Myopathies are disorders of the skeletal muscle usually manifesting with weakness, muscle wasting, myalgias, exercise intolerance, elevated serum creatine-kinase (CK) (hyper-CKemia), abnormal needle electromyography (EMG), and abnormal muscle biopsy.1 Occasionally, however, myopathy may manifest without muscle symptoms but with elevated CK, normal or abnormal EMG, and normal or abnormal muscle biopsy.2 The latter condition is categorized as asymptomatic hyper-CKemia (AHCE, isolated hyper-CKemia, idiopathic CK-elevation, CK-myopathy). The following review aims at summarizing and discussing recent findings concerning the cause, frequency, evolution, and work-up of conditions manifesting as AHCE and normal or abnormal needle EMG, respectively, normal or abnormal muscle biopsy and possibly affection of organs other than the muscle.
METHODS AND MATERIALS
We conducted a systematic search of the database “PubMed” by application of the search terms “creatine-kinase,” “hyper-CKemia,” “CK-elevation,” and “elevated creatine-kinase” in combination with “isolated,” “asymptomatic,” “idiopathic,” “non-symptomatic,” “myopathy,” “neuromuscular disorder,” “muscle disease,” “muscular dystrophy,” “congenital myopathy,” “periodic paralysis,” “malignant hyperthermia,” and “myotonia.” Included were articles reporting patients with isolated hyper-CKemia, who did not report symptoms attributable to a pathology of the skeletal muscle and in whom hyper-CKemia was not attributable to a cardiac, cerebral, endocrine, immunological, infectious, toxic, or drug-induced cause, or to macro-CK. Patients with AHCE were included irrespective of whether they had undergone needle EMG or muscle biopsy. Excluded were patients with symptomatic hyper-CKemia with or without abnormal EMG and with or without abnormal muscle biopsy Fig. 1.
Primary (Hereditary) Myopathies
Most frequently, AHCE occurs in patients with primary myopathies but a number of acquired myopathies (disorders in which the muscle is collaterally affected) have been additionally reported. Primary myopathies manifesting with AHCE include muscular dystrophies, congenital myopathies, myofibrillar myopathies, myotonic dystrophies, channelopathies, and metabolic myopathies (Table 1).
The initial manifestation of Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) is frequently isolated hyper-CKemia in the absence of muscle symptoms or signs. Particularly in neonates and infants, AHCE may be the sole manifestation of the disease.3,4 Accordingly, blood spot tests are applied for screening of early-infancy hyper-CKemia. In a retrospective analysis of 528,410 screening tests for hyper-CKemia of 4–6-week-old boys in Germany between 1977 and 2011, it was found that 147 boys with AHCE developed definite, probable, or possible DMD (incidence: 1:3600) and that 33 boys developed definite, probable, or possible BMD (incidence: 1:15,500).3 In a recent study from Turkey, the presenting manifestation of DMD patients was AHCE in 40%.5 Five patients with presumably AHCE and a dystrophinopathy have been reported by Pelle et al.2 AHCE was also reported in a 3-year-old boy with BMD and pseudodeficiency of the GAA allele.6 AHCE was additionally reported in 3 males aged 9–12 years, with a dystrophin deletion in the rod domain.7
AHCE may also occur in female carriers of a dystrophin mutation but for diagnosing the carrier status, genetic testing is more reliable.8 In a 15-year-old girl with a negative family history for myopathy and absence of any muscle symptoms and signs, elevated resting levels of serum CK ranging between 500 and 1400 U/L were detected.9 Genetic testing by Southern blot and PCR revealed a deletion of exons 46–47 of the dystrophin gene.9 AHCE was additionally reported in other female carriers of dystrophin deletions.10
We recently investigated a patient with an 18-year history of AHCE who underwent muscle biopsy and was initially diagnosed as inclusion body myopathy. After having become symptomatic with muscle weakness at 60 years of age, he underwent exome sequencing and a previously described mutation in the MYOT gene was detected (Finsterer et al, submitted). During the further course, the patient developed progressive dysarthria and dysphagia, hyperlipidemia, coronary artery disease, and hiatal hernia with reflux disease, and underwent resection of a left transverse colon polyp.
