Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin.

Neuromyopathy is a rare side effect of chronic colchicine therapy, most often occurring in patients with chronic renal failure. Drugs interacting with colchicine metabolism through CYP(3)A(4) and P-glycoprotein can accelerate accumulation and toxicity. We describe a case of an interaction between clarithromycin and colchicine resulting in acute neuromyopathy, and we conclude that combined use of macrolides and colchicine should be avoided.

Symptomatic distal myopathy with cardiomyopathy due to a MYH7 mutation.

Mutations in the myosin heavy chain gene (MYH7) can cause several distinct phenotypes depending on the location of the mutation: hypertrophic cardiomyopathy (several exons), myosin storage myopathy (exon 37/39) or Laing distal myopathy (exons 32-36). Here, we describe a unique combination of hypertrophic cardiomyopathy and hypertrophic distal myopathy in a family with a MYH7 Val606Met mutation (exon 16).

Relation between muscle fiber conduction velocity and fiber size in neuromuscular disorders.

To determine the relation between muscle fiber conduction velocity (MFCV) and muscle fiber diameter (MFD) in pathological conditions, we correlated invasively measured MFCV values with MFD data obtained from muscle needle biopsies in 96 patients with various neuromuscular disorders. MFCV was significantly correlated with MFD and independent of the underlying disorder. Pathological diameter changes were fiber-type dependent, with corresponding MFCVs. A linear equation expresses the relation well: MFCV (m/s)=0.043.MFD (microm)+0.83. We conclude that fiber diameter determines MFCV largely independent of the underlying neuromuscular disorders studied.

High myopia and congenital myopathy with partial pachygyria in cutis laxa syndrome.

PURPOSE: Several types of inborn errors of the O-glycan biosynthesis are known, leading to clinically very distinct phenotypes. Children with O-mannosyl glycan biosynthesis defects commonly present as a severe form of congenital muscular dystrophy with decreased alpha-dystroglycan staining, congenital eye anomalies, and brain migration defects. Alpha-dystroglycan is an O-mannosylated glycoprotein with additional mucin type O-glycans. METHODS: Based on overlapping clinical features with O-mannosyl glycan defects, especially with muscle-eye-brain disease, the authors performed a muscle biopsy in a child with severe congenital hypotonia, high myopia, partial pachygyria, mental retardation, cutis laxa, and an inborn error affecting the biosynthesis of both mucin type O-glycans and N-linked glycans. RESULTS: The histology showed no signs of muscle dystrophy, but a mild myopathy with slight increase in the muscle fiber diameter variability and type I fiber predominance. No significant decrease in the alpha-dystroglycan staining was detected; therefore, in spite of the phenotypic similarities the authors could not confirm the role of abnormal dystroglycan in the etiology of the muscle weakness and the developmental anomalies. CONCLUSIONS: High myopia, muscle weakness, and cortical neuronal migration abnormalities are common in disorders of O-mannosylation and also observed in the authors' patient. However, compared to the severe generalized defect observed in mannosyl glycan defects, in this child the cerebral white matter and cerebellum were spared, and no muscle dystrophy could be confirmed. This is the first description of high myopia in cutis laxa syndrome in combination with congenital disorders of glycosylation.

Effects of the creatine analogue beta-guanidinopropionic acid on skeletal muscles of mice deficient in muscle creatine kinase.

To evaluate the effects of phosphocreatine (PCr) and creatine (Cr) depletion on skeletal muscles of mice deficient in muscle creatine kinase (M-CK), we have fed mutant mice a diet containing the creatine analogue beta-guanidinopropionic acid (beta GPA). After 8-10 weeks of feeding, accumulation of the creatine analogue in M-CK-deficient muscles was comparable to that observed in muscles of wild-type mice. Strikingly, and unlike wild types, mutants did not accumulate phosphorylated beta GPA, indicating that MM-CK is the only muscle CK isoform which can phosphorylate beta GPA. In M-CK-deficient muscles there was respective depletion of PCr, Cr and ATP levels to 31, 41 and 83% of normal. The average cross-sectional area of type 2B fibres in gastrocnemius muscles was very much reduced and was similar to type 1 and type 2A fibres which maintained their normal size. The maximal isometric twitch force developed by gastrocnemius-plantaris-soleus (GPS) muscle complexes of beta GPA-treated mutants was reduced by about 30%, but these muscles showed an increased fatigue resistance during 1 and 5 Hz contraction. Mitochondrial enzyme activities in the upper hind limb musculature of null mutants were 20-35% increased by the beta GPA diet. Altogether, these results provide evidence that certain functions of the creatine kinase/phosphocreatine (CK/PCr) system are not eliminated solely by the loss of M-CK.

Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer's disease.

