Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels

A retrospective evaluation of asymptomatic subjects with persistent elevation of serum creatine kinase (CK) levels (hyperCKemia) was made in order to verify the presence of subclinical myopathy or idiopathic hyperCKemia and to define the most appropriate diagnostic pathway. Persistently increased serum CK levels are occasionally encountered in healthy individuals. In 1980 Rowland coined for them the term idiopathic hyperCKemia. Despite the increase of scientific knowledge, several healthy subjects with hyperCKemia still represent a problem for the clinician. We made a retrospective evaluation of 114 asymptomatic or minimally symptomatic individuals with incidentally detected persistent hyperCKemia. They underwent neurological examination and laboratory/instrumental evaluation. Skeletal muscle biopsy was performed and thoroughly investigated. Biochemical and genetic investigations were added in selected cases. Logistic regression analysis was applied. We diagnosed a neuromuscular disorder in 21 patients (18.4 %), and found, by muscle biopsy and/or EMG, pathological but not conclusive findings in 57 subjects (50 %). The statistic correlation between elevated serum CK levels and the probability of making a diagnosis changed according to the age of the patient. Conclusions Muscle biopsy is the basic tool for screening asymptomatic subjects with hyperCkemia. It allowed us to make a diagnosis of disease in 18.4 % of patients, and to detect skeletal muscle abnormalities in 38.6 % of the subjects. Interestingly, 31.6 % of individuals had completely normal muscle findings. These best fit the “diagnosis” of idiopathic hyperCKemia. Received: 13 March 2001, Received in revised form: 3 July 2001, Accepted: 5 July 2001     

Electrodiagnosis and muscle biopsy in asymptomatic hyperckemia

Purpose/aim of the study: An increased serum level of creatine kinase (CK) in asymptomatic individuals is a diagnostic challenge, as it may be associated with either physiological conditions, such as exercise or even signal an ominous neuromuscular disease at a presymptomatic stage. The electromyogram (EMG) and the muscle biopsy play a key role in the evaluation of asymptomatic hyperckemia. The objective of this study was to investigate asymptomatic individuals with increased CK levels. Materials and methods: We comparatively studied EMG, quantitative EMG and muscle biopsy in asymptomatic clinically normal individuals with repeatedly increased CK levels. Results: Conventional EMG was abnormal in 76% of patients, while quantitative EMG showed abnormal results in 88.9%. Muscle biopsy was diagnostic in 28%, one patient had neurogenic findings, 40% showed non-specific changes and 28% had normal results. Conclusions: EMG and especially quantitative EMG are highly sensitive in detecting subclinical neuromuscular diseases, whereas muscle biopsy may better contribute in the final diagnosis. No strong correlations were found between histological abnormalities and electrophysiological data, but further research is needed.     

Myoglobin RIA in detecting carriers of Duchenne's muscular dystrophy

In a prospective study we evaluated myoglobin (MG) and serum creatine kinase (CK) levels in two groups of subjects different in age and carrier status. CK and MG values were significantly lower in the older group. Whereas both parameters fully coincided in the younger group, CK was detected in a higher number of carriers in the older group. MG was always kept within the limits of normality when CK values were normal. We conclude that simultaneous determination of CK and MG does not improve carrier detection rate, the behavior of both biological parameters is similar in the younger age, and CK is more effective than MG for this purpose in the older subjects.     

Retrospective study of a large population of patients affected with mitochondrial disorders: clinical, morphological and molecular genetic evaluation

Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80 % of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defectsAbnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow “protected” against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling. Received: 8 December 2000 / Received in revised form: 18 February 2001 / Accepted: 13 March 2001     

HyperCKemia as the only sign of McArdle's disease in a child

An asymptomatic 13-year-old boy, who never complained of exercise intolerance or myalgia, was found to have markedly elevated serum creatine kinase (CK) levels during a routine check-up. General physical and neurologic examinations were normal. Surprisingly, histochemical and biochemical analysis of muscle showed myophosphorylase deficiency and genetic analysis showed that the patient was homozygous for the most common mutation encountered in McArdle's disease (R49X). This case illustrates the fuzzy correlation between molecular defect and clinical phenotype in patients with McArdle's disease, and suggests that a thorough study of the muscle biopsy is important in patients with idiopathic hyperCKemia for correct diagnosis and careful follow-up.     

Plasma creatine kinase isoenzymes in the Bar Harbor dystrophic mouse

Increased activity of the MM isoenzyme of creatine kinase (CK) was found in plasma from Bar Harbor dystrophic mice of the 129/ReJ dy/dy strain when compared to the findings in non-dystrophic controls. Total plasma CK activity was only slightly increased in dystrophic animals but plasma from both normal and dystrophic mice showed large amounts of the BB isoenzyme of creatine kinase. This isoenzyme was also found to be present in mouse platelets. It is concluded that BB isoenzyme from platelets could have obscured the contribution of muscle CK to the total plasma CK activity and that CK isoenzyme quantitation is needed to evaluate muscle disorders in rodents.     

