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Josef Finsterer - One of the best experts on this subject based on the ideXlab platform.

  • Update Review about Metabolic Myopathies.
    Life (Basel Switzerland), 2020
    Co-Authors: Josef Finsterer
    Abstract:

    The aim of this review is to summarize and discuss recent findings and new insights in the etiology and phenotype of Metabolic myopathies. The review relies on a systematic literature review of recent publications. Metabolic myopathies are a heterogeneous group of disorders characterized by mostly inherited defects of enzymatic pathways involved in muscle cell metabolism. Metabolic myopathies present with either permanent (fixed) or episodic abnormalities, such as weakness, wasting, exercise-intolerance, myalgia, or an increase of muscle breakdown products (creatine-kinase, myoglobin) during exercise. Though limb and respiratory muscles are most frequently affected, facial, extra-ocular, and axial muscles may be occasionally also involved. Age at onset and prognosis vary considerably. There are multiple disease mechanisms and the pathophysiology is complex. Genes most recently related to Metabolic Myopathy include PGM1, GYG1, RBCK1, VMA21, MTO1, KARS, and ISCA2. The number of Metabolic myopathies is steadily increasing. There is limited evidence from the literature that could guide diagnosis and treatment of Metabolic myopathies. Treatment is limited to mainly non-invasive or invasive symptomatic measures. In conclusion, the field of Metabolic myopathies is evolving with the more widespread availability and application of next generation sequencing technologies worldwide. This will broaden the knowledge about pathophysiology and putative therapeutic strategies for this group of neuromuscular disorders.

  • non compaction delineates amyotrophic lateral sclerosis from Metabolic Myopathy
    International Journal of Cardiology, 2014
    Co-Authors: Josef Finsterer, Claudia Stöllberger, Nefzat Guler
    Abstract:

    Particularly in the early stages of the disease, amyotrophic lateral sclerosis (ALS) with bulbar onset is often difficult to delineate from other neuromuscular disorders, in particularMetabolicMyopathy [1]. This is because both entities mimic each other and because both include a plethora of different pathomechanisms. With disease progression, however, both entities develop unique features upon which they may be differentiated as in the following case. A 36 year-old female veterinarian, with a height of 174 cm, and a weight of 62 kg, who is fond of horses and a passionate horse-rider, developed permanent dysarthria and dysphagia, worsening at night, since 5/2011. Her history was noteworthy for recurrent right-sided herpetic keratitis since the age of 5 years old resulting in reduced visual acuity (20% of normal). After corneal abrasion, she was symptom-free until 2005 when she received a rabies vaccination, after which keratitis foudroyantly recurred. For keratitis she had been taking valacyclovir 500–1500 mg/day almost continuously for two years until 1/2012. In 2001 she had a horse-riding accident and experienced a fracture of the right petrosal bone with consecutive anacusis, mild residual peripheral facial palsy, abducens palsy, and a contusional bleeding in the left frontal lobe. Shortly afterwards she experienced a single tonic–clonic seizure. She had a crossbite since childhood, leading to arthrosis of the mandibular joints since 6/2012. Extensive blood immunological investigations in 2004 were normal. In 1/2012 myasthenia gravis was suspected but low dosages of pyridostigmine did not improve symptoms. Clinical exam in 5/2012 revealed severely reduced visual acuity on the right side, anacusis and discrete right-sided peripheral facial palsy, signe-des-cils bilaterally, dysarthria, dysphagia, diffuseweakness on theupper limbs (M5−)with proximal predominance, and reduced tendon reflexes on the upper limbs. Marked vitamin-D-deficiency resolved under adequate substitution but did not affect her symptoms (Table 1). MRI of the cerebrum revealed an old contusional lesion in the left frontal area and a righthemispheric, non-specific gliotic white matter lesion. Lung function tests and video-cinematography in 7/2012 were normal. Acetylcholinereceptor antibodies were slightly elevated once but normal on repeated determination (Table 1). Anti-MUSK antibodies were normal. Lowand high-frequency repetitive nerve stimulation under pyridostigmine was normal in 6/2012. Edrophonium testing was negative. CT-scan of the mediastinum revealed a small mass lesion within the thymus, suggesting hyperplasia or thymoma. FDG-PET confirmed the diagnosis whyendoscopic thymectomywas carried out in 8/2012,which excluded a thymoma. Since thymectomy and application of pyridostigmine maximally at 480 mg/day only partially and temporarily resolved dysarthria and dysphagia, myasthenia was ruled out. Next it was assumed that symptoms were triggered by N,N-diethyl m-toluamide (DEET), which worsens myasthenia. She used DEET as a repellent particularly for one of her three horses, which was allergic to the sun, black flies, and gadflies. Occasionally, she also used DEET for herself and sprayed it onto the upper arms and into the face. She used DEET since it was the only repellent with a beneficial effect after having tried various others. She administered 30–40 puffs per horse of either Leovet Phaser® or Leovet Power-Phaser® between April and October during the occurrence of black flies once a day for 7 days/week after grooming. Since discontinuation of DEET did not improve symptoms, DEET was excluded as causative. Clinical exam in 3/2013 revealed, in addition to the previous findings, weak head anteflexion (M4−) and retroflexion (M5−). Trans-cranial magnetic stimulation in 4/2013 revealed an increased motor latency to the right sternocleidomastoid muscle. Since her symptoms were slowly progressive, ALS was suspected despite normal needle EMG from three muscles in 10/2013. The family historywasnoteworthy for polymyalgia, polyarthralgia, short stature, thyroidectomy, cholecystectomy, and depression in her mother and transient speech disturbance during several weeks in 2009 in her monozygotic twin sister who also used DEET, but less extensively. In 4/2014 she reported that she had developed gait disturbance 9 months ago, that she stumbled 3–4 months ago, and that she experienced shortage of breathduringexercise. A clinical examrevealed, in addition to the previous abnormalities, an exaggerated masseter reflex, weak lid closure, tongue atrophy without fasciculations, diffuse weakness (M5−) of the lower limbs, and exaggerated tendon reflexes without fasciculations, ataxia, or pyramidal signs. Nerve conduction studieswere normal. On the contrary, needle electromyography showed chronic neurogenic changes in the brachial biceps and vastus lateralis muscles. Clinical cardiologic examination revealed leg edema, STabnormalities, and surprisingly left ventricular hypertrabeculation/noncompaction (LVHT) on echocardiography (Fig. 1). A previous echocardiography from 7/2012 did not show LVHT. The presented case is interesting for several aspects. First, establishing the correct diagnosis was delayed for 3 years because of several reasons. The patient had a history of a skull base fracturewith damage of the 6th, 7th, and 8th cranial nerves, a contusional bleeding, and a posttraumatic seizure. At the beginning of the diagnostic work-up it was assumed that progressive bulbar symptomswere causally related to the

