Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency

We describe a 41-year-old Moroccan woman with phosphofructokinase (PFK) deficiency who presented slowly progressive muscular weakness since childhood, without rhabdomyolysis episode or hemolytic anemia. Deltoid biopsy revealed massive glycogen storage in the majority of muscle fibers and polysaccharide deposits. PFK activity in muscle was totally absent. A novel homozygous non-sense mutation was detected in PFKM gene. Our observation suggests that juvenile-onset fixed muscle weakness may be a predominant clinical feature of PFK deficiency. Vacuolar myopathy with polyglucosan deposits remains an important morphological hallmark of this rare muscle glycogenosis.     

Metabolic causes of myoglobinuria

To evaluate the proportion of cases of myoglobinuria that can be ascribed to specific metabolic defects, we have studied eight enzymes--phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), and myoadenylate deaminase (MAD)--in muscle biopsy specimens from 77 consecutive patients with myoglobinuria (documented in 44, suspected in 33). Enzyme defects were found in 36 patients: CPT deficiency in 17, phosphorylase deficiency in 10, phosphorylase kinase deficiency in 4, MAD deficiency in 3, PGK deficiency in 1, and a combined defect of CPT and MAD in 1. Exercise was the main precipitating factor, both in patients with and in those without detectable enzymopathies. Thirty patients had specific enzymopathies without myoglobinuria: 14 had phosphorylase deficiency, 9 had MAD deficiency, 3 had phosphorylase kinase deficiency, 3 had PFK deficiency, and 1 had PGAM deficiency. Systematic biochemical evaluation of muscle biopsy specimens revealed specific enzymopathies in about half of the patients with idiopathic myoglobinuria. The rest may have blocks of metabolic pathways not yet studied routinely, such as beta oxidation, or genetic defects of the sarcolemma, such as Becker's muscular dystrophy.     

A case of very-long-chain acyl-CoA dehydrogenase deficiency with adolescent onset being diagnosed by immunostain of biopsy muscle]

We report a case of myopathic form of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency with adolescent onset which presented with recurrent rhabdomyolysis and was diagnosed by immunostain of biopsy muscle. She was an 18-year-old woman who showed recurrent episodes of rhabdomyolysis after exercise since the age of 15. The diagnosis was made by the immunostain using anti-VLCAD antibody and the measurement of acyl-CoA dehydrogenase activity for the biopsy muscle. Her elder sister had also showed recurrent episodes of rhabdomyolysis at least two times. The analysis of genomic DNA on blood samples of the patient and her sister was performed and the same mutations were identified. Hence, these sister were revealed to have VLCAD deficiency. We should keep in mind this disorder for those presenting with recurrent rhabdomyolysis. In addition, as far as we know, this is the first report that a correct diagnosis was obtained by immunostain. Immunostain is probably a useful diagnostic procedure to identify an uncommon myopathy.     

Chronic myopathy with a partial deficiency of the carnitine palmityltransferase enzyme

To date, chronic myopathy has not been reported (to our knowledge) to occur in carnitine palmityltransferase (CPT) deficiency, a disorder of muscle lipid metabolism. We describe two patients with CPT deficiency: a mother, who had a partial CPT deficiency associated with fixed proximal weakness but without rhabdomyolysis, and her son, who had a complete CPT deficiency (95% reduction in enzyme activity) and who suffered from classic attacks of exercise-induced rhabdomyolysis but had normal strength on recovery. Careful examination of family members of patients with complete CPT deficiency is suggested in order to identify clinically affected heterozygotes.     

Myopathies Related to Glycogen Metabolism Disorders

Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), β-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations.     

Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases

Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16-year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies.     

