Lipid Myopathy Research Articles

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

PurposeMitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease. MethodsMultinational series of new genetically confirmed cases from six pediatric centers. ResultsNine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase–deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. ConclusionsInfantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

LIPID MYOPATHIES: P.85TANGO2-related disorder: spectrum of mutations and clinical phenotype characterized by recurrent rhabdomyolysis and metabolic crisis

LIPID MYOPATHIES: P.85TANGO2-related disorder: spectrum of mutations and clinical phenotype characterized by recurrent rhabdomyolysis and metabolic crisis

Lipid Myopathies.

Disorders of lipid metabolism affect several tissues, including skeletal and cardiac muscle tissues. Lipid myopathies (LM) are rare multi-systemic diseases, which most often are due to genetic defects. Clinically, LM can have acute or chronic clinical presentation. Disease onset can occur in all ages, from early stages of life to late-adult onset, showing with a wide spectrum of clinical symptoms. Muscular involvement can be fluctuant or stable and can manifest as fatigue, exercise intolerance and muscular weakness. Muscular atrophy is rarely present. Acute muscular exacerbations, resulting in rhabdomyolysis crisis are triggered by several factors. Several classifications of lipid myopathies have been proposed, based on clinical involvement, biochemical defect or histopathological findings. Herein, we propose a full revision of all the main clinical entities of lipid metabolism disorders with a muscle involvement, also including some those disorders of fatty acid oxidation (FAO) with muscular symptoms not included among previous lipid myopathies classifications.

P.386 - Late onset riboflavin responsive lipid myopathy with multiple acyl-CoA dehydrogenase deficiency: Report of four patients

P.386 - Late onset riboflavin responsive lipid myopathy with multiple acyl-CoA dehydrogenase deficiency: Report of four patients

Muscle Disease

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

Symptomatic lipid storage in carriers for the PNPLA2 gene

Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis.

Evaluation of Muscle Atrophy: Comparison between Limb-Girdle Muscular Dystrophies, ALS and Metabolic Myopathies (P07.197)

Objective: To study neuromuscular disorders by a quantitative measurement to evaluate muscle atrophy by MRI. Background The fibro-fatty replacement and myoedema are the most common indexes used to evaluate the muscle involvement in LGMD on MRI. However, many published scores are not quantitative and do not assess the extent of muscle atrophy in neuromuscular disorders. Design/Methods: We selected images obtained from T1 MRI sequences of the thigh muscles, at a distance of about 15 cm from the head of the femur. We measured the muscle area of the left quadriceps femoris and of the left vastus lateralis in 11 patients matched by sex and age, affected with 2 lipid myopathies, amyotrophic lateral sclerosis, FSHD, myofibrillar myopathy, metabolic myopathy, 2 LGMD2A, LGMD1F, localized myositis ossificans, aspecific myopathy. Results: Vastus lateralis muscle. The area was in average 963 ± 303 mm 2 . In this group of patients we have identified two subgroups, one including 5 patients with a high degree of atrophy ( high atrophic group ), whose values ranged from 400 to 900 mm 2 (mean 658.7), and one including 6 patients with a low degree of atrophy ( low atrophic group ), whose values ranged from 900 to 1400 mm 2 (mean 1217.8). Quadriceps femoris muscle in-toto. The measure of muscle area was in average 3711 ± 792 mm 2 . In the high atrophic group the values ranged from 2400 to 3400 mm 2 (mean 2966), while in the low atrophic group the values ranged from 3700 to 5000 mm 2 (mean 4332). Conclusions: Imaging examination may suggest a characteristic pattern of muscle involvement: i.e. in LGMD2A the posterior compartment is often involved. The values of cross sectional muscle area appeared to be useful indexes to evaluate muscle atrophy in LGMD, ALS and metabolic myopathies. The effect of drug treatment or of exercise or rehabilitation can be evaluated by quantitative muscle MRI. Disclosure: Dr. Angelini has received personal compensation for activities with Genzyme Corporation. Dr. Fanin has nothing to disclose. Dr. Peterle has nothing to disclose.

Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency with unknown genetic defect

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessively inherited disorder of fatty acid metabolism due to ETFA, ETFB or ETFDH mutations. Riboflavin treatment ameliorates symptoms and metabolic profile in ETFDH-related MADD patients. We report on a 20-year-old boy with an 8-year history of progressive difficulty in walking, running and climbing stairs. Muscle biopsy showed a lipid myopathy and the acylcarnitine profile analysis was suggestive of MADD. Nevertheless, no evidence of molecular defects in the ETFA, ETFB and ETFDH exons or intron-exon boundaries was found. Treatment with riboflavin for 1 year resulted in a clear improvement in motor functions. Our report shows that some cases of MADD are not linked to ETFA, ETFB and ETFDH exon or intron-exon boundary changes. They could be due to quite rare promoter or deep intronic mutations or, most likely, to some unknown genetic defect. We therefore suggest to extend in these cases molecular studies to cDNA analysis and indicate the need of extensive pedigree studies to identify other possible disease-related loci. Most important, treatment of these cases with riboflavin can also be effective. Therefore, early diagnosis is essential to achieve the best treatment response.

