Intermittent claudication -- atypical presentation, diagnosis and treatment.

A unique case of a man with Fabry's disease and associated small vessel vasculopathy manifesting as recurrent episodes of intermittent claudication is described. The case highlights the concept that microvascular involvement due to local accumulation of glycosphingolipid in the smooth muscle fibres of vessel walls may be responsible for claudicant symptoms in such patients rather than the more classical macrovascular insufficiency.

Clinical course correlates poorly with muscle pathology in nemaline myopathy.

OBJECTIVE: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal alpha-actin. Nemaline myopathy due to mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.

Diagnostic criteria for respiratory chain disorders in adults and children.

BACKGROUND: Respiratory chain (RC) disorders are clinically, biochemically, and molecularly heterogeneous. The lack of standardized diagnostic criteria poses difficulties in evaluating diagnostic methodologies. OBJECTIVE: To assess proposed adult RC diagnostic criteria that classify patients into "definite," "probable," or "possible" categories. METHODS: The authors applied the adult RC diagnostic criteria retrospectively to 146 consecutive children referred for investigation of a suspected RC disorder. Data were collected from hospital, genetics, and laboratory records, and the diagnoses predicted by the adult criteria were compared with the previously assigned assessments. RESULTS: The authors identified three major difficulties in applying the adult criteria:lack of pediatric-specific criteria; difficulty in segregating continuous data into circumscribed major and minor criteria; and lack of additivity of clinical features or enzyme tests. They therefore modified the adult criteria to allow for pediatric clinical and histologic features and for more sensitive coding of RC enzyme and functional studies. Reanalysis of the patients' data resulted in congruence between the diagnostic certainty previously assigned by the authors' center and that defined by the new general RC diagnostic criteria in 99% of patients. CONCLUSIONS: These general diagnostic criteria appear to improve the sensitivity of the adult criteria. They need further assessment in prospective clinical and epidemiologic studies.

Quadriceps muscle wasting persists 5 months after total hip arthroplasty for osteoarthritis of the hip: a pilot study.

AIMS: To determine whether additional muscle fibre wasting of the ipsilateral vastus lateralis muscle occurs in the early postoperative period after total hip arthroplasty for osteoarthritis of the hip and whether there is an improvement in preoperative measures of quadriceps muscle thickness, strength, pain and function over a 5-month postoperative period. METHODS: Twelve patients had ipsilateral needle quadriceps biopsy for muscle morphology and bilateral quadriceps muscle thickness ultrasound preoperatively, 5 days and 4 weeks postoperatively and a further muscle thickness measurement at 5 months. Seven additional patients and five age-matched control subjects had bilateral quadriceps muscle ultrasound thickness preoperatively, 6 weeks and 5 months postoperatively, with assessment of quadriceps muscle dynamometry, pain scores and Timed Up and Go (TUG) test. RESULTS: Preoperatively, all 19 patients demonstrated significant atrophy of the ipsilateral compared with the contralateral quadriceps muscle (P = 1.8 x 10(-7)) on muscle ultrasound, which persisted at 5 months follow up (P = 0.009). Muscle morphology preoperatively showed type 2A and 2B muscle fibre atrophy on needle muscle biopsy, with further atrophy of all three fibre types (P = 0.029) at 5 days postoperatively associated with a fibre type shift from type 1 to 2A fibres (P = 0.0011) at 1 month. There was improvement in hip pain postoperatively and a significant improvement in the TUG test (P = 0.007). However, there was no improvement in muscle strength on dynamometry. CONCLUSIONS: There is significant ipsilateral quadriceps atrophy and weakness with 2A and 2B fibre atrophy preoperatively in patients with osteoarthritis of the hip with exacerbation and further atrophy of all three fibre types 5 days postoperatively. Postoperative follow up showed that the reduction in ipsilateral quadriceps muscle thickness persisted at 5 months despite physical rehabilitation. Patients did note significant improvement in pain postoperatively and improvement on functional assessment with the TUG test. Other therapeutic strategies may have to be developed to reverse disuse muscle atrophy.

Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study.

