H.J. ter Laak

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. NEUROLOGY 1996;47: 243-248

Deficiency of the voltage-dependent anion channel: a novel cause of mitochondriopathy.

A patient with a deficient voltage-dependent anion channel (VDAC) is reported, presenting clinically with psychomotor retardation and minor dysmorphic features. Biochemical studies on muscle mitochondria showed impaired rates of pyruvate oxidation and ATP production; however, no specific deficient activity of one of the mitochondrial enzymes was involved. Western blotting experiments indicated an almost complete VDAC deficiency in skeletal muscle. The only moderately decreased VDAC content in the patients fibroblasts might indicate that VDAC is expressed in a tissue-specific manner. The deficiency is likely caused by a mutation in the HVDAC1 gene or by a disturbed posttranslational modification. This is the first described deficiency of a component of the outer mitochondrial membrane associated with the pyruvate oxidation pathway. Defects in this membrane should be considered as a possible cause of otherwise unexplained mitochondrial disorders.

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

Article abstract 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.

Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

Myositis during long-term interferon-α treatment

Interferon-α (IFNα) is an established treatment for chronic viral hepatitis and certain malignant diseases (e.g., hairy cell leukemia, chronic myelogenous leukemia, and essential thrombocytosis). The most frequent side effect of IFNα is the occurrence of a transient, viral-like illness characterized by fever, chills, myalgia, and headaches. A rare but well-documented side effect is the occurrence of autoimmune diseases, including thyroid diseases, autoimmune hemolytic anemia, pernicious anemia, thrombocytopenic purpura, and systemic lupus erythematosus.1nnWe report a patient who contracted an inflammatory myopathy, with clinical and histologic characteristics of polymyositis (PM), during IFNα-2b treatment for essential thrombocytosis. After discontinuation of IFNα, a significant clinical improvement was observed.nnA 50-year-old woman was treated with IFNα-2b (Intron A; Schering-Plough, Kenilworth, NJ) at a dose of 4.5 × 106 units per day for essential thrombocytosis. Two months after the initiation of treatment, a slowly progressive proximal muscle weakness of the lower extremities developed gradually, followed by generalized fatigue and …

Primary respiratory failure in inclusion body myositis

The idiopathic inflammatory myopathies are a group of disorders characterized by acquired muscle weakness and presence of inflammatory infiltrates in skeletal muscle.1,2⇓ The three most common diseases within this group are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Respiratory muscle weakness with respiratory failure is a well-recognized complication in PM and DM but has only rarely been reported in IBM.3,4⇓ Symptomatic respiratory failure in IBM is considered to be secondary to coincidental pulmonary disease.5 We report a patient with IBM who developed subacute respiratory failure caused by primary respiratory muscle weakness.nnA 58-year-old woman sought treatment for slowly progressive muscle weakness, dysphagia, and weight loss. Her medical history was unremarkable, and she did not use any myotoxic drugs. Physical examination revealed normal speech, mild facial weakness, dysphagia without aspiration, and generalized muscle weakness (Medical Research Council [MRC] score, 4) with asymmetric weakness of the forearm muscles (right, MRC 4; left, MRC 3). …

Familial inclusion body myositis with histologically confirmed sensorimotor axonal neuropathy

Sirs: In inclusion body myositis (IBM) there is a significantly higher incidence of peripheral neuropathy than in other forms of idiopathic inflammatory myopathy [2, 4, 6, 8]. Nevertheless the association of IBM with peripheral neuropathy is controversial, as it is usually based solely on clinical, and especially neurophysiological evidence, without being substantiated by sural nerve biopsy [4, 6]. So far only ten cases, all involving sporadic IBM, have been reported in which the diagnosis of peripheral neuropathy was confirmed histologically by sural nerve biopsy [2, 5, 8]. We performed a combination of muscle and nerve biopsies in two sisters with clinical and electrophysiological characteristics of inclusion body myositis and sensorimotor axonal neuropathy. Patient 1 was a 77-year-old woman with no relevant medical history and with slowly progressive generalised muscle weakness and dysphagia. She had first experienced swallowing difficulty 4 years previously, followed by slowly progressive generalised muscle wasting. About 6 months before presentation at our clinic she developed weakness in both hands and difficulty in walking. At presentation she was no longer able to climb stairs or walk without support. Examination revealed generalised symmetrical muscle weakness, especially of the distal musculature in which the forearm extensors and flexors were equally affected, generalised muscular atrophy, distal hypaesthesia of the lower extremities and absence of Achilles tendon and knee tendon reflexes. All other aspects of the general and neurological examinations were normal. Laboratory investigations demonstrated a slightly elevated creatine kinase of 164 U/l (normal < 90 U/l) and a marginally elevated erythrocyte sedimentation rate (26 mm/h; normal < 20 mm/h). No autoantibodies were detected except for a positive antinuclear autoantibody titre (1:160). All other investigations including haemoglobin, white blood cell count with differentiation, platelet count, electrolytes, creatinine, urea, glucose, immunoelectrophoresis, vitamins B1, B6, B12, E and folic acid, cholesterol, triglycerides, Borrelia serology and cerebrospinal fluid studies were normal or negative. Electromyography (EMG) demonstrated fibrillation potentials with positive sharp waves, polyphasia and small-duration smallamplitude motor unit potentials (MUP) in the distal muscles and polyphasia with small-duration/ small-amplitude MUP in the proximal musculature. Nerve conduction studies showed absent H responses and absent sensory responses in the lower extremities, normal sensory responses in the upper extremities and strongly decreased compound motor action potential amplitudes and slightly reduced motor conduction velocities in the arms and legs. Muscle and sural nerve biopsies were performed using established methods [7, 11]. The muscle biopsy specimen of the quadriceps revealed the presence of endomysial inflammatory infiltrates consisting of CD4+ and CD8+ T cells, invasion of nonnecrotic muscle fibres, increased number of muscle fibres containing internal nuclei, ragged-red fibres, atrophic muscle fibres and positive staining of the sarcolemma for HLAABC (Fig. 1a). No rimmed vacuoles were observed. Sural nerve biopsy demonstrated a slight decrease in density of myelinated fibres with a preferential loss of large myelinated fibres. Many clusters of small regenerated axons were present (Fig. 1b). A small epineural perivascular lymphocytic infiltrate of CD4+ and CD8+ T cells was observed. There were no signs of vasculitis. The patient was treated with corticosteroids, but this did not alter the slowly progressive course of the disease. LETTER TO THE EDITORS