De Novo Mutations in POLG Presenting with Acute Liver Failure or Encephalopathy

De Novo Mutations in <i>POLG</i> Presenting with Acute Liver Failure or Encephalopathy

Perioperative management of a child with short‐chain acyl‐CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase (SCAD) is a mitochondrial enzyme that catalyzes the dehydrogenation of short chain fatty acids (4 to 6 carbons in length) thereby initiating the cycle of beta-oxidation. This process generates acetyl-CoA, the key substrate for hepatic ketogenesis or ATP production by the Kreb's cycle. A deficiency of SCAD results in the build-up of potentially cytotoxic metabolites including ethylmalonic acid, methylsuccinyl CoA and butyryl-carnitine. The end-organ involvement is heterogeneous, but most commonly includes hypotonia with possible lipid myopathy and developmental delay. Other reported complications include dysmorphic craniofacial features, hypoglycemia, seizures, scoliosis, hypertonia and hyperreflexia, cyclic vomiting and myocardial dysfunction. We present a 23-month-old girl with SCAD deficiency, who required posterior fossa decompression for type 1 Chiari malformation. The potential perioperative implications of SCAD deficiency are reviewed.

Adult-Onset Presentation of Glutaric Acidemia Type II With Myopathy

Glutaric acidemia type II (GA II) typically presents with profound metabolic acidosis, hypoketotic hypoglycemia, and mild dysmorphic features in newborns. Since its description, 11 patients with adult-onset GA II have been reported. A 23-year-old woman presented at 6 months gestation with preterm labor and weakness for 3 months. Her weakness worsened to the point of not being able to walk despite treatment with corticosteroids for presumed myositis. Biopsies of skeletal muscle revealed extensive lipid myopathy. Metabolic studies and urine organic acids were suggestive of a multiple acyl-CoA dehydrogenase deficiency. Immunoblot of skin fibroblasts demonstrated a deficiency of electron transfer flavoprotein-ubiquinone oxidoreductase. Treatment with carnitine, riboflavin, and diet restrictions improved muscle strength and decreased urine organic acids. This patient had the unique presentation of GA II with only myopathy. In adults with late-onset weakness, metabolic disorders should be considered in the differential diagnosis.

Combined biochemical and molecular diagnosis in blood of a common lipid myopathy

Muscle & NerveVolume 23, Issue 11 p. 1773-1775 Letter to the Editor Combined biochemical and molecular diagnosis in blood of a common lipid myopathy Georgirene D. Vladutiu PhD, Georgirene D. Vladutiu PhD Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, 936 Delaware Avenue, Buffalo, New York 14209, USASearch for more papers by this authorAlfred E. Slonim MD, Alfred E. Slonim MD Department of Pediatrics, North Shore University Hospital, New York University School of Medicine, Manhasset, New York, USASearch for more papers by this author Georgirene D. Vladutiu PhD, Georgirene D. Vladutiu PhD Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, 936 Delaware Avenue, Buffalo, New York 14209, USASearch for more papers by this authorAlfred E. Slonim MD, Alfred E. Slonim MD Department of Pediatrics, North Shore University Hospital, New York University School of Medicine, Manhasset, New York, USASearch for more papers by this author First published: 23 October 2000 https://doi.org/10.1002/1097-4598(200011)23:11<1773::AID-MUS18>3.0.CO;2-5Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue11November 2000Pages 1773-1775 RelatedInformation

Anaesthesia in lipid myopathy

Anaesthesia in lipid myopathy

Rapid, Cost-effective Gene Mutation Screening for Carnitine Palmitoyltransferase II Deficiency Using Whole Blood on Filter Paper