Marked neuron loss in the nucleus basalis of Meynert complex (NBMC) in Alzheimer's disease has repeatedly been reported in the literature. However, most of these studies quantitated only magnocellular, hyperchromatic (putative cholinergic) neurons of just a small part of the NBMC, and counts were expressed as numerical density. Applying a 3-dimensional-sampling design throughout the entire rostrocaudal extent of the NBMC and sampling neurons regardless of their size and staining characteristics, an overall neuron loss of only 15.5% was demonstrated for the whole NBMC. Neuron loss varied from 0% rostrally in the NBMC up to 36% in the most caudal part of the nucleus basalis of Meynert. Moreover, a significant increase in the number of small-sized neurons and a significant decrease in the number of large, putative cholinergic neurons could be detected, suggesting that apart from neuron loss neuron shrinkage appears to be another characteristic neuropathological feature of this degenerating cholinergic NBMC system. Preservation of these magnocellular cholinergic neurons in shrunken form renders it likely that cholinergic dysfunction, characteristic of Alzheimer's disease, may be responsive to neurotrophic influences.

Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve.

BACKGROUND: Reflex sympathetic dystrophy (RSD) (recently reclassified as complex regional pain syndrome type I) is a syndrome occurring in extremities and, when chronic, results in severe disability and untractable pain. RSD may be accompanied by neurologic symptoms even when there is no previous neurologic lesion. There is no consensus as to the pathogenic mechanism involved in RSD. To gain insight into the pathophysiology of RSD, we studied histopathology of skeletal muscle and peripheral nerve from patients with chronic RSD in a lower extremity. METHODS: In eight patients with chronic RSD, an above-the-knee amputation was performed because of a nonfunctional limb. Specimens of sural nerves, tibial nerves, common peroneal nerves, gastrocnemius muscles, and soleus muscles were obtained from the amputated legs and analyzed by light and electron microscopy. RESULTS: In all patients, the affected leg showed similar neurologic symptoms such as spontaneous pain, hyperpathy, allodynia, paresis, and anesthesia dolorosa. The nerves showed no consistent abnormalities of myelinated fibers. In four patients, the C-fibers showed electron microscopic pathology. In all patients, the gastrocnemius and soleus muscle specimens showed a decrease of type I fibers, an increase of lipofuscin pigment, atrophic fibers, and severely thickened basal membrane layers of the capillaries. CONCLUSION: In chronic RSD, efferent nerve fibers were histologically unaffected; from afferent fibers, only C-fibers showed histopathologic abnormalities. Skeletal muscle showed a variety of histopathologic findings, which are similar to the histologic abnormalities found in muscles of patients with diabetes.

Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle.

A 2-month-old boy died of a lethal infantile mitochondrial disease with severe lactic acidosis and involvement of the CNS. Histochemical analysis of skeletal muscle showed that cytochrome c oxidase staining was lacking in all muscle fibers but was present in arterioles. Ragged red fibers were not seen, but some fibers showed excessive staining for succinate dehydrogenase. Biochemical analysis revealed a combined complex I and IV deficiency in skeletal muscle but only a complex I deficiency in his fibroblasts. Two-dimensional native SDS electrophoresis confirmed these enzymatic findings at the protein level. Analysis of mitochondrial translation products in fibroblasts revealed no abnormalities, and analysis of mitochondrial DNA in muscle showed no depletion, large-scale deletions, or frequently occurring point mutations. We conclude that this disease must have been the result of either a nuclear DNA mutation in a gene controlling the expression or assembly of both complex I and the muscle-specific isoform of complex IV or, alternatively, a heteroplasmic point mutation in a mitochondrial tRNA, which codon is used more often by mtDNA encoded subunits of complex I than by mtDNA encoded subunits of complex IV. A different degree of heteroplasmy in skeletal muscle and fibroblasts would then explain the curious heterogeneous tissue expression of defects in this patient.

Spinal muscular atrophy-like picture, cardiomyopathy, and cytochrome c oxidase deficiency.

The authors report a child with a spinal muscular atrophy (SMA)-like picture, cardiomyopathy, and cytochrome c oxidase (COX) deficiency. Electromyography and muscle biopsy showed findings typical of SMA. However, COX staining of the muscle was negative. DNA analysis did not detect deletions in the survival motor neuron (SMN) gene. The lactate and lactate-to-pyruvate ratios were increased in blood and CSF. COX activity was decreased in muscle and fibroblasts. Western blot analysis showed reduced contents for all COX subunits. Patients with clinical features resembling SMA but with an intact SMN gene should be screened for a mitochondrial disorder.

Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders.