Partial block of glycolysis in late-onset phosphofructokinase deficiency myopathy

A late-onset, myopathic variant of phosphofructokinase (PFK) deficiency has been previously described in two patients of Ashkenazic descent. We report here on a non-Ashkenazic woman with the onset, at the age of 48 years, of a progressive limb girdle myopathy that was not preceded by a history of exercise intolerance. Muscle biopsy findings at the age of 58 years showed deposition of amylopectin-like material in muscle fibers and the absence of histochemical PFK activity. Enzymatic PFK activity in vitro was only 4% of normal. Since the forearm ischemic exercise test induced a sub-normal production of serum lactate, the patient underwent phosphorus magnetic resonance spectroscopy (³¹P-MRS), a non-invasive method that allows in vivo assessment of the functional status of the glycolytic pathway and mitochondrial oxidative metabolism by measuring the high-energy phosphates and cytosolic pH. In vivo, ³¹P-MRS disclosed a residual glycolytic flux and a normal rate of ATP production both at rest and during exercise. These results suggest that, in some patients, muscle PFK deficiency may be partial in vivo, and more severe in vitro, possibly due to protein or mRNA instability rather than absence. The presence of these findings in a patient with the late-onset myopathic form is compatible with a distinct pathogenetic mechanism, relying on progressive polysaccharide accumulation, rather than on acute energetic shortage in muscle fibers. Received: 4 May 1995 / Revised, accepted: 28 September 1995     

Cytochrome c oxidase reaction improves histopathological assessment of zidovudine myopathy

Zidovudine can induce a mitochondrial myopathy with ragged-red fibers and partial cytochrome c oxidase deficency. In an attempt to improve histological assessment of zidovudine myopathy, we evaluated cytochorme c oxidase histochemical reaction in the muscle of 10 patients with biopsy-proven zidovudine myopathy (Group 1), 10 myopathic immunodeficiency virus (HIV)-infected patients not treated by zidovudine who had an immunohistological profile of HIV-associated myopathy or other neuromuscular disorders (Group 3). Among zidovudine receivers, cytochrome c oxidase deficiency was found in 10 of 10 patients from Group 1 and 7 of 10 from Group 2. No cytochrome c oxidase deficiency was observed in patients not treated by zidovudine. When present, cytochrome c oxidase-negative fibers accounted for 2 to 28% of fibers, and there was no difference for the number of cytchrome c oxidase-negative fibers between Group 1 and Group 2. Most patients with cytochrome c oxidase deficiency that could be evaluated clinically after muscle biopsy improved after withdrawal of zidovudine (5 of 7 in Group 1,5 of 5 in Group 2). Patients who did not improve had an HIV-associated myopathy concurrently with zidovudine myopathy. We conclude that cytochrome c oxidase reaction may be used as a reliable marker of zidovudine mitochondrial toxicity in HIV-infected patients with muscular symptoms.     

Mitochondrial trifunctional protein deficiency: A rare cause of adult‐onset rhabdomyolysis

Introduction: Mitochondrial trifunctional protein deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid β‐oxidation that may be due to mutations in 2 different nuclear genes, HADHA and HADHB. Perturbation of this multienzyme complex compromises the oxidation of long‐chain fatty acids, which leads to multiorgan dysfunction. Childhood‐ or adolescent‐onset recurrent rhabdomyolysis is a common muscular manifestation and is preceded frequently by clinically overt peripheral neuropathy. Methods: In this report we describe a patient with late adult‐onset recurrent rhabdomyolysis. Results: Despite normal sensory examination, nerve conduction studies showed a mild axonal peripheral neuropathy. The acylcarnitine profile showed elevated long‐chain and 3‐hydroxy long‐chain acylcarnitine species. HADHA sequencing revealed known compound heterozygous mutations c.180+3A>G (p.Thr37SerfsX6) and c.1528G>C (p.Glu510Gln). During a 10‐month follow‐up period, he had no further episodes of rhabdomyolysis after appropriate dietary modifications. Conclusions: Mitochondrial trifunctional protein deficiency should be considered in patients with adult‐onset recurrent rhabdomyolysis, especially in those with either clinically overt or subclinical peripheral neuropathy. Muscle Nerve 48 : 989–991, 2013     

Muscle phosphorylase b kinase deficiency revisited

Muscle phosphorylase b kinase (PHK) deficiency (glycogenosis type VIII) is a rare disorder caused by mutations in the PHKA1 gene encoding the α_M subunit of PHK. Only 5 patients with molecular defects in the X-linked PHKA1 gene have been described until now, and they all presented with exercise intolerance. Here, we report a patient with a new mutation in the PHKA1 gene who presented with PHK deficiency, cognitive impairment, but no overt myopathy. This report supports the concept that PHK deficiency is a mild metabolic myopathy and suggests that PHK mutations may interfere with normal brain function.     