  • Aborted sudden cardiac death and a mother with suspected Metabolic Myopathy.
    Clinical Medicine Insights. Cardiology, 2014
    Co-Authors: Josef Finsterer, Claudia Stöllberger, Hans Keller
    Abstract:

    Aborted sudden cardiac death (SCD) has not been reported as initial manifestation of cardiac involvement in Metabolic Myopathy (MM). A 20-year-old female with a previous history of three syncopes, hyperhidrosis, and recurrent tick bites experienced aborted SCD. Her mother presented with MM, and a history of pituitary adenoma, nephroptosis, arterial hypertension, depression, migraine, goiter, pancreatitis, osteoporosis, hyperhidrosis, multiple muscle ruptures, and hyperlipidemia. After a few days of disorientation and amnesia, the young female recovered completely. Clinical neurological examination was noticeable for partial ophthalmoparesis and mild hyperprolactinemia. She received an implantable cardioverter defibrillator, which did not discharge so far. Recurrent syncopes and aborted SCD may be the initial manifestation of MM with multiple organ involvement. The family history is important in cases with aborted SCD to guide the diagnostic work-up. Phenotypic heterogeneity between the family members may be an indicator of MM.

  • Ischemic stroke and intestinal bleeding under dabigatran in Metabolic Myopathy.
    Cardiovascular Therapeutics, 2013
    Co-Authors: Josef Finsterer, Gernot Paul, Claudia Stöllberger, Adam Bastovansky
    Abstract:

    Summary Objectives The subsequent occurrence of an ischemic thromboembolic event and a bleeding shortly after discontinuation of dabigatran has not been published. Case report In an 89-year-old female with atrial fibrillation dabigatran had been started 11 days before admission, following a transitory ischemic attack. Phenprocoumon had been stopped 1 month earlier because of a hematoma after a fall. Although dabigatran was discontinued already on hospital day 1, she experienced an intestinal bleeding on hospital day three and an ischemic stroke on hospital day 6. As blood coagulation parameters were still abnormal on hospital day 2, intestinal bleeding was attributed to the prolonged antithrombotic effect or the interaction of dabigatran with the comedication. Stroke was attributed to the absence of a sufficient antithrombotic effect or a rebound effect 5 days after discontinuation of dabigatran. Clinical neurological examination additionally suggested a neuromuscular disorder. Conclusions Ischemic stroke and intestinal bleeding may consecutively occur shortly after stopping dabigatran. Coagulation parameters may remain abnormal even 2 days after discontinuation of dabigatran. Dabigatran should be applied with caution in elderly patients with renal insufficiency who also take drugs, which enhance the absorption of dabigatran.

