Deficiency Myopathy Research Articles

Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) Myopathy Misdiagnosed as Polymyositis

Barp, Andrea MD∗; Bellance, Rémi MD†; Malfatti, Edoardo MD, PhD‡,§; Rigal, Odile PharmD∥; Acquaviva-Bourdain, Cécile PhD¶; Laforet, Pascal MD, PhD‡ Author Information

P.362 - Late onset multiple acyl-CoA dehydrogenase deficiency (MADD) myopathy misdiagnosed as polymyositis

P.362 - Late onset multiple acyl-CoA dehydrogenase deficiency (MADD) myopathy misdiagnosed as polymyositis

Caveolin 3 deficiency myopathy associated with dyslipidemia: Treatment challenges and possible pathophysiological association

We report the case of a patient treated at the lipid clinic because of high cholesterol levels with consistently elevated creatine kinase concentrations that precluded statin treatment. Electromyography showed a rippling muscle disease pattern. A muscle biopsy confirmed caveolin 3 deficiency, and a missense mutation in the CAV3 gene was identified. The patient could be properly managed with ezetimibe and cholestyramine, which reduced the low-density lipoprotein cholesterol by 30%. He remains asymptomatic after 10 years of follow-up. Caveolae and caveolins are essential to membrane integrity, and their deficit has been associated with insulin resistance and hypercholesterolemia in animal models. Therefore, a putative pathophysiological association between myopathy and lipid metabolism mediated by functional alterations of membrane receptors is considered.

Lamellar ichthyosis with severe vitamin D deficiency rickets and myopathy in siblings

Vitamin D deficiency and rickets are not uncommon associations with keratinizing disorders. Children with ichthy- osiform erythroderma are more prone to develop vitamin D deficiency and rickets, due to decreased exposure to sunlight, and dietary insufficiency. We report a case of lamellar ichthyosis in two siblings with vitamin D deficiency developing severe rickets and musculoskeletal features with myopathy.

G.P.26: Vitamin D deficiency myopathy in Egypt: A treatable myopathy

Vitamin D deficiency could be due to decreased bioavailability (decreased intake or exposure to sunlight, urinary loss or malabsorption), abnormal metabolism (liver disease, renal disease) or abnormal target tissue response (vitamin D resistant or gastrointestinal disorders). Vitamin D deficiency is one of the causes of osteomalacic myopathy. To highlight the clinical and laboratory characteristics of vitamin D deficiency myopathy in Egypt and to discuss its therapeutic implications. All patients presented with gradual progressive limb-girdle weakness with or without bony pains, pains of limb muscles, low backache or joint pains. All patients had detailed clinical assessment, laboratory study (including serum calcium, phosphorus, alkaline phosphatase, total creatine kinase, parathyroid hormone and 25 (OH) vitamin D levels together with neurophysiological study and muscle biopsy in some cases. 30 patients were found to have vitamin D deficiency myopathy. Most of them were females, adolescents or early adults. Decreased dairy intake and decreased exposure to sunlight were the main causes for their illness. Most of them had stereotyped clinical presentation with marked deficiency of serum calcium, increased serum phosphorus and increased alkaline phosphatase levels. Parathyroid hormone serum level was high and vitamin D serum level was low. Muscle biopsy showed non-specific myopathic changes in studied specimens. Therapy with a combination of daily calcium and vitamin D intake greatly improve both pains and weakness within few months of all patients. Vitamin D deficiency myopathy is a common condition among females in Egypt due to decreased dairy intake and exposure to sunlight. Clinicians must take attention to this type of myopathy as it is a treatable myopathy.

P32 Mutations in SPG7 cause chronic progressive external ophthalmoplegia through disordered mtDNA maintenance

P32 Mutations in SPG7 cause chronic progressive external ophthalmoplegia through disordered mtDNA maintenance

P31 Genotypic and phenotypic heterogeneity in adult-onset progressive external ophthalmoplegia (PEO) with mitochondrial DNA instability: a systematic review

P31 Genotypic and phenotypic heterogeneity in adult-onset progressive external ophthalmoplegia (PEO) with mitochondrial DNA instability: a systematic review

Lipid storage myopathy with clinical markers of Marfan syndrome: A rare association

Disorders of lipid metabolism can cause variable clinical presentations, often involving skeletal muscle, alone or together with other tissues. A 19-year-old boy presented with a 2-year history of muscle pain, cramps, exercise intolerance and progressive weakness of proximal lower limbs. Examination revealed skeletal markers of Marfan syndrome in the form of increased arm span compared with height, Kyphoscoliois, moderate pectus excavatum, high arched palate and wrist sign. He also had mild neck flexor weakness and proximal lower limb weakness with areflexia. Pathologic findings revealed lipid-laden fine vacuoles in the muscle fibers. Possibility of carnitine deficiency myopathy was considered and the patient was started on carnitine and Co Q. The patient made remarkable clinical improvement over the next 2 months. This case is reported for rarity of the association of clinical markers of Marfan syndrome and lipid storage myopathy and sparse literature on lipid storage myopathy in the Indian context.

Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron–sulphur cluster deficiency myopathy

Myopathy with exercise intolerance and deficiency of iron–sulphur cluster proteins is caused by an intronic IVS5+382 G > C mutation in ISCU, the gene encoding the iron–sulphur cluster assembly protein (IscU). The mutation causes alternative splicing resulting in a truncated protein and severely reduced levels of IscU protein in muscle tissue. Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria. Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease. A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation, whereas another biopsy obtained nine years after the episode showed the typical hallmarks of the disease. The apparent explanation for the normal succinate dehydrogenase activity during regeneration was a markedly increased level of IscU protein in regenerating muscle tissue and an increase in normally spliced ISCU transcripts in the patient. The results have implications for diagnosis of the disease based on muscle biopsy findings and support the concept that an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients.

Reversible infantile respiratory chain deficiency: A clinical and molecular study

To characterize the clinical features and clarify the pathogenicity of "benign cytochrome c oxidase deficiency myopathy." The study included 8 patients with the phenotype of this disease. Six patients underwent muscle biopsies and all the 8 underwent mitochondrial DNA analyses. To confirm the pathogenicity of the detected mitochondrial DNA mutation, we performed northern blot analysis, using muscle specimens, and blue native polyacrylamide gel electrophoresis and respiratory chain enzyme activity assay of transmitochondrial cell lines (cybrids). Clinical symptoms were limited to skeletal muscle and improved spontaneously in all cases; however, 2 siblings had basal ganglia lesions. In all patients, we identified a homoplasmic m.14674T>C or m.14674T>G mitochondrial transfer RNA-glutamate mutation. Northern blot analysis revealed decreased levels of mitochondrial transfer RNA-glutamate molecules. Muscle specimens and cybrids derived from patients showed decreased activity of respiratory complexes IV, and/or I, III; however, this was normal in naive myoblasts. Identification of a novel m.14674T>G mutation in addition to m.14674T>C indicated the importance of this site for disease causation. Analyses of cybrids revealed the pathogenicity of m.14674T>C mutation, which resulted in defects of cytochrome c oxidase and multiple respiratory chain enzymes. Furthermore, patients with basal ganglia lesions provided new insights into this disease, in which only skeletal muscle was thought to be affected. Normal respiratory chain enzyme activities in naive myoblasts suggested the compensatory influence of nuclear factors, which may be a clue to understanding the mechanisms of spontaneous recovery and low penetrance in families carrying the mutation.

57. Benign infantile cytochrome c oxidase deficiency myopathy: Reversible or not?

Background: Benign infantile cytochrome c oxidase deficiency myopathy is a mitochondrial disorder with reversible cytochrome c oxidase (COX) deficiency that presents in infants and is characteristic because spontaneous recovery can occur if affected in infants survive the first few months of life. This is because the enzyme defect in this condition is thought to be reversible. Recently, the m.14674T > C mt-tRNAGlu mutation has been associated with this condition.

High-resolution, imaging TOF-SIMS: novel applications in medical research

The use of high-resolution, imaging TOF-SIMS is described and examples are made to demonstrate the application of the method in medical research. Cytochemistry by TOF-SIMS is shown by localization of diacylglycerol (DG) in cryostat sections of hyaline cartilage and by localization of corticosterone in cryostat sections of the adrenal gland cortex. Quantitative measurements and comparison of groups is shown by comparing the lipid content of adipose tissue from two mouse strains, transgenic mouse expressing the FOXC2 gene and wild-type controls. Finally, biopsies made for histopathological diagnosis of infantile reversible cytochrome c oxidase deficiency myopathy were analyzed in order to define the chemical content of areas showing a pathological structure in the light microscope. The use of high-resolution, imaging TOF-SIMS in medical research allows analysis of intact tissue and probe-free localization of specific target molecules in cells and tissues. The TOF-SIMS analysis is not dependent on penetration of reagents into the sample and also independent of probe reactivity such as cross-reactivity or background staining. The TOF-SIMS method can be made quantitative and allows for analysis of specific target molecules in defined tissue compartments.