To study the incidence of rimmed basophilic vacuoles (RBV) and 15-21 nm filamentous inclusions in neuromuscular disorders, other than inclusion body myositis (IBM) and to determine the diagnostic value of RBV quantitation in the differential diagnosis of IBM, we reviewed 1600 muscle biopsies for RBV and 750 biopsies for filamentous inclusions. The number of RBV-positive fibers per 10 mm2--the RBV-fiber density--was determined. The incidence of RBV in non-IBM biopsies was 8.8 per 1000. Major diagnostic categories were neurogenic disorders (n = 7) and limb girdle muscular dystrophies (LGMD) (n = 3). In IBM (n = 7) the RBV-fiber density ranged from 10.4 to 63.1 and was significantly higher than in neurogenic disorders (0.9-4.4) and LGMD (1.1-2.7). The highest value was found in rigid spine syndrome (205.8). Filamentous inclusions were seen in 2.7 per 1000 non-IBM biopsies, including familial oculopharyngeal muscular dystrophy with distal myopathy (OPMD-DM), rigid spine syndrome, acid maltase deficiency and amyloid neuropathy. RBV and filamentous inclusions coexisted in rigid spine syndrome and in familial OPMD-DM. RBV, as well as filamentous inclusions, has a very low incidence in non-IBM neuromuscular disorders; the RBV-fiber density may help to discriminate neurogenic disorders and LGMD from IBM.

Dystrophic myopathy of the diaphragm in a neonate with severe respiratory failure during infectious episodes.

In this study a boy is described who showed slight postnatal asphyxia related to isolated dystrophic diaphragmatic musculature. Development was complicated by several periods of bronchopneumonia necessitating artificial respiration each time.

Mitochondrial creatine kinase containing crystals, creatine content and mitochondrial creatine kinase activity in chronic progressive external ophthalmoplegia.

Mitochondrial crystals containing mitochondrial creatine kinase (Mi-CK) protein were described recently. From in vitro studies it has been suggested that alterations in creatine concentration are connected to the occurrence of these crystals. In the present study free, phosphorylated and total creatine concentrations as well as Mi-CK activity were determined in muscle samples of six patients with chronic progressive external ophthalmoplegia (CPEO). Two of them showed Mi-CK containing mitochondrial crystals. The activity of Mi-CK was found to be clearly enhanced in those muscle samples in which mitochondrial crystals were present. No relationship was found between the concentration of total, free or phosphorylated creatine and the occurrence of mitochondrial crystals. An up to now unknown mechanism seems to cause the formation of Mi-CK containing crystals in human muscle mitochondria.

Coxsackie B1 virus-induced murine myositis: relationship of disease severity to virus dose and antiviral antibody response.

Inoculation of Coxsackie B1 virus (CB1) in newborn CD1 Swiss mice induces a chronic myositis of proximal hindlimb muscles (CB1 myositis). To study the possible role of the virus dose, and of antiviral antibodies in the development of CB1 myositis, we infected groups of newborn mice with six CB1 doses, ranging from 30 to 10,000 plaque forming units (pfu); after 4 and 8 weeks we determined morbidity and antiviral antibody titer, and quantified histopathological changes. At 4 weeks, morbidity and mononuclear cell infiltration differed significantly for the various groups, with the most prominent changes in 300 pfu animals. At 4 and 8 weeks diseased animals had significantly higher antibody titers than clinically unaffected animals, and at 4 weeks myopathic and infiltrative changes correlated positively with the serum antibody titer. Our data indicate that the virus dose plays a pathogenic role in CB1 myositis, and they suggest further study on the role of humoral immune mechanisms in the early phase of CB1 myositis.

A new phenotype of autosomal dominant nemaline myopathy.

We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.

Postnatal centralization of muscle fibre nuclei in centronuclear myopathy.

Postnatal centralization of muscle fibre nuclei, which were previously located subsarcolemmally, is described in a case of centronuclear myopathy (CNM) in a male patient with generalized muscle weakness since birth. A muscle biopsy was taken at the age of 11 months; no particular abnormalities were observed at this stage apart from an unusual variation in fibre size. A distinctly below average muscle fibre diameter, increased endomysial connective tissue, and features typical for CNM were found in a biopsy taken 9 yr later. Immunohistochemical studies using antibodies to desmin, vimentin, laminin and type IV collagen revealed altered staining patterns compared with normal fibres. The abnormalities in the patterns of cytoskeletal proteins point to a defective regulation of the composition and organization of the cytoskeletal network during development, paralleled by abnormalities in the extracellular matrix.

Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients.

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy.

Modulation of experimental allergic encephalomyelitis in Lewis rats by monoclonal anti-T cell antibodies.