The effect of dantrolene sodium in Very Long Chain Acyl-CoA Dehydrogenase Deficiency

We present a patient, who experienced recurrent episodes of rhabdomyolysis. Her beneficial response to treatment with dantrolene sodium was previously reported. Adult onset Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency has been diagnosed only recently. In adults, VLCAD deficiency results in recurrent fasting-, exercise-, or infection-induced muscle stiffness, muscle pain and myoglobinuria caused by rhabdomyolysis. This case illustrates for the first time the beneficial effect of dantrolene in VLCAD deficiency. We discuss the therapeutic mechanism of dantrolene sodium and its possible role as additional treatment modality for patients with VLCAD deficiency.     

A novel mitochondrial tRNA phenylalanine mutation presenting with acute rhabdomyolysis

We describe a patient who presented with acute rhabdomyolysis and had 68% cytochrome c oxidase (COX)-deficient fibers in skeletal muscle. Further investigations confirmed a respiratory chain defect that was associated with a novel heteroplasmic point mutation in the phenylalanine tRNA gene of the mitochondrial genome (mtDNA). Analysis of single muscle fibers revealed a significantly greater level of mutant mtDNA in COX-negative fibers. This is the first case of a mitochondrial tRNA gene point mutation presenting with acute rhabdomyolysis and recurrent myoglobinuria.     

Muscle phosphofructokinase deficiency in a myopathic child with severe mental retardation and aplasia of cerebellar vermis

Muscle phosphofructokinase (PFK) deficiency in man is responsible for at least two forms of myopathy; one is characterized by painful contractures of muscles and typically occurs in adults, whereas the other is often disabling and typically occurs in childhood, with psychomotor and growth retardation. In this investigation, a young myopathic patient with severe mental retardation and aplasia of the cerebellar vermis presented with muscular hypotrophy of the limbs, generalized hypotonia, convergent strabismus and marked pain during passive movement. Biopsy of quadriceps femoris muscle showed variation in the fiber size with sarcoplasmic areas positive for periodic acid-Schiff stain. Histochemical qualitative reaction for PFK showed no staining of muscle fibers; ultrastructural studies showed abnormal accumulation of glycogen granules in both intermyofibrillar and subsarcolemmal areas. While some enzyme activities in the muscular crude extract were significantly lower than in controls, direct assay of PFK revealed no activity, thus demonstrating that the child's myopathy was due to the lack of PFK activity.     

Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1

Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. Ann Neurol 2013;74:914–919     

Muscle phosphofructokinase deficiency: two cases with unusual polysaccharide accumulation and immunologically active enzyme protein

Two patients with phosphofructokinase (PFK) deficiency had exercise intolerance and increased serum activity of creatine kinase; one presented with hemolytic anemia, hyperuricemia, and gouty arthritis. The glycogen concentration in the muscle of these patients was about twice normal. PFK activity was virtually absent in muscle, but antibodies against the M subunits of the normal human PFK showed cross-reacting material in muscle from both patients. The PFK level in red blood cells, studied in one case, was lower than normal in the patient and both parents. Morphologically, there was extensive deposition of normal glycogen underneath the sarcolemma and in the intermyofibrillar space. In addition, 2% to 3% of the myofibers contained hyaline, PAS-positive, diastase-resistant inclusions that had a filamentous fine structure; histochemical reactions suggested an insoluble form of glycogen. Similar inclusions have not been described previously in PFK deficiency. Accumulation of an abnormal polysaccharide in muscle may be due to a second undiscovered enzymatic defect or may be a metabolic consequence of PFK deficiency.     