Mutations in the CAV3 gene may phenotypically manifest with 5 different phenotypes, including limb-girdle muscular dystrophy-1C (LGMD1C), rippling muscle disease, characterized by increased muscle irritability, such as percussion-induced rapid contraction, percussion-induced muscle mounding, or electrically silent muscle contractions (rippling muscle), as distal myopathy, hypertrophic cardiomyopathy, or as AHCE.11 Phenotypic heterogeneity has been attributed to variable haploinsufficiency (reduced levels of wild-type caveolin-3).12 In 2 unrelated children with persistent AHCE, muscle biopsy with immunohistochemistry and quantitative immunoblot analysis revealed partial caveolin-3 deficiency as the culprit.11 Caveolinopathy with dyslipidemia may be also associated with long-term AHCE.13 In a study of 29 patients with idiopathic hyper-CKemia, 2 patients were detected who carried variants in CAV3.14 AHCE was additionally reported in an Italian mother and son in whom caveolin-3 was reduced on muscle biopsy.15
At an early stage of the disease, patients with limb-girdle muscular dystrophy 2A, which is due to mutations in the CAPN1 gene, may be asymptomatic but may present with elevated CK.16 In this particular report, one among 250 patients with AHCE was homozygous for the R110X mutation in the CAPN1 gene and showed total absence of calpain-3 on muscle biopsy.16 Histological analysis of muscle tissue in these preclinical cases showed isolated fascicles of degenerating fibers in an almost normal muscle.16
LGMD2B is due to mutations in the DYSF gene. One patient with presumably AHCE and dysferlinopathy has been reported by Pelle et al.2 Unfortunately, no details about the clinical and instrumental findings in this patient were provided.2 In addition, studies of pedigrees with dysferlinopathy showed that some patients have AHCE.
Fukutin-Related Protein (LGMD2I)
In an 8-year-old boy with dilated cardiomyopathy requiring heart transplantation, genetic work revealed a mutation in FKRP.17 Apart from elevated CK-levels, he remained asymptomatic even at 20 years of age.17 Only CT scans showed mild involvement of the skeletal muscles.17
When studying 19 patients with AHCE by means of EMG and muscle biopsy, an abnormal EMG was found in 14 patients.18 In one of these patients, muscle biopsy was indicative of central core disease and in another patient, muscle biopsy showed the features of multicore disease.18
In a study of 114 patients with idiopathic hyper-CKemia and minimal or no muscle symptoms, 18% received a definite diagnosis after work-up for myopathy with blood tests, EMG, muscle biopsy, and in vitro contracture tests (IVCTs).2 Among these 114 patients, one was diagnosed with desminopathy, but it is not mentioned whether this particular patient belonged to the AHCE or minimal symptomatic group.2
Rarely, myotonic dystrophies may present with AHCE as the initial manifestation.
In a 55-year-old woman with a family history positive for myotonic dystrophy type 1 (MD1), the individual history was positive for matutinal palpitations, a single syncope 4 years before presentation, and daytime sleepiness.19 She denied muscular symptoms but revision of previous blood tests revealed mildly but repeatedly elevated CK. Clinical neurologic and cardiologic examination was normal. Work-up for syncopes was noninformative. Interestingly, genetic testing revealed a CTG-repeat expansion of 70 in the DMPK gene.19 It was concluded that a short CTG-expansion in the DMPK gene may be associated with AHCE.
AHCE has been reported in some patients with myotonic dystrophy type-2 (MD2).20 In a 49-year-old man, isolated hyper-CKemia without muscle symptoms and absence of electrical myotonia was observed during 8 years before muscle biopsy, which showed features reminiscent of myotonic dystrophy. Genetic investigations revealed a CCTG expansion of 2500–3000 repeats in ZNF9.20 The further course was not reported. In a 52-year-old woman with MD2 due to a CCTG expansion of 134 bp, AHCE was the initial muscle manifestation during 20 years (Finsterer et al, 2019). She developed exercise-induced muscle weakness of the thighs not earlier than at age 51 years.