The effect of monoclonal antibodies to different T lymphocyte populations of the rat on the induction and the course of experimental allergic encephalomyelitis (EAE) was investigated. EAE was induced by injection of guinea pig spinal cord in adjuvant. Subcutaneous injections of monoclonal antibodies to all peripheral T lymphocytes (W3/13) abrogated or prevented the development of clinical EAE. Similar results were obtained in animals injected with monoclonal antibodies to T helper cells (W3/25) mixed with monoclonal antibodies to T nonhelper cells (OX8). Animals treated with either W3/25 or OX8 developed clinical EAE as the control rats (subcutaneous injected with normal mouse serum). Histological examination after the acute stage revealed no significant differences between rats treated prophylactically with W3/13, W3/25 or OX8 and rats injected with normal mouse serum. Animals treated prophylactically with a mixture of W3/25 and OX8 developed, on the whole, EAE with less histological severity compared to the control animals. Treatment of rats after the onset of the first clinical symptoms of EAE (tail flaccidity) with W3/13 resulted in a less fatal course of the disease. Compared to surviving rats injected with mouse serum (controls) the number of infiltrates were reduced in these rats treated therapeutically.

White matter abnormalities in congenital muscular dystrophy.

Central nervous system (CNS) characteristics were examined in seventeen patients with autosomal recessive classic or "pure" congenital muscular dystrophy (CMD). In three patients, neuroradiological examination (CT/MRI) indicated hypodense white matter areas. Two out of these three patients had epilepsy (seizures and epileptic discharges on their EEG). Only two of the remaining patients had epileptic EEG discharges, but without clinical seizures. By comparing our results to data in the literature, we could conclude that the classic or "pure" form of CMD can be subdivided into two subtypes, i.e. those with and those without white matter hypodensities. A mild form of epilepsy or an epileptic predisposition on EEG can be part of the subtype with white matter hypodensities.

Immunophenotyping of congenital myopathies: disorganization of sarcomeric, cytoskeletal and extracellular matrix proteins.

We have studied the expression and distribution patterns of the intermediate filament proteins desmin and vimentin, the sarcomere components titin, nebulin and myosin, the basement membrane constituents collagen type IV and laminin, and the reticular layer component collagen type VI in skeletal muscle of patients with "classic" congenital myopathies (CM), using indirect immunofluorescence assays. In all biopsy specimens obtained from patients with central core disease (CCD), nemaline myopathy (NM), X-linked myotubular myopathy (XLMTM) and centronuclear myopathy (CNM), disease-specific desmin disturbances were observed. Vimentin was present in immature fibres in severe neonatal NM, and as sarcoplasmic aggregates in one case of CNM, while the amounts of vimentin and embryonic myosin, observed in XLMTM, decreased with age of the patients. Abnormal expression of myosin isoforms was found in several CM biopsies, although the organization of myosin and other sarcomere components was rarely disturbed. Basement membrane and reticular layer proteins were often prominently increased in severe cases of CM. We conclude that (i) desmin is a marker for individual types of CM and might be used for diagnostic purposes; (ii) the expression patterns of the differentiation markers desmin, vimentin and embryonic myosin in XLMTM, point either to a postnatal muscle fibre maturation or to a variable time-point of maturational arrest in individual patients; (iii) the correlation between the distribution patterns of extracellular matrix proteins and clinical presentation points to a role of these proteins in pathophysiology of CM.

Early-onset sensorineural hearing loss and late-onset neurologic complaints caused by a mitochondrial mutation at position 7472.

OBJECTIVES: To detect a mitochondrial mutation responsible for maternally transmitted hearing loss with late-onset neurologic features in a 3-generation Dutch family, and to describe the hearing loss, associated symptoms, and vestibular dysfunction. PATIENTS AND METHODS: All maternally related family members (n = 69) were investigated using standard audiometry. In a selected group, vestibulo-ocular examinations and additional neurologic and ophthalmologic examinations were performed. Twenty milliliters of venous blood was taken from all participants for genetic studies. SETTING: University medical center. RESULTS: All maternally related individuals carried an extra C at position 7472 of the mitochondrial genome. Hearing loss was the only symptom or presenting symptom in most family members and most pronounced at higher frequencies. Hearing loss at lower frequencies was demonstrated in individuals 10 years and older. Most patients had vestibular hyperreactivity and were susceptible to motion sickness, suggesting vestibulocerebellar dysfunction. Neurologic complaints were infrequent and presented by older individuals; however, numerous enlarged mitochondria were found in a muscle biopsy specimen of an individual with hearing impairment but without neurologic symptoms. CONCLUSIONS: Respiratory chain dysfunction should be considered as a possible cause of progressive sensorineural hearing loss. More research into the causes of high-frequency impairment should be considered, especially when sensorineural hearing loss, syndromal or nonsyndromal, is exclusively maternally transmitted. Maternal transmission of hearing impairment can also be valuable in the diagnosis of unclear neurologic syndromes.