BACKGROUND: The validity and magnitude of an association between myositis and malignant disease continue to be debated. Such issues as the legitimacy of a myositis diagnosis and distinction among myositis subgroups in previous population-based studies remain unresolved. OBJECTIVE: To determine the risk for malignant disease in patients with biopsy-proven inflammatory myopathies. DESIGN: Population-based, retrospective cohort study. SETTING: Victoria, Australia. PATIENTS: 537 patients in whom a biopsy-positive idiopathic inflammatory myopathy was first diagnosed from 1981 through 1995. MEASUREMENTS: Standardized incidence ratios were calculated to compare the incidence of malignant disease in patients with inflammatory myopathy and the general population. RESULTS: A total of 116 cases of malignant disease were found in 104 patients. Seventy-four cases were identified concurrently with (within 7 days) or after diagnosis of myositis. The highest risk for malignant disease was associated with dermatomyositis (standardized incidence ratio, 6.2 [95% CI, 3.9 to 10.0]). The risk was also increased in polymyositis (standardized incidence ratio, 2.0 [CI, 1.4 to 2.7]), although the relative risk for malignant disease in dermatomyositis compared with polymyositis was 2.4 (CI, 1.3 to 4.2). An increased risk for malignant disease was also found in inclusion-body myositis (standardized incidence ratio, 2.4 [CI, 1.2 to 4.9]). The excess risk for malignant disease diminished with time (standardized incidence ratio, 4.4 [CI, 2.7 to 7.1] in the first year; 3.4 [CI, 2.3 to 5.1] between 1 and 3 years; 2.2 [CI, 1.3 to 3.9] between 3 and 5 years; and 1.6 [CI, 1.0 to 2.6] beyond 5 years [ P for trend, 0.002]). CONCLUSION: The risk for malignant disease is increased in biopsy-proven dermatomyositis and polymyositis and also appears to be increased in inclusion-body myositis.

A novel clinical phenotype of myopathy, sensorimotor neuropathy, infertility, and hypogonadism with multiple mitochondrial DNA deletions.

We describe a patient with myopathy, sensorimotor neuropathy, hypogonadism, and infertility with abnormal sperm mobility and morphology. Analysis of the deltoid muscle DNA revealed a G to A change at nt 1102 in the twinkle gene and multiple mitochondrial DNA deletions. Histochemistry revealed "ragged-red" fibers and many cytochrome-c oxidase negative fibers (32%) that lacked the mitochondrial encoded respiratory chain subunits I and II and the nuclear encoded subunit VIc. Respiratory chain enzyme analysis showed severe deficiency of complex I, III, and IV. This patient has no documented family history of progressive external ophthalmoplegia, which suggests either a sporadic or autosomal-recessive syndrome. This case is a novel phenotype for twinkle gene mutations and multiple mitochondrial DNA deletion syndromes, as these syndromes generally follow an autosomal-dominant inheritance pattern.

Elevated aminotransferase as a presenting finding in a patient with occult muscle disease.

We report a patient with occult muscle disease who presented with raised serum aminotransaminases. This case report emphasises the importance of considering muscle disease in the differential diagnosis of raised serum aminotransaminases, as it may negate the need for invasive investigations such as liver biopsy.

Benign acute childhood myositis: laboratory and clinical features.

BACKGROUND: Benign acute myositis of childhood is a disorder of midchildhood, typically affecting boys. Symptoms include calf pain and difficulty walking after a viral illness. There is an epidemiologic association with influenza. OBJECTIVES: To describe the clinical and laboratory features of benign acute myositis. RESULTS: Thirty-eight children (32 boys, 6 girls) were seen with 41 episodes of myositis between 1978 and 1997. Two were siblings and three had recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted: toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle tenderness was isolated to the gastrocnemius-soleus muscles in 82% of episodes. Recovery occurred within 1 week. Creatine kinase levels were elevated during all episodes. Viral studies were positive in 10 of 24 episodes, 5 because of influenza B. CONCLUSION: Benign acute myositis is a syndrome of midchildhood that can be differentiated from more serious causes of walking difficulty by the presence of calf tenderness, normal power, intact tendon reflexes, and elevated creatine kinase. The gait patterns noted may minimize power generation of the calf muscles by splinting the ankles. Onset in childhood may reflect an age-related response to viral infection, and occurrence primarily in boys may reflect a genetic predisposition or an as-yet unknown metabolic defect.

Incidence of inflammatory myopathies in Victoria, Australia, and evidence of spatial clustering.