McArdle's disease: biochemical and molecular genetic studies

We have analyzed muscle biopsy specimens from 48 patients with biochemically proven phosphorylase deficiency (McArdle's disease) by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, and immunotitration (enzyme-linked immunosorbent assay [ELISA]). Thirty-five of the 42 patients studied by SDS-PAGE and immunoblot, and 41 of the 48 patients studied by ELISA had no detectable enzyme protein. Six patients had markedly decreased phosphorylase protein by all three assays, and only 1 patient had a normal amount of protein. No apparent correlation existed between the presence or absence of enzyme protein and the clinical presentation or muscle glycogen concentration. Northern analysis was performed on muscle RNA in 4 patients: messenger RNA was normal in 2, abnormally short in 1, and absent in the fourth, indicating heterogeneity of the molecular lesion in McArdle's disease.     

Increased frequency of rhabdomyolysis in familial dysautonomia

Introduction:Familial dysautonomia (FD; OMIM # 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. Methods: This study was a retrospective chart review of 665 FD patients. Results: Eight patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person‐years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person‐years. Mean maximum creatine kinase (CK) level was 32,714 ± 64,749 U/L. Three patients had hip magnetic resonance imaging showing gluteal hyperintensities. Conclusions: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities. Muscle Nerve, 2015     

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole‐body 3.0‐T magnetic resonance imaging study

Objectives and methods – Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0‐T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). Results – Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole‐body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. Conclusions – Whole‐body 3.0‐T MRI is a non‐invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole‐body high‐field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.     

Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency

Very Long-Chain Acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of mitochondrial long-chain fatty acid oxidation (FAO) most often occurring in childhood with cardiac or liver involvement, but rhabdomyolysis attacks have also been reported in adults. We report in this study the clinical, biochemical and molecular studies in 13 adult patients from 10 different families with VLCAD deficiency. The enzyme defect was demonstrated in cultured skin fibroblasts or lymphocytes. All patients exhibited exercise intolerance and recurrent rhabdomyolysis episodes, which were generally triggered by strenuous exercise, fasting, cold or fever (mean age at onset: 10 years). Inaugural life-threatening general manifestations also occurred before the age of 3 years in four patients. Increased levels of long-chain acylcarnitines with tetradecenoylcarnitine (C14:1) as the most prominent species were observed in all patients. Muscle biopsies showed a mild lipidosis in four patients. For all patients but two, molecular analysis showed homozygous (4 patients) or compound heterozygous genotype (7 patients). For the two remaining patients, only one mutation in a heterozygous state was detected. This study confirms that VLCAD deficiency, although being less frequent than CPT II deficiency, should be systematically considered in the differential diagnosis of exercise-induced rhabdomyolysis. Measurement of fasting blood acylcarnitines by tandem mass spectrometry allows accurate biochemical diagnosis and should therefore be performed in all patients presenting with unexplained muscle exercise intolerance or rhabdomyolysis.     

Coenzyme Q in serum and muscle of 5 patients with Kearns-Sayre syndrome and 12 patients with ophthalmoplegia plus

Summary Coenzyme Q₁₀ (CoQ) was measured in serum and muscle of 17 patients with ophthalmoplegia plus (including 5 patients with Kearns-Sayre syndrome), in muscle of 9 patients with neurogenic atrophies, 5 patients with myositis, and 5 patients with progressive muscular dystrophies (including 1 patient with oculopharyngeal dystrophy), and in serum and muscle of normal controls. CoQ was markedly decreased in serum and muscle of 1 patient with Kearns-Sayre syndrome and treatment with CoQ resulted in a significant clinical improvement. The other 4 patients with Kearns-Sayre syndrome and the patients with ophthalmoplegia plus exhibited normal concentrations of CoQ in serum and muscle. CoQ levels in muscle of patients with progressive muscular dystrophies, myositis or neurogenic atrophies were within the normal range. Concentrations of CoQ in serum and muscle of normal controls were independent of age and showed no sex difference. The data indicate that CoQ deficiency might be the specific cause of mitochondrial encephalomyopathy in 1 patient but it was not the underlying defect common to all cases with Kearns-Sayre syndrome and ophthalmoplegia plus, although the possibility of a focal CoQ deficiency affecting only single muscle fibres cannot be excluded.Dedicated to the late Dr. Saburo Ogasahara