Rare Causes of Calcitriol-Mediated Hypercalcemia: A Case Report and Literature Review

Calcitriol-mediated hypercalcemia resulting from elevated extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase) activity has not previously been described in giant cell polymyositis. We report an unusual case of hypercalcemia due to disseminated granulomatous disease in a 62-yr-old woman with profound proximal muscle weakness and weight loss. She was initially diagnosed with vitamin D deficiency myopathy with a low serum 25-hydroxyvitamin D; serum calcium at this time was low-normal. Vitamin D(3) 3000 IU daily was prescribed. One month later, blood work showed new hypercalcemia and hypercalciuria with normalized 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D was high-normal, despite a suppressed PTH, undetectable PTHrP, and essentially normal renal function. Her hypercalcemia resolved, and her strength improved only after prednisone was added to bisphosphonate therapy. Two weeks later, she died from acute congestive heart failure. Autopsy revealed a disseminated giant cell myositis affecting skeletal, cardiac, and gastrointestinal smooth muscle. Immunohistochemistry localized 1alpha-hydroxylase to the inflammatory infiltrates in skeletal and cardiac muscle. A review of English publications in Medline and Embase, including a reference search of retrieved articles, revealed that calcitriol-mediated hypercalcemia has been described in over 30 conditions, most of which are granulomatous in nature, ranging from inflammatory conditions and foreign body exposures to infections and neoplasms. Hypercalcemia resulting from autonomous 1alpha-hydroxylase activity may be unmasked by low-dose vitamin D supplementation and should not be excluded from the differential diagnosis of nonparathyroid causes if the serum calcitriol is inappropriately normal, rather than frankly elevated.

P75 Infantile reversible COX deficiency myopathy caused by the m.14674T>C mutation in mt-tRNA Glu in a German family

P75 Infantile reversible COX deficiency myopathy caused by the m.14674T>C mutation in mt-tRNA Glu in a German family

Antisense oligonucleotide therapeutics for iron–sulphur cluster deficiency myopathy

Iron–sulphur cluster deficiency myopathy is caused by a deep intronic mutation in ISCU resulting in inclusion of a cryptic exon in the mature mRNA. ISCU encodes the iron–sulphur cluster assembly protein IscU. Iron–sulphur clusters are essential for most basic redox transformations including the respiratory-chain function. Most patients are homozygous for the mutation with a phenotype characterized by a non-progressive myopathy with childhood onset of early fatigue, dyspnoea and palpitation on trivial exercise. A more severe phenotype with early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy is caused by a missense mutation in compound with the intronic mutation. Treatment of cultured fibroblasts derived from three homozygous patients with an antisense phosphorodiamidate morpholino oligonucleotide for 48 h resulted in 100% restoration of the normal splicing pattern. The restoration was stable and after 21 days the correctly spliced mRNA still was the dominating RNA species.

P320 A treatable metabolic myopathy: riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency and coenzyme Q10 myopathy

P320 A treatable metabolic myopathy: riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency and coenzyme Q10 myopathy

Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as ‘benign cytochrome c oxidase deficiency myopathy’ is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNAGlu mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNAGlu may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Clinical manifestation and a new ISCU mutation in iron–sulphur cluster deficiency myopathy

Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 + 382G>C splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial iron-sulphur cluster assembly protein IscU. Iron-sulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405,000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle iron-sulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 G>A missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.

Deficiency of mannose-binding lectin, myopathy, calcified endomyocardial fibrosis, and left ventricular noncompaction

In a patient with mannose-binding lectin deficiency and metabolic myopathy with recurrent respiratory infections, left ventricular hypertrabeculation/noncompaction was diagnosed by echocardiography and confirmed at autopsy. In contrast with previously described cases, extensive endocardial calcifications were found, possibly as a result of recurrent endomyocarditis during the recurrent infections.

Assessment of serum thyroid hormone concentrations in lambs with selenium deficiency myopathy

To assess changes in serum concentrations of thyroid hormones associated with selenium deficiency myopathy in lambs. 35 lambs with selenium deficiency myopathy and 30 healthy lambs. Blood samples were collected via jugular venipuncture from lambs with selenium deficiency myopathy and healthy lambs. Activities of markers of selenium deficiency myopathy (erythrocyte glutathione peroxidase [GSH-Px] and plasma creatine kinase [CK]) and serum thyroid-stimulating hormone (TSH) and total thyroxine (tT(4)) and total triiodothyronine (tT(3)) concentrations were assessed; values in affected lambs were compared with those in healthy lambs. Correlations of erythrocyte GSH-Px and plasma CK activities with serum concentrations of TSH, tT(4), and tT(3) were investigated, and the tT(3):tT(4) concentration ratio was evaluated. Compared with findings in healthy lambs, erythrocyte GSH-Px activity, serum tT(3) concentration, and tT(3):tT(4) concentration ratio were significantly decreased and serum concentrations of tT(4) and TSH and the activity of plasma CK were significantly increased in affected lambs. Analysis revealed a significant negative correlation in the affected group between erythrocyte GSH-Px activity and each of the following: plasma CK activity (r = -0.443), serum TSH concentration (r = -0.599), serum tT(4) concentration (r = -0.577), and serum tT(3) concentration (r = -0.621). Results suggested that notable changes in circulating amounts of thyroid hormones develop in association with selenium deficiency in lambs. Such alterations in thyroid hormone metabolism may be involved in the high incidence of disorders, such as stillbirths and neonatal deaths, in selenium-deficient flocks.