Czy zwiększona aktywność kinazy kreatynowej w surowicy zawsze świadczy o chorobie mięśni?

Despite advanced diagnostic procedures in muscle disorders, creatine kinase (CK) activity is still one of the parameters most often investigated in serum. It is used mainly in neuromyology, and helps to differentiate between myogenic and neurogenic processes. Furthermore, it is applied to monitor the course of the disease and treatment results. Occasionally, marked elevated CK activity requires detailed diagnostic work-up, including electrophysiological, histopathological and genetic studies. In some cases, it enables the final diagnosis to be established. However, there is still a group of patients with so-called idiopathic hyper-CKemia and with no evidence of neuromuscular disorder. As little is known about potentially asymptomatic hyper-CK-emia, these patients should be carefully monitored.     

The detection of carriers of X-linked muscular dystrophy genes. A review of some methods studied in Newcastle upon Tyne

The serum creatine kinase level is by far the best and the only essential index of the carrier state (in X-linked Duchenne dystrophy). At present we suggest taking at least 2 and preferably 3 venous blood samples on different occasions from possible carriers after normal daily activity but definitely not within 3–4 days after any strenuous activity. A CK level over 75 IU/1 in any one sample (unless the others are very low) should be taken as evidence of the carrier state. The only possible exception may be in the case of a young girl (under 10 years old), when interpretation of the significance of slightly elevated CK levels should be deferred and the tests repeated after a few years. In older subjects the formula of Emery and Morton (1968) is used to assess the significance of CK levels within the normal range. It may be that further studies of the effect of exercise upon serum CK levels will suggest better standardised conditions for obtaining blood samples.     

Characterisation of dystrophin in carriers of Duchenne muscular dystrophy

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, was studied in needle biopsy samples taken from the quadriceps muscle of 15 asymptomatic carriers of DMD (13 adults and 2 young girls) and one symptomatic adult carrier. Antibodies to N- and C-terminal regions of dystrophin were used for both Western blot analysis and immunocytochemistry and a monoclonal antibody to beta-spectrin used to assess membrane integrity. All asymptomatic adult carriers showed some abnormality in dystrophin immunostaining but very few negative fibres were present. A clear mosaic of dystrophin positive and negative fibres was seen only in the adult symptomatic carrier and the two young girls. On a Western blot, all carriers studied had dystrophin of normal molecular weight, but most had reduced abundance. In adult carriers, the amount of dystrophin relative to normal controls varied, but it was unrelated to age, serum creatine kinase (CK) levels or to the degree of pathology. Carriers with normal CK showed abnormalities in dystrophin expression. The dystrophin immunoblotting profile of the 2 young girls was very similar to that of their mothers, but the mosaic pattern of immunostaining was not apparent in the older carriers. In conclusion, dystrophin immunostaining and Western blot analysis of biopsy samples from asymptomatic carriers is often abnormal and they may be useful additional aids for establishing carrier status, particularly in younger girls.     

The diagnostic value of plasma myoglobin levels in the adult and fetus at-risk for Duchenne muscular dystrophy

In boys with Duchenne muscular dystrophy (DMD) plasma myoglobin levels remained approximately constant with age while creatine kinase (CK) activity progressively decreased. For carrier detection, plasma myoglobin level was found to be less reliable than CK activity. The myoglobin level was raised only in some of those subjects who also showed a raised CK activity and was normal in those with a normal CK activity. The myoglobin level in fetal muscle at 18-22 weeks gestational age was found to be low compared with adult skeletal muscle levels and, consequently, the myoglobin level in fetal plasma and in amniotic fluid was found to be negligible. It is concluded that measurement of myoglobin offers no advantage over CK for the investigation of any aspect of DMD.     

Eosinophilic perimyositis as the presenting feature of a monoclonal T-cell expansion

A 51-year-old physically active man was investigated for exertional myalgias and muscle stiffness. On examination he had mild proximal muscle weakness of the upper extremities and retraction of the digit flexors. Blood eosinophilia was present, but serum creatine kinase (CK) levels and an electromyographic study were normal. A skin-fascia-muscle biopsy of the calf revealed a macrophagic and CD4+ T-cell infiltration of the perimysium, and a T-cell expansion was observed in blood, bone marrow, and muscle. A diagnosis of eosinophilic perimyositis was made, and prednisone and azathioprine were administrated with a good clinical response. This case highlights the differential diagnosis of blood eosinophilia with muscle disorders, and underscores that eosinophilic perimyositis may be the expression of a T-cell monoclonal expansion. Although the pathogenesis behind the T-cell expansion is unclear but probably inflammatory, we suggest regular follow-up to allow early treatment of any T-cell lymphoproliferative malignancy that may develop.     