A patient with a history of rhabdomyolysis developed fluctuating, AHCE.21 Work-up revealed the mutation p.ArgLe528 in the CACNA1S gene.21 Mutations in this gene have been previously reported in association with hypokalemic periodic paralysis (hypoPP), malignant hyperthermia susceptibility (MHS), and congenital myopathy.21 Muscle biopsy showed core-like structures occurring predominantly in type-2 muscle fibers.21 In addition, AHCE has been reported in a single patient with idiopathic hypoPP who additionally suffered from hypogammaglobulinemia.22
Patients with MHS may be asymptomatic with only mild and possibly fluctuating CK-elevation.23–25 In a study of 37 patients with AHCE or mildly symptomatic, persistent hyper-CKemia, one patient with MHS was detected who did not complain about muscle symptoms.25 Muscle biopsy in this patient only revealed mild fiber size variation.25 In another study of patients with MHS and AHCE, muscle biopsy showed necrotic fibers, size variability, small angular fibers, and internal nuclei.26 In a 4-generation Japanese family, idiopathic hyper-CKemia was attributed to a mutation in RYR1.27 Hyper-CKemia cosegregated with the presence of the RYR1 mutation in this family.27 In a study of 49 patients with AHCE, 24 patients had an abnormal IVCT of at least one muscle strip, compatible with MHS.28
Pompe disease, also known as glycogen storage disease (GSD)-II, is a metabolic disorder due to impaired glycogen metabolism, predominantly affecting the muscle and the myocardium.29 In a study of 140 patients with myopathy of unknown origin or idiopathic CK-elevation, work-up for GAA activity and GAA mutations revealed asymptomatic Pompe disease manifesting as CK-elevation in 2 patients.30 Also, in early-onset Pompe disease, isolated CK-elevation may be the initial manifestation of the disease, as has been documented in a 2.5-year-old girl, who did not develop muscle symptoms until the last follow-up at 3.5 years of age. Despite starting enzyme replacement therapy at 2.5 years of age, mild hyper-CKemia was still present at 3.5 years of age.31 In a study of 348 patients with AHCE or unclassified limb-girdle muscular dystrophy, Pompe disease was found in 2.5% of the patients with AHCE.32 AHCE was also the initial manifestation in a 6-year-old boy with juvenile-onset Pompe disease.33
When studying 19 patients with AHCE by means of EMG and muscle biopsy, an abnormal EMG was found in 14 patients.18 In one of these patients, muscle biopsy was indicative of GSD-V.18 A 13-year-old boy without muscle symptoms became apparent for hyper-CKemia during a routine check-up.34 Clinical examination was normal but histochemical and biochemical investigations of the muscle biopsy showed myophosphorylase deficiency.34 Genetic work-up revealed the common mutation R49X in PYGM.34 In an apparently healthy 1-year-old girl, hyper-CKemia was observed only during episodes of fever.35 Work-up for neuromuscular disorders revealed histological and biochemical features of McArdle disease.35
In a study of 26 patients carrying the c.34C>T variant in the MAD gene, 5 manifested with AHCE.36 Unfortunately, no follow-up data of these patients were provided.36 One patient with presumably AHCE and MADA-deficiency has been additionally reported by Pelle et al.2 In a study of 20 patients with AHCE by muscle biopsy, MADA-deficiency was detected by means of histological investigations in one.37
Mitochondrial disorders (MIDs) manifesting with myopathy frequently present with AHCE at an early stage of the disease. In a 40-day-old boy with axial congenital hypotonia, macrocephaly, hepatomegaly, and mild coarsening facial features, elevated serum CK and lactate were detected.38 Needle EMG and muscle histology were normal but biochemical investigations of the muscle homogenate surprisingly revealed combined deficiency of complex-I and complex-III of the respiratory chain.38 Since age 13 m clinical abnormalities improved spontaneously together with declining serum CK and lactate values.38 Two patients with AHCE and an MID have been also reported by Pelle et al.2 When studying 19 patients with AHCE by means of EMG and muscle biopsy, an abnormal EMG was found in 14 patients.18 In 2 of these patients, muscle biopsy revealed morphological features of a MID.18 Between attacks of rhabdomyolysis, AHCE may be the only manifestation of carnitine-palmytoyl-transferase-2 deficiency.39