Carnitine palmitoyltransferase II (CPT II; EC 2.3.1.21), an enzyme associated with the inner mitochondrial membrane, is important in the transport of long-chain fatty acids from the cytosol into the mitochondrial matrix for β-oxidation (1). CPT II deficiency presents as three distinct clinical phenotypes: adult myopathic (MIM 255110), lethal neonatal (MIM 600649), and a severe infantile phenotype (2). The adult form is the most common lipid myopathy in humans and is characterized by muscle pain, stiffness, and myoglobinuria triggered by exercise, fasting, anesthesia, or other metabolic stressors (3). CPT II is a homotetramer (4) encoded by a gene (MIM 600650) on chromosome 1p32 (5) that spans 20 kb and contains five exons ranging in length from 81 to 1305 bp (6). At least 15 mutations in CPT2 are associated with the adult and infantile disorders (7)(8)(9). CPT II deficiency is an autosomal recessive disorder (3)(9); however, recent biochemical and molecular evidence suggests the existence of manifesting carriers, predicting that the prevalence of the disease may be even higher than previously believed (9). Screening for mutations in CPT2 has been performed using DNA isolated from biopsied muscle tissue (9), venous blood (10), lymphoblasts (11), or fibroblasts (8). Isolation of DNA from these specimens is time-consuming, and mutation screening generally has been performed using restriction fragment length polymorphisms (12) or allele-specific oligonucleotide (ASO) detection (9), requiring portions of several days for completion (9). Large-scale screening has not been performed to determine the carrier frequency of the common mutations in the general population. Although the methods for DNA isolation, PCR amplification, and ASO analysis developed previously by our laboratory are effective for detecting known mutations in the CPT2 gene (9), they were too costly and laborious for application to large family studies or population screening. We proposed …

THE IDENTIFICATION OF A NOVEL G4.5 MUTATION IN BARTH SYNDROME• 96

Barth syndrome is an X-linked recessive cardioskeletal myopathy associated with neutropenia, growth retardation, abnormal mitochondria (abnormal cristae), and elevated levels of urinary 3-methylglutaconic acid and 2-ethylhydracrylic acid. Lipid myopathy, decreased plasma free carnitine, lowered cytochrome concentrations, and granulocytopenia are also characteristic of this disease. The gene for Barth syndrome, which was previously mapped to Xq28, was recently identified as G4.5. This 6,234 bp gene consists of 11 exons, three of which (exons 5, 6, and 7), are differentially spliced resulting in five protein products. These proteins, classified as tafazzins, show no homolgy to any previously identified proteins, and thus, are unique. Four mutations in G4.5 have previously been described in patients with Barth syndrome. We report a new mutation in G4.5 in one family having three males affected with Barth syndrome.

Hereditary protein C deficiency associated with riboflavin‐responsive lipid storage myopathy

We report a 14 year old patient who presented lung emboli and deep vein thrombosis in relationship to protein C deficiency. He had a carnitine‐deficient lipid myopathy. Fresh muscle homogenate showed low activities in oxidizing [1‐14C]‐butyrate, [1‐14C]‐octonoate and [1‐14C]‐palmitate. A deficient short chain butyryl‐CoA dehydrogenase (SCAD) was found in isolated muscle mitochondria. The patient improved dramatically with daily therapy of 200 mg riboflavin, 2 g carnitine and anticoagulation with Coumadin. The treatment was found to restore fatty acid oxidation in fresh muscle homogenate, deficient acylCoA‐dehydrogenases in mitochondria and decrease lipid droplets.These results suggest that in this type of lipid myopathy riboflavin supplementation may be effective. The link with protein C deficiency is discussed.

Long‐chain 3‐hydroxyacyl‐Coenzyme A dehydrogenase (L‐CHAD) deficiency in a patient with the Bannayan‐Riley‐Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.

Cramps following exercise

A 13-year old boy presented with a 10-year history of severe muscle cramps experienced an hour after prolonged exercise. There was no history of exercise intolerance or myoglobinuria. A muscle biopsy showed a lipid myopathy and a deficiency of muscle carnitine palmityl transferase. He has responded to a high carbohydrate, low fat diet with added carbohydrate intake preceding extensive exercise. Diagnosis of this entity before an episode of rhabdomyolysis is unusual.

Muscle carnitine deficiency in old age: Case report and therapeutic results

A muscle carnitine deficiency was discovered in a 67-year-old retired factory worker with a clinical picture of late-onset myopathy. The diagnosis was made by muscle biopsy and free carnitine assay. Therapy including a medium chain triglycerides diet and 6 g/day of D, L-carnitine per os produced a remarkable clinical improvement confirmed by a control muscle biopsy 15 months later. Our patient is the oldest one described with muscle carnitine deficiency. The differential diagnosis of a late-onset myopathy should include lipid myopathies, some of which can be treated successfully.

Autosomal dominant syndrome of lipid neuromyopathy with normal carnitine

A family (mother and two sons) have had lifelong muscle weakness and intolerance to fatty food. Histochemistry of muscle biopsies of all three patients demonstrated increased lipids in type I muscle fibers and type II muscle fiber atrophy and paucity. Electronmicroscopy of muscle revealed increased lipids, abnormal mitochondria, and increased lipofuscin granules. Electronmicroscopy of sural nerve showed inclusions in most of the Schwann cell cytoplasm, with lipid droplets, zebra bodies, lipofuscin granules, and abnormal mitochondria. Carnitine and CPT I and II levels were normal in serum and muscle. Treatment with long-chain fatty-acid-free diet resulted in remarkable clinical improvement and in decrease of lipid droplets in the muscle. This dietary program may be useful in other forms of lipid myopathy.