia was associated with specific, focal disruptions in white matter microstructure and organization in the vicinity of gray matter nodules. The degree of white matter integrity correlated with reading fluency in this population. CONCLUSIONS: We demonstrate that a genetic disorder of gray matter heterotopia shares behavioral characteristics with developmental dyslexia, and that focal white matter defects in this disorder may serve as the structural brain basis of this phenomenon. Our findings represent a potential model for the use of developmental brain malformations in the investigation of abnormal cognitive function.

A familial syndrome of unilateral polymicrogyria affecting the right hemisphere.

A number of familial syndromes of bilateral polymicrogyria (PMG) have been described, but reported unilateral PMG cases have generally been sporadic. The authors identified four families in which unilateral right-sided PMG on MRI was present in more than one individual, with pathologic confirmation in one. Core clinical features included contralateral hemiparesis, developmental delay, and focal seizures. The authors' findings suggest that unilateral PMG exists in a familial syndrome of probable germline genetic origin.

Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia.

OBJECTIVE: To define the behavioral profile of periventricular nodular heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. METHODS: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. RESULTS: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. CONCLUSION: The neuronal migration disorder of periventricular nodular heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence.

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.

OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells.

Recent studies have shown that hyperglycemia is a principal cause of cellular damage in patients with diabetes mellitus. A major consequence of hyperglycemia is increased oxidative stress. Glucose-6-phosphate dehydrogenase (G6PD) plays an essential role in the regulation of oxidative stress by primarily regulating NADPH, the main intracellular reductant. In this paper we show that increased glucose (10-25 mm) caused inhibition of G6PD resulting in decreased NADPH levels in bovine aortic endothelial cells (BAEC). Inhibition was seen within 15 min. High glucose-induced inhibition of G6PD predisposed cells to cell death. High glucose via increased activity of adenylate cyclase also stimulated an increase in cAMP levels in BAEC. Agents that increased cAMP caused a decrease in G6PD activity. Inhibition of cAMP-dependent protein kinase A ameliorated the high glucose-induced inhibition of G6PD. Finally, high glucose stimulated phosphorylation of G6PD. These results suggest that, in BAEC, high glucose stimulated increased cAMP, which led to increased protein kinase A activity, phosphorylation of G6PD, and inhibition of G6PD activity. We conclude that these changes in G6PD activity play an important role in high glucose-induced cell damage/death.

Importance of glucose-6-phosphate dehydrogenase activity in cell death.

The intracellular redox potential plays an important role in cell survival. The principal intracellular reductant NADPH is mainly produced by the pentose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme, and by 6-phosphogluconate dehydrogenase. Considering the importance of NADPH, we hypothesized that G6PDH plays a critical role in cell death. Our results show that 1) G6PDH inhibitors potentiated H2O2-induced cell death; 2) overexpression of G6PDH increased resistance to H2O2-induced cell death; 3) serum deprivation, a stimulator of cell death, was associated with decreased G6PDH activity and resulted in elevated reactive oxygen species (ROS); 4) additions of substrates for G6PDH to serum-deprived cells almost completely abrogated the serum deprivation-induced rise in ROS; 5) consequences of G6PDH inhibition included a significant increase in apoptosis, loss of protein thiols, and degradation of G6PDH; and 6) G6PDH inhibition caused changes in mitogen-activated protein kinase phosphorylation that were similar to the changes seen with H2O2. We conclude that G6PDH plays a critical role in cell death by affecting the redox potential.