OBJECTIVE: To determine the incidence of idiopathic inflammatory myopathies (IIM) in Victoria, Australia, and look for evidence of space-time or spatial clustering. METHODS: Cases of IIM diagnosed between 1989 and 1991 were identified by muscle biopsy and hospital discharge diagnosis review. Diagnosis was verified by medical record review and included if Bohan and Peter criteria for definite or probable disease were met. The pair-wise Euclidean distances between cases' residences were computed using grid references, and temporal distances were calculated between biopsy dates. The Mantel test for space-time clustering was computed. Each patient was also characterized by statistical local area (SLA) according to place of residence. For each SLA, the expected annual incidence of IIM was calculated, based upon its population distribution, and these were compared to the observed annual incidence. Confidence intervals for the true rate ratio (RR) for each SLA were calculated assuming a Poisson distribution, and the level of heterogeneity in the data was examined by calculation of a chi-squared for homogeneity. RESULTS: Ninety-four cases met inclusion criteria for an annual incidence of 7.4 (95% CI 6.0-9.0) per million person-years. No space-time clustering was found (z = -0.434, p = 0.665), but there was evidence of spatial clustering. A total of 67 observed cases were distributed among 58 urban SLA. Four SLA had a greater than expected incidence of myositis (95% Poisson based CI excluded 1), accounting for 20 of the observed cases. CONCLUSION: The incidence of IIM in Australia is higher than most previous population based estimates. The finding of spatial clustering supports the hypothesis that environmental factors may be important in the pathogenesis of these diseases.

Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder.

OBJECTIVE: To define the spectrum of clinical and biochemical features in 51 children with isolated complex I deficiency. BACKGROUND: Mitochondrial respiratory chain defects are one of the most commonly diagnosed inborn errors of metabolism. Until recently there have been technical problems with the diagnosis of respiratory chain complex I defects, and there is a lack of information about this underreported cause of respiratory chain dysfunction. METHODS: A retrospective review of clinical features and laboratory findings was undertaken in all diagnosed patients who had samples referred over a 22-year period. RESULTS: Presentations were heterogeneous, ranging from severe multisystem disease with neonatal death to isolated myopathy. Classic indicators of respiratory chain disease were not present in 16 of 42 patients in whom blood lactate levels were normal on at least one occasion, and in 23 of 37 patients in whom muscle morphology was normal or nonspecific. Ragged red fibers were present in only five patients. Tissue specificity was observed in 19 of 41 patients in whom multiple tissues were examined, thus the diagnosis may be missed if the affected tissue is not analyzed. Nine patients had only skin fibroblasts available, the diagnosis being based on enzyme assay and functional tests. Modes of inheritance include autosomal recessive (suggested in five consanguineous families), maternal (mitochondrial DNA point mutations in eight patients), and possibly X-linked (slight male predominance of 30:21). Recurrence risk was estimated as 20 to 25%. CONCLUSION: Heterogeneous clinical features, tissue specificity, and absence of lactic acidosis or abnormal mitochondrial morphology in many patients have resulted in underdiagnosis of respiratory chain complex I deficiency.

Haycocknema perplexum n. g., n. sp. (Nematoda: Robertdollfusidae): an intramyofibre parasite in man.

Haycocknema perplexum n. g., n. sp. (Nematoda: Robertdollfusidae) is described from a man in Tasmania, Australia. Adult male and female nematodes and larvae were recovered from myofibres following biopsy of the right vastus lateralis muscle and were associated with a polymyositis. H. perplexum is distinguished from all other genera of the Muspiceoidea by the presence of a large amorphous "cell" supporting a granule-filled, flask- or gourd-shaped reservoir in the rectal region of mature and gravid female nematodes, often containing one or more large, refractile, thick-rimmed "globules" on the external surface of the reservoir, by the small number of ova/eggs/larvae developing in each uterus, by the minute, weakly-sclerotised, almost tubular spicule, by the presence of a pair of ampulla-shaped glands posteriorly and by the presence of lateral bacillary bands comprised of a single row of pore cells spaced irregularly and extending posteriorly to the region of the vulva in immature females.

Idiopathic granulomatous myositis: does the clinical spectrum include polymyalgia rheumatica?

Granulomatous inflammation restricted to muscle is an uncommon cause of myopathic syndromes. Two patients were diagnosed with idiopathic granulomatous polymyositis after appropriate investigations failed to reveal a systemic or alternative explanation for the granulomas seen in their muscle biopsy. One patient presented with a syndrome indistinguishable from polymyalgia rheumatica but both patients manifested disabling myalgias which were strikingly corticosteroid responsive. The two cases underscore the potential importance of muscle biopsy in polymyalgic states, the non-specificity of polymyalgia rheumatica as a syndrome which can be simulated by other disorders including granulomatous myositis, and the potential corticosteroid responsiveness of prominent, functionally limiting myalgias which can be seen in this disorder. Some controversy continues regarding the correct nosology of this disease, largely perpetuated by an awareness of the inherent limitations of current non-invasive evaluation techniques to confirm occult granulomatous involvement of non-myogenous organs.

Congenital muscular dystrophy, white-matter abnormalities, and neuronal migration disorders: the expanding concept.

