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Byline: Terese FolgerA[cedilla], Norunn Storbakk, Torberg Torbergsen, PA[yen]l Aian Keywords: Preeclampsia; genetics; mitochondrial dysfunction; mitochondrial transfer ribonucleic acid mutations Abstract: OBJECTIVE: We investigated whether maternally inherited mitochondrial deoxyribonucleic acid mutations could be associated with preeclampsia because mendelian models fail to explain all the aspects of inheritance in preeclampsia. STUDY DESIGN: In two families with a high occurrence of preeclampsia and eclampsia the 22 mitochondrial transfer ribonucleic acid genes were sequenced in eight and three women, respectively. RESULTS: An A-to-G mutation in transfer ribonucleic acid.sup.leu[UUR] at nucleotide 3243 was found in one family, and in the other there was an A-to-G mutation at nucleotide 12308 in transfer ribonucleic acid.sup.leu[CUN]. Mutations of mitochondrial transfer ribonucleic acid genes are generally considered to have systemic consequences, which might explain the multiorgan involvement seen in preeclampsia. CONCLUSION: We report for the first time mutations in mitochondrial transfer ribonucleic acid genes in two families with a high occurrence of preeclampsia and eclampsia. Mitochondrial dysfunction caused by point mutations of mitochondrial deoxyribonucleic acid is maternally inherited, but in the case of mutations of nuclear genes mitochondrial dysfunction can be inherited as an autosomal recessive or dominant trait. (AM J OBSTET GYNECOL 1996;174:1626-30.) Author Affiliation: TromsA[cedilla], Norway Article History: Received 25 May 1995; Revised 18 September 1995; Accepted 28 September 1995 Article Note: (footnote) [star] From the Departments of Obstetrics and Gynecologya and Neurology, b University of TromsA[cedilla]. , [star][star] Reprint requests: Terese FolgerA[cedilla], MD, Department of Obstetrics and Gynecology, University of TromsA[cedilla], N-9038 TromsA[cedilla], Norway., a 0002-9378/96 $5.00 + 0 6/1/69617

We describe the case of a six year old boy with findings consistent with myotonia congenita: muscular hypertrophy, stiffness when commencing movements and typical warm-up signs. The most prominent symptom was myotonia of the eyelid muscles with apparent swelling around the eyes. Even though the pronounced warm-up phenomena in our patient suggested a chloride channel-associated myotonia congenita, the myotonia of his eyelid muscles indicated an involvement of sodium channels. Screening for mutations in the underlying CLCN1gene was negative, however, in the SCN4Agene, we identified the missense mutation c.2108T>C; p.Leu703Pro for which there is strong evidence of pathogenicity because it arose de novoin the index patient.

Heterozygous missense mutations in the caveolin‐3 gene (CAV3) cause different muscle disorders. Most patients with CAV3alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3mutations underlie the progressive limb‐girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin‐3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3mutations. Ann Neurol 2003

Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb-girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin-3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations. Ann Neurol 2003

Mitochondrial dysfunction is a newly found group of inborn errors of metabolism in which there is a failure in the aerobic energy production. Disorders of mitochondrial metabolism exhibit a wide range of clinical symptoms which are related to the nature, severity and tissue distribution of the metabolic defect. Most reported cases are published in the neurological literature. In this report we describe for the first time a family with mitochondrial dysfunction with a high incidence of pre-eclampsia/ eclampsia. The diagnosis of a mitochondrial disorder is verified by electronmicro-scopic, electromyographic, histochemical and biochemical examinations. During pregnancy, the energy demand is increased due to both fetal and maternal requirements. A mitochondrial dysfunction, clinically symptomless in the non-pregnant state, may therefore become manifest during pregnancy. Characteristic features of pre-eclampsia such as disturbed ion transport, disturbed prostaglandin synthesis, vasoconstriction, platelet aggregation and hyperuricemia may be explained by mitochondrial dysfunction