Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci.

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine.

Mitochondrial dysfunction in migraine.

Migraine is the most frequent type of headache in children. In the 1980s, scientists first hypothesized a connection between migraine and mitochondrial (mt) disorders. More recent studies have suggested that at least some subtypes of migraine may be related to a mt defect. Different types of evidence support a relationship between mitochondria (mt) and migraine: (1) Biochemical evidence: Abnormal mt function translates into high intracellular penetration of Ca(2+), excessive production of free radicals, and deficient oxidative phosphorylation, which ultimately causes energy failure in neurons and astrocytes, thus triggering migraine mechanisms, including spreading depression. The mt markers of these events are low activity of superoxide dismutase, activation of cytochrome-c oxidase and nitric oxide, high levels of lactate and pyruvate, and low ratios of phosphocreatine-inorganic phosphate and N-acetylaspartate-choline. (2) Morphologic evidence: mt abnormalities have been shown in migraine sufferers, the most characteristic ones being direct observation in muscle biopsy of ragged red and cytochrome-c oxidase-negative fibers, accumulation of subsarcolemmal mt, and demonstration of giant mt with paracrystalline inclusions. (3) Genetic evidence: Recent studies have identified specific mutations responsible for migraine susceptibility. However, the investigation of the mtDNA mutations found in classic mt disorders (mt encephalomyopathy with lactic acidosis and stroke-like episodes, myoclonus epilepsy with ragged red fibers, Kearns-Sayre syndrome, and Leber hereditary optic neuropathy) has not demonstrated any association. Recently, 2 common mtDNA polymorphisms (16519C→T and 3010G→A) have been associated with pediatric cyclic vomiting syndrome and migraine. Also, POLG mutations (eg, p.T851 A, p.N468D, p.Y831C, p.G517V, and p.P163S) can cause disease through impaired replication of mtDNA, including migraine. Further studies to investigate the relationship between mtDNA and migraine will require very large sample sizes to obtain statistically significant results. (4) Therapeutic evidence: Several agents that have a positive effect on mt metabolism have shown to be effective in the treatment of migraines. The agents include riboflavin (B2), coenzyme Q10, magnesium, niacin, carnitine, topiramate, and lipoic acid. Further study is warranted to learn how mt interact with other factors to cause migraines. This will facilitate the development of new and more specific treatments that will reduce the frequency or severity or both of this disease.

Epilepsy and respiratory chain defects in children with mitochondrial encephalopathies.

OBJECTIVE: The purpose of this study was to determine the relationship between epilepsy and respiratory chain defects in children with mitochondrial encephalopathies (ME). STUDY DESIGN: We conducted a retrospective review of the medical records of children referred for evaluation of an ME. Only patients assigned a definite diagnosis of ME using modified Walker criteria and with a respiratory chain defect were included. Clinical data pertaining to the ME and epilepsy type were collected. Mitochondria were isolated by subcellular fractionation from a vastus lateralis muscle biopsy and studies were performed using polarographic and spectroscopic techniques for the quantitative determination of NADH and cytochrome components of the respiratory chain. RESULTS: A total of 38 children with ME were identified. Seizures were present in 61%. Sixteen of 23 children with epilepsy (70%) had refractory epilepsy associated with a progressive encephalopathy. Children with epilepsy had a significantly higher incidence of complex I defects than children without epilepsy (p<0.01). Complex III and IV defects were significantly higher in patients without epilepsy (p<0.01 and p<0.05, respectively) than in those with epilepsy. CONCLUSIONS: Epilepsy is an important component of ME. The higher incidence of complex I defects in patients with epilepsy suggests a possible relationship between mitochondrial oxidative stress dysfunction and epileptogenic process.

Relapse of herpes encephalitis after acyclovir therapy: report of two new cases and review of the literature.

Relapse of herpes simplex virus (HSV) encephalitis following acyclovir therapy has been reported infrequently in children beyond the neonatal period. The pathogenic mechanism of the recurrence is not fully understood. We report two new cases that support a mechanism of latent HSV infection with reactivation of the disease. Our patients were 2 years (#1) and 8 months (#2) old at initial infection. Both presented with fever, lethargy, focal seizures, and focal motor abnormalities. Serum HSV antibodies (Abs) were negative. The patients were treated with acyclovir for 14 and 21 days, respectively. They were readmitted at 1 month, and 4 days after discharge, respectively, with recurrent lethargy, seizures, and choreo-athetoid movements. Serum and CSF HSV Abs were significantly increased. CSF PCR was positive. In patient # 2 acyclovir-sensitive HSV was isolated from a brain biopsy. Both patients were re-treated with acyclovir, but progressed to a neurovegetative state. In our cases, latent HSV infection and reactivation is the most likely explanation for recurrent encephalitis. The immuno-pathogenic mechanisms of the infection recurrence are discussed. Based on the reported cases in the literature, patients younger than 2 years of age and with lower total dose of acyclovir treatments have a higher risk of recurrence.