Calendar of events

We compared serum creatine kinase (CK) levels between spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) and reviewed available histochemical studies of frozen sections of muscle biopsies. CK levels and the frequency of patients with elevated CK levels were significantly higher in the SBMA group when compared with the ALS group. CK levels occasionally approached values up to 8 times the upper limit of normal in the SBMA group. In addition to the chronic neurogenic changes in the muscle biopsy, all SBMA patients showed one or more myopathic changes. Increased numbers of markedly hypertrophic fibers were consistently seen in all patients. It is not clear whether the elevated CK level is directly related to the increased number of hypertrophic fibers or to other myopathic features. Based on these findings, we recommend genetic testing for SBMA in cases of male patients with motor neuron disease who present with a significantly elevated serum creatine kinase level, even when other characteristic clinical features of SBMA are absent. Muscle Nerve 40: 126–129, 2009     

The significance of simultaneous estimation of serum creatine kinase and myoglobin in neuromuscular diseases

Summary Serum creatine kinase (CK) and myoglobin (Mb) levels were measured in patients with different neuromuscular diseases, carriers of X-linked Duchenne-type muscular dystrophy and normal volunteers. The highest levels were found in Duchenne dystrophy and both values decreased in parallel with age. In patients suffering from limb-girdle dystrophy the increases in CK activity and Mb concentration were also pronounced. However, there were families with normal and others with elevated CK and Mb levels in facioscapulohumeral dystrophy. In neurogenic atrophies both CK and Mb levels generally increased only slightly. Serum Mb and CK levels have similar values as indicators of muscle damage in primary and secondary skeletal muscle disorders. The serum Mb level helps in the detection of carriers but is not more sensitive than CK measurement.     

High plasma creatine kinase: review of the literature and proposal for a diagnostic algorithm

Abstract The condition of persistently high plasma CK levels is frequently encountered in asymptomatic patients with normal neurological examination. This condition may be the unique manifestation of several neuromuscular disorders, whose diagnosis is now possible using new diagnostic techniques. However, even if these patients are intensely investigated, specific diagnoses are not always forthcoming. Because of the lack of a widely accepted diagnostic protocol, hyperCKaemia in asymptomatic subjects is a potentially difficult clinical problem. In this paper we review the literature on conditions associated with variations in plasma CK levels and the literature on investigations carried out in asymptomatic persons with high CK to identify neuromuscular diseases. In the light of these data, and the deliberations of a working group of the Italian Association of Myology, we propose a diagnostic algorithm to guide the diagnostic work-up of persons presenting with persistently high levels of plasma CK. This algorithm has been discussed and approved by the Committee of the Italian Association of Myology.     

Pure quadriceps myopathy in two sisters

The authors carried out a clinical, laboratory and muscle computed tomographgy CT follow-up study of 18-21 years on two sisters affected by quadriceps myopathy (QM). The onset in the fourth decade was a weakness in the thighs. During the follow-up study, the patients showed only vasti muscles involvement, normal creatine kinase (CK) levels, myopathic muscle biopsy and electromyography (EMG) and normal membrane protein expression on immunocytochemical analysis. Therefore, all muscle pathologies known to have quadriceps involvement as a leading feature have been ruled out. We conclude that our patients have pure QM with probable autosomal recessive inheritance.     

Serum parvalbumin, an indicator of muscle disease in murine dystrophy and myotonia

The soluble Ca(++)-binding protein parvalbumin (PV) is highly concentrated in fast muscle fibers of the wild type mouse. Employing Sandwich ELISA, we have shown that PV is present in the serum of normal mice and that its level is indicative of the disease status of muscle. Elevated PV levels were found in mice with X-linked dystrophy (mdx) and reduced levels in myotonic (ADR) mice. Serum creatine kinase (CK) levels were elevated in mdx and normal in ADR mice. Because myotonic mouse muscle has a strongly reduced PV content, the reduced PV serum level in ADR mice indicated that serum PV is derived from skeletal muscle. Serum PV in mdx mice, in which muscle PV content is close to normal, is a measure of the necrosis of fast muscle fibers. Serum levels of PV and CK were not significantly elevated in heterozygous (mdx/+) carrier females. Serum PV in Duchenne patients was below the limit of detection.     

Carrier detection in X-linked Becker muscular dystrophy by muscle provocation test (MPT)

The muscle provocation test (MPT: 40 min of strenuous exercise on a bicycle ergometer) is a sensitive method for the detection of carriers of Duchenne muscular dystrophy. The diagnostic applicability of MPT for carrier detection in X-linked Becker muscular dystrophy is demonstrated. Obligate carriers with mean creatine kinase (CK) values on repeated determination within the normal range showed a greater CK elevation after MGP than control subjects. Three of seven daughters of obligate carriers with normal resting CK activity had increased CK activity after MPT. These data suggest that the use of MPT may enhance the capability to discriminate carriers for these X-linked recessive genes.     