Other Primary Myopathies
In a recent study of 41 patients from 13 families with AHCE, familial occurrence of hyper-CKemia was documented in 13 of 28 patients (46%). Serum CK was also elevated in some relatives of these patients.40 Muscle biopsy in a single subject of this cohort showed mild nonspecific abnormalities exclusively.40 The authors classified familial AHCE as benign condition with autosomal dominant trait of inheritance in 60% of the cases.40 In a study of 114 patients with idiopathic hyper-CKemia and minimal or no muscle symptoms, 18% received a definite diagnosis after work-up for myopathy with blood tests, EMG, muscle biopsy, and IVCTs.2 One of these patients each was diagnosed with myopathy with tubular aggregates and central core disease.2 Unfortunately, the authors did not specify how many of these patients belonged to the asymptomatic or minimal symptomatic group. In a study of 100 patients with elevated CK of unknown cause, 41% did not exhibit any muscle symptoms.41 Hyper-CKemia was attributed to metabolic myopathies in 5 cases, to inflammatory myopathies in 4 cases, and to muscular dystrophies in 3 patients.41 Unfortunately, the authors did not specify how many of these patients had in fact muscle symptoms before diagnosis or not.41 AHCE has been recently reported in association with anoctamin-5-related myopathy.42 In a study of 3 Italian patients, AHCE and late‐onset tubular aggregate myopathy and congenital miosis were attributed to a novel mutation in the ORAI1 gene.43 In a single patient with AHCE and mild muscular dystrophy on muscle biopsy, exome sequencing revealed a pathogenic variant in the DAG1 gene.44 In a single patient with 4q35 facioscapulohumeral muscular dystrophy, AHCE was the initial manifestation of the disease.45
Acquired Myopathies and Nonmyopathic Genetic Conditions
Acquired, nonhereditary myopathies are increasingly recognized as a cause of AHCE and include nonmyopathic genetic disorders, inflammatory myopathies, endocrine disorders, myocardial damage, conditions characterized by muscle overactivity, and drug-induced conditions.
Nonmyopathic Genetic Conditions
Nonmyopathic genetic conditions going along with AHCE include motor neuron disease but not familial amyotrophic lateral sclerosis, hereditary neuropathies, hereditary spastic paraplegias, or spinocerebellar ataxias. AHCE has been rarely reported in bulbospinal muscular atrophy (BSMA).46 In 2 patients with BSMA, AHCE was documented during the preceding 10 years before onset of symptoms.46 In patients with choreoacanthocytosis due to mutations in the VPS13A gene, onset of neurological manifestations was preceded by AHCE during 2–20 years in some cases.47 In other patients, choreoacanthocytosis may be preceded by hypertrophic cardiomyopathy or trichotillomania.47 In a female infant with AHCE and generalized lipodystrophy, exome sequencing revealed a mutation in the PTRF-CAVIN gene (Table 1).48
In a 67-year-old man with AHCE, muscle MRI revealed edema of the vastus medialis and vastus lateralis muscles one year after detection of elevated CK-values.49 Muscle biopsy in this patient was diagnostic for inclusion body myositis.49 In a recent report, asymptomatically elevated CK was due to anti-SRP-associated necrotizing autoimmune myopathy in a 54-year-old woman and 56-year-old woman, respectively.50 Muscle symptoms developed not earlier than 4 months after detection of hyper-CKemia in both patients.50 When studying 19 patients with AHCE by means of EMG and muscle biopsy, an abnormal EMG was found in 14 patients.18 In 5 patients, muscle biopsy was indicative of polymyositis.18 In one of these patients, each muscle biopsy was indicative of inclusion body myositis and sarcoid myopathy, respectively.18 AHCE has been also reported in patients with idiopathic inflammatory myositis.51 In a study of 12 patients with polymyositis, 6 had AHCE before onset of clinical manifestations.52