Outcome of children with primary intramedullary spinal cord tumors.

The influence of clinical and treatment factors on the outcome of children with primary intramedullary spinal cord tumors (PST) was evaluated by reviewing the records of 26 children diagnosed during the 15-year period 1970-1984. Five-year survival was 39%, but 5-year event-free survival (EFS) was only 14%. Eighteen-month EFS was 53% (9/17) among children with low-grade astrocytoma. 100% (2/2) with ependymoma, and 0 of 7 with anaplastic astrocytoma or ganglioglioma. There was no significant difference in the 18-month EFS by location of tumor, duration of symptoms, or extent of surgical removal. Five of 9 children with locally recurrent PST had a second operation, and 4 were alive a median of 56 months later. PST disseminated to the leptomeninges or the III ventricle in 5 children: 2 at diagnosis, 2 as the first sign of disease relapse, and 1 after local recurrence. Given the poor outcome of our children, different methods of treatment for children with tumors in this location should be evaluated.

Iron deficiency in children: the relationship between pretreatment laboratory tests and subsequent hemoglobin response to iron therapy.

The goal of detecting iron deficiency in children is to identify those whose Hb concentration will rise in response to treatment with iron. In a controlled treatment trial conducted among Eskimo children, we examined the effectiveness of various measures of iron nutrition in predicting a response to iron therapy (greater than 1.0 g/dl rise in Hb). A response was seen in 43%, and an additional 26% had an intermediate response (0.5 to 1.0 g/dl rise). When individual Hb values were expressed as SD scores of the Hb distribution of a reference population, a marked skew toward low scores was seen before treatment. After treatment, the distribution became more Gaussian, indicating that iron deficiency had been the major cause of anemia. Serum ferritin, transferrin saturation, and free erythrocyte protoporphyrin levels moved toward normal with treatment, however, none of the tests used was very effective in distinguishing individuals who would have a response t Hb from those who would not (sensitivities: 63 to 42%, specificities: 45 to 61%). Laboratory measures of iron nutrition were far more helpful in depicting the iron status of the population than they were in distinguishing iron-responsive from nonresponsive individuals.

Primary hepatocellular carcinoma in Alaskan natives, 1969-1979.

The records of 20 Alaskan Native patients with primary hepatocellular carcinoma (PHC) diagnosed in the 11-year period 1969-1979 were reviewed. The annual incidence of PHC was found to be high among Alaskan Native males and especially high among Alaskan Eskimo males (7.6 and 11.2 per 100,000 respectively) in comparison to Greenland and Canadian Eskimos and US white males. Familial and geographic clustering of PHC patients was noted in areas known to be hyperendemic for hepatitis B virus (HBV) infection. A bimodal age distribution among PHC patients occurred with peaks at 15-25 years and 40-65 years. A high prevalence of hepatitis B surface antigen (HBsAg) in serum of patients in the younger age group suggests that HBV infection might be a factor associated with the development of PHC in young Eskimos. PHC in Alaskan Natives is apparently not closely associated with alcoholic cirrhosis.

Hepatitis B testing in the families and villages of five young eskimos with primary hepatocellular carcinoma.

A 15-year-old female Eskimo and a 22-year-old male Eskimo from a southwestern Alaskan village (population 540) were diagnosed as having primary hepatocellular carcinoma (PHC) in December, 1977. The fathers of both patients also died of PHC. Three additional cases of PHC affecting young Alaskan Eskimos had been diagnosed since 1972, all from neighboring villages. Four of the five young patients were positive for hepatitis B surface antigen (HBsAg), and the family members of three patients were all positive for HBsAg or antibody to this antigen (anti-HBs). The other two families had no members positive for HBsAg. The prevalence of HBsAg in the villages of these patients ranged from 0--5%, and the prevalence of anti-HBs ranged from 3--25%. This part of Alaska has a high rate of infection with hepatitis B virus and an increased incidence of PHC. However, other Alaskan villages of similar ethnic background have considerably higher rates of hepatitis B infection than the four villages described and to date they have no PHC. This suggests that genetic and/or environmental factors in addition to hepatitis B infection may have a role in the etiology of PHC in Alaska.