Darryl C. DeVivo

Mitochondrial DNA Deletions in Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome

We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.

Cytochrome c Oxidase Deficiency

ABSTRACT: Cytochrome c oxidase (COX) is a complex enzyme composed of 13 subunits, three of which are encoded by the mitochondrial DNA (mtDNA). The other 10 subunits are encoded by the nuclear DNA, synthesized in the cytoplasm, and transported into the mitochondria. The complexity of the enzyme and its dual genetic control explain the heterogeneity of clinical phenotypes associated with COX deficiency. There are two major syndromes, one characterized by muscle involvement (fatal infantile or benign infantile myopathy), the other dominated by brain disease (Leigh syndrome, myoclonic epilepsy with ragged red fibers, Menkes disease). Partial defects of COX have been shown in muscle of patients with progressive external ophthalmoplegia, either alone (ocular myopathy) or as part of Kearns-Sayre syndrome. Biochemical studies have documented either muscle-specific or generalized defects of COX; COX deficiency is reversible in the benign infantile myopathy. Immunologically detectable protein may be normal (benign myopathy) or variably decreased (fatal myopathy, Leigh syndrome). The subunit pattern of COX is normal by immunoblot in patients with fatal myopathy and Leigh syndrome; a disproportionate decrease of subunit II was seen in a patient with myoclonic epilepsy with ragged red fibers. Availability of the three mtDNA genes and of complementary DNA probes for eight of the 10 nuclear DNA-encoded subunits makes it possible to investigate the different diseases at the molecular level. Large deletions of mtDNA have been found in patients with ocular myopathy and Kearns-Sayre syndrome: the deleted mtDNA appear to be transcribed but not translated, thus explaining the partial COX deficiency.

Association of Plastin 3 Expression With Disease Severity in Spinal Muscular Atrophy Only in Postpubertal Females

OBJECTIVEnTo investigate the potential association of plastin 3 (PLS3) expression levels in the blood with disease severity in spinal muscular atrophy (SMA).nnnDESIGNnMeasurement of PLS3 messenger RNA levels in the blood of patients with types I, II, and III SMA.nnnSETTINGnPediatric Neuromuscular Clinical Research Network SMA Natural History study.nnnPARTICIPANTSnA cohort of 88 patients of both sexes who had SMA.nnnMAIN OUTCOME MEASURESnLevels of PLS3 messenger RNA in relation to SMA type and SMN2 copy number.nnnRESULTSnPrepubertal female and younger male (<11 years) patients hadxa0approximatelyxa02-fold-higher levels of PLS3 expression than did postpubertal female and older male (≥11 years) patients, respectively (Pxa0≤xa0.001). Expression of PLS3 in male patients did not correlate with SMA clinical type or SMN2 copy number in either age group (Pxa0>xa0.10). In postpubertal female patients, PLS3 expression was greatest in patients with type III SMA, was intermediate in patients with type II SMA, and was lowest in patients with type I SMA. Expression of PLS3 correlated with SMA type, SMN2 copy number, and the gross motor function measure only in postpubertal female patients.nnnCONCLUSIONnThe PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.

Acute Hepatic Failure in a Child Treated With Lamotrigine

An 8-year-old boy with a known seizure disorder that was being treated with lamotrigine developed acute hepatic failure. The patient, who had been well previously, presented with jaundice, elevated liver enzymes, and a coagulopathy. After discontinuation of lamotrigine and aggressive resuscitation, the patient made an uneventful recovery. We believe that the hepatic failure in our patient was secondary to the use of lamotrigine. We recommend careful monitoring of liver function when lamotrigine is administered.

Turcot's syndrome Evidence for linkage to the adenomatous polyposis coli (APC) locus

Objective: To investigate the possibility that neuroepithelial tumors in Turcots syndrome are caused by pleiotropic mutations in the gene for adenomatous polyposis coli (APC), a tumor-suppressor gene implicated in colonic cancer. Methods: We studied the inheritance patterns of genetic markers for the chromosome 5q21 region in 12 members of a Turcots syndrome kindred with five affected members. We performed linkage analysis to detect linkage between the disease phenotype and DNA markers. Results: Marker D5S346, located 30 to 70 kilobases from the APC locus, showed evidence highly suggestive of linkage to the disease phenotype (lod score = 1.92). Conclusions: The data provide evidence that the tumor-suppressor gene implicated in APC and sporadic colon cancers may also cause malignant neuroepithelial tumors in Turcots syndrome.

Mitochondrial Morphology and Intracellular Calcium Homeostasis in Cytochrome Oxidase-Deficient Human Fibroblasts

Mitochondrial encephalomyopathies arise from mutations in the mitochondrial or nuclear genome and result in defective energy metabolism. Investigation of cellular pathophysiology in these disorders has been limited to nonneuronal explant cultures such as fibroblasts and myoblasts. While investigating mitochondrial structure and function in fibroblasts obtained from control and cytochrome oxidase-deficient (COX) patients, we observed possible abnormalities by vital dye confocal microscopy. Most notable were swelling, reticulation (e.g., intricate fusion of mitochondria), and proliferation of mitochondria. However, a detailed quantitative comparison of mitochondrial morphology in age-, sex-, and passage-matched cultures revealed no significant differences between control and cytochrome oxidase-deficient fibroblasts, nor any differences with passage. In addition, COX fibroblasts exhibited no obvious impairment of intracellular calcium handling, measured by fura-2. These results indicate that cytochrome oxidase deficiency, at the level in these cultures, does not produce structural or ionic concentration alterations in fibroblasts. Future investigation of the pathophysiology of this respiratory chain disorder may require excitable tissue.

Ventriculitis and hydrocephalus in a child with CNS Candida granulomas

mental scales of intelligence (Bayley). Differences were noted on mental performance (Bayley) between cohorts, while social skills, temperament, and motor development were comparable using MANOVA. Preterm infants had lower scores (R 2 = 0.62 and 0.57, P < .0001) when they were not corrected for prematurity at 12 and 24 months of age. Even after correcting for prematurity at these ages, lower scores were again noted for preterm infants (R 2 = 0.22 and 0.25; P < .01 and .03, respectively). Specific neonatal sleep measures at birth correlated with these lowered developmental performances (i.e., lower spectral EEG energies, less cardiorespiratory regulation, lower REM counts, longer sleep cycles, and higher EEG correlations). Although healthy preterm infants escaped major neonatal illnesses, specific neonatal EEG sleep measures are associated with lower developmental performances at 12 and 24 months postnatal age with or without correction for prematurity. Sleep-EEG differences between preterm and term groups reflect differences in functional brain development which predict neurodevelopmental performance at older ages. This study was supported in part by NS26793.