Rarely, AHCE has been reported in patients with endocrine disorders (Table 2). AHCE has been particularly reported in patients with thyroid dysfunction, parathyroid dysfunction, and diabetes. In a study of 55 patients with idiopathic hyper-CKemia, elevated CK was attributed to hypo-respectively hyper-thyroidism in one of them each.53
Drugs that may go along with AHCE include raltegravir, an integrase inhibitor used in HIV-therapy,54 olanzapine, an atypical neuroleptic drug,55 statins,51,56 infliximab,57 and ipilimumab, tremelimumab, nivolumab, and pembrolizumab given for metastatic skin cancer.58
CK-elevation in the absence of muscle symptoms may also occur in patients with malignancy.53 In a single female, idiopathic hyper-CKemia was associated with myoma of the uterus.53 CK-values normalized after removal of the tumor.53 AHCE has been also reported in patients with muscle overactivity, particularly restless leg syndrome.59 Elevated CK in these patients was attributed to muscle overactivity during episodes of hyperkinesia.59 AHCE may be the initial manifestation of an HIV infection together with elevated ferritin.60 AHCE may also occur after seizures,61 extensive physical activity or competitive sport,62,63 traumatic muscle damage,64 delivery,65 pregnancy,66 muscle stimulation,67 or a number of other conditions (Table 2). AHCE does not seem to occur in amyotrophic lateral sclerosis or polio. AHCE may spontaneously disappear during pregnancy.66 In healthy looking children, isolated hyper-CKemia can be also a benign condition.68 In a study of 14 patients with isolated amyloid myopathy (anoctaminopathy and dysferlinopathy), 21% had AHCE at onset of the disease.69
Work-up for AHCE includes a thoroughly taken history, an extensive neurological examination, blood/urine tests at rest and during exercise, muscle MRI or muscle ultrasound, EMG, nerve conduction studies, a muscle biopsy, biochemical investigations of the muscle, and genetic tests.1 In patients with AHCE and an individual or family history positive for adverse reactions to volatile anesthetics or depolarizing muscle relaxants, an IVCT should be considered. The individual and family history may reveal a hereditary cause of AHCE or AHCE due to endocrine abnormalities or drugs. Clinical neurological examination is per definition normal in AHCE. Blood tests during exercise include the ischemic forearm test and the lactate stress test, although the relevance of the ischemic forearm test is under debate. In case of a colored or dark (Cola‐like) urine, myoglobin levels in the urine should be determined because AHCE due to rhabdomyolysis may be associated with elevated urinary myoglobin.70 Although rhabdomyolysis is frequently associated with myalgia, exercise intolerance, or muscle weakness,70 it may be asymptomatic in some cases.71,72 Rhabdomyolysis may be due to trauma or endogen injury, excessive muscle activity, hereditary muscle enzyme defects, and other less obvious medical causes, such as drugs and toxins, muscle hypoxia, metabolic and endocrine disorders, infections, temperature alterations, and miscellaneous causes.70 Muscle imaging may be normal or may show fibrosis or inflammatory edema. Needle EMG may be normal, myopathic, or nonspecifically abnormal. In a cohort of patients with AHCE, conventional EMG was abnormal in 76% and quantitative EMG was abnormal in 89% of the cases.73 A recently proposed method for the work-up of AHCE is single-fiber EMG.74 However, single-fiber EMG may reveal only nonspecific findings. In some patients, the cause of AHCE may remain elusive even years after the first recognition of elevated CK (idiopathic hyper-CKemia).56 In patients with idiopathic hyper-CKemia, CK frequently does not further increase during exercise.75 In patients with AHCE of unknown cause, repeated routine diagnostic approaches are recommended and genetic work-up with exome sequencing should be considered (Fig. 1).