The congenital muscular dystrophies are a heterogeneous, recessively inherited group of disorders that have been subclassified on the basis of clinical central nervous system involvement. We report two children with "pure" congenital muscular dystrophy, one merosin negative and one merosin positive with extensive white matter and occipital cortical neuromigration abnormalities on magnetic resonance imaging (MRI). The first patient (merosin-negative congenital muscular dystrophy) presented with hypotonia and weakness in the neonatal period and subsequently was found to have a leukoencephalopathy and occipital cortical dysplasia on magnetic resonance imaging. The second patient presented with developmental delay without definite weakness. Initial investigations revealed a leukoencephalopathy and cortical dysplasia, but the patient subsequently was shown to have merosin-positive congenital muscular dystrophy. These patients illustrate that white-matter changes are not specific for merosin-negative congenital muscular dystrophy alone and that extensive cortical abnormality can be found in both groups of patients. In addition, our second patient illustrates a nonmuscular mode of congenital muscular dystrophy presentation that should be considered in patients with a "nonprogressive leukodystrophy."

Polymyositis caused by a new genus of nematode.

We report two patients who presented with increasing malaise and myalgia, and had biopsy-proven polymyositis. Their conditions deteriorated after corticosteroid treatment, and repeat muscle biopsies showed adult and larval nematodes. Anthelminthic treatment was completely successful in both cases. The infecting nematode appears to belong to a new genus and is, to our knowledge, the first known muspiceoid nematode to infect humans. Its life cycle and the route of infection are unknown.

McArdle's disease resembling an inflammatory myopathy.

Previous reports have shown that McArdle's disease may occasionally present in older patients (i.e. greater than 40 years of age) as a progressive myopathy that is clinically and sometimes electrophysiologically indistinguishable from idiopathic polymyositis. We report two such patients who in addition had muscle biopsies showing inflammatory infiltrates compatible with polymyositis. However, subsequent enzyme histochemistry demonstrated complete myophosphorylase deficiency and, in the absence of an alternative explanation, may be the reason for the inflammatory changes seen. These cases highlight the importance of a thorough evaluation of patients with an 'inflammatory myopathy' and the occasional diagnostic confusion that may arise in differentiating metabolic myopathies from idiopathic polymyositis. Diagnostic clarification is important to avoid the use of incorrect and potentially toxic treatment.

Proximal myotonic myopathy: a report of a kindred.

We describe a family with an autosomal dominant myotonic myopathy with absence of the abnormal CTG expansion characteristic of myotonic dystrophy. We believe that the findings in this family concur with those of recent case reports which have postulated the existence of a new adult onset myotonic disorder, distinct from myotonic dystrophy: 'proximal myotonic myopathy'.

Muscle abnormalities in idiopathic toe-walkers.

The cause of toe-walking is unknown. Muscle biopsies were taken from a group of 25 toe-walkers who were treated at this hospital to try to identify the pathological cause of the condition. The most common abnormality noted was an increase in the proportion of type I muscle fibers with type grouping; other less common changes included the presence of angulated atrophic fibers and thickened capillaries and cases in which occasional fibers were undergoing active degeneration and regeneration. The combination of these changes suggests that there may be an underlying neuropathic process in idiopathic toe-walkers.

Are mitochondrial DNA deletions causative in chronic progressive external ophthalmoplegia patients?

Twenty-one patients with long standing unexplained ptosis (3), chronic progressive external ophthalmoplegia (CPEO, 16) or Kearns-Sayre syndrome (KSS, 2) were studied for the presence of mitochondrial DNA (mtDNA) deletions and the major disease-associated mtDNA point mutations with the aim of correlating mitochondrial genetic abnormalities with pathogenesis in these patients. Only 52% were found to have a deletion; of these, 82% harboured the 'common deletion'. Two of 2 KSS patients and 9 of 16 CPEO patients were deletion positive. None of the 3 patients with bilateral ptosis only had a deletion. Of those patients with ragged red fibres (RRF) on histology, 69% had a deletion. No disease associated mtDNA point mutation was observed with the exception of the nucleotide (nt) 11084 A-G mutation associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) in a patient also harbouring the common deletion. The role of deletions in CPEO patients is discussed.

Mitochondrial electron transport chain defect presenting as hypoglycemia.

A profoundly deaf female infant was found to have hypoglycemia and lactic acidemia after an episode of decreased oral intake and vomiting. Electron transport chain (ETC) enzyme studies revealed a combination defect of complexes I, III, and IV in liver but not in skeletal muscle. This case highlights the fact that defects of the ETC are clinically highly heterogeneous and should be considered with hypoglycemia and lactic acidosis in the absence of a glycogen storage disorder. Moreover, ETC defects can occur with a biochemical profile suggestive of a fatty acid oxidation disorder.