Biomedical subjects
L Bindoff
Publications and source records attributed to L Bindoff.
[Acute dystonia caused by metoclopramide (Afipran) therapy].
BACKGROUND: Metoclopramide is an antiemetic drug used frequently both in general practice and hospitals. The drug has few side effects, mainly drowsiness, and can be used both in pregnancy and breastfeeding. Acute dystonia is a rare side effect mostly affecting children and young adults within 1-3 days after start of the medication. Women are more frequently affected than men. MATERIAL AND METHODS: We present a clinical description of two patients admitted to our department with acute dystonia precipitated by metoclopramide. RESULTS: Both patients received treatment with biperiden; one received additional benzodiazepine. Both recovered rapidly and were discharged symptom free the next day. INTERPRETATION: Metoclopramide-induced dystonia is frightening both for the patient and the family. Because of concomitant anxiety and psychiatric symptoms, individuals are often regarded as hysterical. The attack can be abbreviated by parenteral administration of anticholinergic drugs. It is important that all doctors prescribing metoclopramide know of this side effect, especially when their patients are young females.
Nonrandom tissue distribution of mutant mtDNA.
Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.
Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.
Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases. Frameshift, stop, and splice mutations of SURF-1 were detected in 18 of 24 (75%) of the LS(COX) cases. No mutations were found in the LL(COX) and non-LS(COX) group of patients. Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically associated with LS(COX), although a proportion of LS(COX) cases must be the result of abnormalities in genes other than SURF-1. SURF-1 is the first nuclear gene to be consistently mutated in a major category of respiratory chain defects. DNA analysis can now be used to accurately diagnose LS(COX), a common subtype of Leigh syndrome.
Facial vasculitic rash associated with intravenous immunoglobulin.
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Abnormal merosin in adults. A new form of late onset muscular dystrophy not linked to chromosome 6q2.
We have identified seven patients (including two sib pairs) with a predominantly late onset limb-girdle muscular dystrophy in whom an absence of merosin was noted on immunoblotting. Merosin immunocytochemistry was normal, and no abnormalities were detected on immunostaining for the various proteins known to be involved in the limb-girdle muscular dystrophies (alpha, beta, gamma, delta sarcoglycan and calpain 3). Apart from one patient, where muscle problems began in childhood, reported age at onset of muscle weakness involving initially the proximal muscles of the lower limbs ranged from 17 to 40 years. The pattern of muscle involvement was similar from patient to patient, with hypertrophy of at least the calf muscles, absence of scapular winging and predominant involvement of hip flexors and adductors and hamstrings more than quadriceps. Serum creatine kinase in all patients was at least 10 times normal, and muscle biopsies showed non-specific dystrophic features. We believe that the patients described here may represent a genetically distinct subset within the limb-girdle muscular dystrophy group.
Duplications of mitochondrial DNA in Kearns-Sayre syndrome.
mtDNA duplications were detectable in 10 of 10 patients with mtDNA deletions and Kearns-Sayre syndrome (KSS) and in none of 8 patients with chronic progressive external ophthalmoplegia (CPEO). Thus, duplications of mtDNA seem to be a distinctive feature of KSS, including patients where Pearson's syndrome is the first manifestation. Diabetes mellitus was identified in 4 of 7 patients with high or moderate levels of mtDNA duplications. The balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.
Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome?
The phenotypes of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) are closely associated with deletions of mitochondrial DNA (mtDNA). Recent evidence suggesting that more than one type of rearrangement may be present in KSS led us to reinvestigate 18 patients with KSS or CPEO for the presence of mtDNA rearrangements other than deletion. mtDNA duplication was detectable in 10 of 10 patients with KSS, while deletion monomers were the only recombinant mtDNA easily detectable in eight of eight patients with CPEO. Deletion dimers were found only in cases having duplications. Thus, duplications of mtDNA seem to be a hallmark of KSS, including a patient where Pearson's syndrome was the first manifestation. We suggest that duplication of mtDNA is characteristic of the early-onset disease KSS, and that the balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.
Families of mtDNA re-arrangements can be detected in patients with mtDNA deletions: duplications may be a transient intermediate form.
In three patients with mitochondrial DNA duplications, there are two additional re-arranged molecules derived from mitochondrial DNA. Two forms of closed circular deletions of mitochondrial DNA have been characterised in all three patients, one being a monomer, and the other a dimer. The junction fragments appear to be the same in the deletion and the duplication, suggesting that both re-arrangements arose from the same initial recombination event, followed by homologous recombination. Sequential muscle biopsy and cell culture studies suggest that the duplication is present only transiently in muscle and cloned fibroblast lines. The duplicated molecule could thus be an intermediate in the formation of the deletion. Evidence is presented for the presence of duplicated mtDNA in 6/11 patients known to have deletions of mitochondrial DNA in muscle, suggesting that this could be a general mechanism for major re-arrangements of mitochondrial DNA. There may be parallels between the families of re-arrangements found in plant mitochondrial DNA, and the three distinct re-arranged molecules described here.
Methylprednisolone in multiple sclerosis: a comparative dose study.
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Morphologic aspects of muscle breakdown and lysosomal activation.
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Experimental (-) emetine myopathy. Ultrastructural and morphometric observations.
The ultrastructural changes induced by (-) emetine hydrochloride were studied in two skeletal muscles of the rat. (-) Emetine was administered at a dose level of 2 mg/kg for periods ranging from one to four weeks. Changes were noted after the one week stage and were progressive with all muscle components appearing to be affected. Myofibrillar changes included Z line streaming, rod formation, myofilament loss and contraction clumping. Mitochondrial degeneration was detected, but the most striking feature of the induced myopathy was the extensive membrane proliferation. The membranes were considered to be involved in the isolation of sarcoplasmic constitutents in the production of autophagic vacuoles. Morphometry was carried out in order to quantify some of the changes in the fibre components.
A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin.
The identification of a CAG trinucleotide repeat expansion, located within the coding sequence of the ataxin-2 gene, as the mutation underlying spinocerebellar ataxia 2 (SCA2) has facilitated direct investigation of pedigrees previously excluded from linkage analysis due to insufficient size or pedigree structure. We have previously described the identification of the ancestral disease haplotype segregating in the Cuban founder population used to assign the disease locus to chromosome 12q23-24.1. We now report evidence for the segregation of the identical core haplotype in pedigrees of diverse ethnic origin from India, Japan and England, established by the analysis of the loci D12S1672 and D12S1333 located 20kb proximal and 200 kb distal to the triplet repeat motif respectively. Interpretation of this data is suggestive that for these pedigrees at least, the mutation has arisen on a single ancestral or predisposing chromosome.