Patients with AHCE require counseling, explaining the avoidance of excessive exercise and have proper hydration. They need to know the risk of malignant hyperthermia in case they did not have the IVCT or a genetically confirmed MHS, and need to inform the anesthesiologist and surgeon about AHCE before elective surgery. It is also crucial to advice females, particularly if a biopsy is not informative or no DNA testing is done, that they could be asymptomatic carriers of a neuromuscular disorder and to give advice concerning these possibilities. If AHCE is due to Pompe disease, MHS, acquired myopathy, or complicated by rhabdomyolysis and renal insufficiency, appropriate treatment is indicated. In patients with Pompe disease, enzyme replacement therapy should be initiated as soon as the diagnosis is established. In a patient with MHS, general anesthesia should be performed with caution, avoiding volatile inhalation anesthetics or depolarizing muscle relaxants. In case of secondary myopathy, the trigger needs to be identified and eliminated. Renal insufficiency from rhabdomyolysis requires warranty of sufficient diuresis or dialysis.
CK is an enzyme that cleaves creatine-phosphate into creatinine and phosphate to promote the generation of ATP from phosphate and ADP. CK is expressed in all tissues but particularly in those with high energy requirement. Isoforms of CK (CK-MB, CK-MM, and CK-BB) indicate whether the source of CK is the muscle (CK-MM), the myocardium (CK-MB), or the brain (CK-BB), the organs most frequently responsible for hyper-CKemia. Macro-CK type-1 derives from association with different types of immunoglobulins76 may indicate autoimmune disease and macro-CK type-2 may indicate malignancy, particularly small cell lung cancer, colorectal cancer, and gastrointestinal cancer.77 Most patients with permanent (fixed) or episodic myopathy have hyper-CKemia, either permanently, exercise-induced, or recurrently.78 Particularly at an early, subclinical stage, some myopathies may present with AHCE (Table 1).3 Sources of hyper-CKemia in addition to the skeletal muscles are abnormalities of the endocrine organs, myocardium, uterus, and brain. Hyper-CKemia is usually accidentally detected in these patients, who do not report muscle symptoms and have a normal or abnormal needle EMG and a normal or abnormal muscle biopsy. Because reference limits for serum CK vary considerably between laboratories, it is crucial to consider different laboratory methods for determining CK and the different reference limits when comparing different studies or results from different laboratories.
AHCE with normal EMG and normal muscle biopsy is rare. Nonetheless, these patients should be carefully screened for primary (hereditary) or acquired myopathies and if negative should undergo regular follow-up investigations and CK-determinations because some of them may develop a clinically manifesting myopathy in the further course of the disease. If muscle biopsy in such patients is normal, biochemical investigations should be considered because respiratory chain defects may go along with normal muscle morphology but reduced activity of single respiratory chain complexes.38 However, it has to be considered that CK-levels may also increase in nonmyopathic conditions and acquired myopathic conditions such as after intense physical exercise, consumption of certain drugs (eg, statins), rhabdomyolysis, or muscle trauma.51 Patients with AHCE but myogenic EMG should undergo biopsy and genetic testing if specific, pathogenic findings become evident. If muscle biopsy findings are nonspecific, these patients should be closely followed up because they have an increased risk of developing arterial hypertension according to a previous population study in healthy controls.79
It is concluded that AHCE most frequently occurs in patients with dystrophinopathies, congenital myopathies, myofibrillar myopathies, myotonic dystrophies, channelopathies, or metabolic myopathies, particularly MIDs or glycogenoses. AHCE in these patients may go along with or without abnormal needle EMG and with or without abnormal muscle biopsy. Even AHCE with normal EMG and normal muscle biopsy may indicate primary or acquired myopathy. Absence of muscle symptoms does not exclude myopathy. AHCE should be taken seriously and should prompt exclusion of a particular primary or acquired myopathy. If AHCE results in the diagnosis of Pompe disease, MHS, or an acquired myopathy, appropriate therapeutic management should be initiated. Most likely, other primary or acquired myopathies manifesting with AHCEs will be detected and reported in the future.
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