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.

Chronic progressive external ophthalmoplegia caused by an m.4267A>G mutation in the mitochondrial tRNAIle

Sirs: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, which mainly affects extraocular muscles. The majority of CPEO patients have single deletions or point mutations in the mitochondrial DNA (mtDNA) [1, 3]. Pathogenic point mutations are exclusively located in tRNA coding regions, the isoleucine tRNA (tRNAIle) coding region being one of the hotspots. Mutation in four loci of this tRNAIle hotspot have been associated with CPEO, while mutations in nine other loci can cause a variety of mitochondrial disorders, mainly hypertrophic cardiomyopathy [1]. The m.4267A > G mutation in the tRNAIle has been reported once in a patient with mitochondrial myopathy [4]. Here, we present a patient with an isolated CPEO caused by the m.4267A > G mutation in tRNAIle. A 52-year-old male had a five year history of double vision for which he was treated with prism glasses. He reported muscle cramps after intensive exercise, without muscle weakness, dysphagia or dysarthria. Family history was unrevealing. His medical history included surgery for a L5-S1 lumbar disc herniation and lactase deficiency, which was well under control with a lactose-free diet. On neurological examination, he had symmetrical ophthalmoparesis in all directions and bilateral ptosis. Both ptosis and ophthalmoparesis worsened after prolonged horizontal gaze. Further neurological examination was normal. Electromyography (EMG), including single fiber EMG, showed evidence of generalized myopathy with normal nerve conductions and neuromuscular transmission. Brain MRI and echocardiography were normal. Serum lactate was normal and creatine kinase was mildly elevated (391 U/l, normal < 200). Antibodies against skeletal muscle and acetylcholine receptor were undetectable. Needle biopsy of the quadriceps muscle revealed 10 % ragged-red fibers, 50 % cytochrome c oxidase (COX) negative fibers and abnormal mitochondria in electron microscopy (size differences, compact circular cristae, and paracrystalline inclusions) (Fig. 1). Measured according to standard procedures, both complex I activity as well as complex III activity and ATP production rate from pyruvate were decreased (53, 58 and 64 % of lowest reference value, respectively) in fresh skeletal muscle [2]. Activities of complex II, IV and V were normal. Molecular analysis of skeletal muscle mtDNA excluded large-scale rearrangements. Sequencing of several tRNA genes previously reported to be associated with CPEO revealed a heteroplasmic A to G mutation at position 4267 in the tRNAIle with a heteroplasmy level of approximately 50 % in muscle [1]. This is the second report of a mitochondrial disease caused by a m.4267A > G mutation in the mitochondrial tRNAIle and the first report of an association with CPEO. Previously, Taylor et al. found the m.4267A > G in a patient with deafness, cerebellar dysarthria, muscle ache, fatigue and mental slowing since the age of 30 [4]. The level of heteroplasmy in muscle tissue in Taylor’s patient was 88 %, compared to 50 % in our patient. It is tempting to speculate that the percentage of heteroplasmy of the m.4267A > G mutation in skeletal muscle correlates with the age of onset and the disease severity, although in general, genotype-phenotype correlations in mitochondrial disorders caused by mtDNA mutations are not clear. We can only speculate about the link between the tRNAIle mutation and the combined complex I and III deficiency. Since complex I and III both have a high isoleucine content, impaired incorporation of isoleucine due to the tRNAIle mutation could have altered their assembly, thereby resulting in loss of function [1]. LETTER TO THE EDITORS