Involvement of nervous system in maternally inherited diabetes and deafness (MIDD) with the A3243G mutation of mitochondrial DNA

OBJECTIVES: The A3243G mutation of mitochondrial DNA (mtDNA) has been associated with maternally inherited diabetes and deafness (MIDD) in a number of reports; however, the involvement of the nervous system has rarely been mentioned, prompting this exploration of the manifestation of neurological disorders in MIDD cases. MATERIAL AND METHODS: We investigated four generations of a large Taiwanese family in which MIDD is manifest. We conducted a series of clinical examinations, including computed tomography (CT) and magnetic resonance imaging (MRI) of the head, brain 99mTc-HMPAO single photon emission computed tomography (SPECT), cognitive function tests, and nerve conduction velocity (NCV) studies. Blood levels of creatine kinase (CK) and lactate, pathology of muscle biopsy samples and proportions of mutant mtDNA in blood cells, hair follicles, muscle and skin were also analyzed. Mean follow-up period was 4 years. RESULTS: The patients exhibited the clinical features of diabetes mellitus including sensorineural hearing loss, short stature, and/or histories of spontaneous abortion. No stroke-like episodes were reported. Analysis for mtDNA revealed that the A3243G mutation existed in 11 members (6 symptomatic and 5 asymptomatic members) of this MIDD-prone family, with the proportion of mutant mtDNA ranging from 21% to 47% in leukocytes. Head CT revealed diffuse brain atrophy for all 6 (100%) patients examined and bilateral basal ganglia calcification in 4 of 6 (67%) patients. Brain 99mTc-HMPAO SPECT revealed diminished uptake in the bilateral parieto-occipital or occipital regions for all 6 tested patients, cognitive function for these patients was normal. Results of head CT and SPECT were normal in one asymptomatic member of the family. One muscle biopsy revealed abundant ragged-red fibers with modified Gomori-trichrome stain. Muscle-enzyme activity and serum-lactate levels were normal. CONCLUSION: We have demonstrated that a wide spectrum of sub clinical pathologies of the central nervous system and muscle are present for this MIDD-prone family, none of whom developed typical MELAS during the 4-year period of follow-up study.     

Effect of newly proposed CK reference limits on neuromuscular diagnosis

The objective was to determine the effect of a proposed increase in the upper reference limits of serum creatine kinase (CK) on neuromuscular disease diagnosis. This was a retrospective study of 94 Caucasian subjects (49 women and 45 men) in whom a neuromuscular physician ordered a CK as part of their evaluation. The patients were divided into two groups: those with diagnoses that either should or could elevate serum CK, and those with diagnoses that should not elevate serum CK. Sensitivities and specificities of the manufacturer's and the newly proposed upper reference limits were determined. For women, raising the upper reference limit of CK from 140 IU/L to 201 IU/L reduced the sensitivity of the test from 50% to 29%, while increasing the specificity from 67% to 80%. For men, raising the upper reference limit of CK from 174 IU/L to 322 IU/L reduced the sensitivity from 80% to 60%, while increasing the specificity from 63% to 80%. The newly proposed upper reference limits resulted in a false‐negative CK of clinical significance in 7 of 94 subjects. Increasing the upper reference limit for CK reduced the sensitivity and increased the specificity of serum CK for neuromuscular disease diagnosis. Such a change will reduce unnecessary referrals and invasive diagnostic testing in patients with asymptomatic CK elevations. The clinical impact of the loss in sensitivity is small. If these new upper reference limits are adopted, neuromuscular physicians should be aware that a normal CK level does not exclude a diagnosis of myopathy. Muscle Nerve, 2009     

Clinical investigation in Duchenne dystrophy: V. Use of creatine kinase and pyruvate kinase in carrier detection

We have determined the value of creatine and pyruvate kinase (CK and PK) in carrier detection by evaluating 811 females in 73 families participating in the Collaborative Investigation of Duchenne Dystrophy. Thirty-nine obligate carriers, 244 normal controls (paternal females), as well as 76 possible carriers and 351 carrier suspects had three CK and PK specimens analyzed at a central laboratory. The CK and PK values varied with age in normals: both fell with age early in life, and CK rose after the fifth decade. Discriminant analysis indicated that the combination of mean CK and PK corrected for age yielded the best data for calculation of carrier probability. Using the best model, only 45% of obligate carriers could be identified at a false-positive rate of 2.5%. Daughters of obligate carriers have a disproportionate decline in CK and PK with age as compared to noncarrier females, suggesting that the rate of carrier detection will be higher in the first two decades. Our low rate of carrier detection, as compared to other studies, may reflect both the age of our obligate carrier population and the use of a control group that is more representative of the carrier population.