  • acquired familial noncompaction and eccentric hypertrophic cardioMyopathy associated with Metabolic Myopathy and epilepsy
    International Journal of Cardiology, 2012
    Co-Authors: Josef Finsterer, Claudia Stöllberger
    Abstract:

    2008;359:1811–21. [6] SoMW, Lee SG, Kim YG, Lee CK, Yoo B. Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study. Scand J Rheumatol 2011;40:444–7. [7] McCarty DJ. Gout without hyperuricemia. JAMA 1994;271:302–3. [8] Schlesinger N, Baker DG, Schumacher Jr HR. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–6. [9] Schumacher Jr HR, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488–92. [10] Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004;50:598–606. [11] Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout. J Rheumatol 2009;36:1287–9. [12] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [13] Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–32. [14] Bertazzo A, Punzi L, Bertazzolo N, et al. Tryptophan catabolism in synovial fluid of various arthropathies and its relationship with inflammatory cytokines. Adv Exp Med Biol 1999;467:565–70. [15] Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357–61. [16] Inokuchi T, Moriwaki Y, Tsutsui H, et al. Plasma interleukin (IL)-18 (interferongamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. Cytokine 2006;33:21–7. [17] Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597–605.

Claudia Stöllberger - One of the best experts on this subject based on the ideXlab platform.

  • non compaction delineates amyotrophic lateral sclerosis from Metabolic Myopathy
    International Journal of Cardiology, 2014
    Co-Authors: Josef Finsterer, Claudia Stöllberger, Nefzat Guler
    Abstract:

    Particularly in the early stages of the disease, amyotrophic lateral sclerosis (ALS) with bulbar onset is often difficult to delineate from other neuromuscular disorders, in particularMetabolicMyopathy [1]. This is because both entities mimic each other and because both include a plethora of different pathomechanisms. With disease progression, however, both entities develop unique features upon which they may be differentiated as in the following case. A 36 year-old female veterinarian, with a height of 174 cm, and a weight of 62 kg, who is fond of horses and a passionate horse-rider, developed permanent dysarthria and dysphagia, worsening at night, since 5/2011. Her history was noteworthy for recurrent right-sided herpetic keratitis since the age of 5 years old resulting in reduced visual acuity (20% of normal). After corneal abrasion, she was symptom-free until 2005 when she received a rabies vaccination, after which keratitis foudroyantly recurred. For keratitis she had been taking valacyclovir 500–1500 mg/day almost continuously for two years until 1/2012. In 2001 she had a horse-riding accident and experienced a fracture of the right petrosal bone with consecutive anacusis, mild residual peripheral facial palsy, abducens palsy, and a contusional bleeding in the left frontal lobe. Shortly afterwards she experienced a single tonic–clonic seizure. She had a crossbite since childhood, leading to arthrosis of the mandibular joints since 6/2012. Extensive blood immunological investigations in 2004 were normal. In 1/2012 myasthenia gravis was suspected but low dosages of pyridostigmine did not improve symptoms. Clinical exam in 5/2012 revealed severely reduced visual acuity on the right side, anacusis and discrete right-sided peripheral facial palsy, signe-des-cils bilaterally, dysarthria, dysphagia, diffuseweakness on theupper limbs (M5−)with proximal predominance, and reduced tendon reflexes on the upper limbs. Marked vitamin-D-deficiency resolved under adequate substitution but did not affect her symptoms (Table 1). MRI of the cerebrum revealed an old contusional lesion in the left frontal area and a righthemispheric, non-specific gliotic white matter lesion. Lung function tests and video-cinematography in 7/2012 were normal. Acetylcholinereceptor antibodies were slightly elevated once but normal on repeated determination (Table 1). Anti-MUSK antibodies were normal. Lowand high-frequency repetitive nerve stimulation under pyridostigmine was normal in 6/2012. Edrophonium testing was negative. CT-scan of the mediastinum revealed a small mass lesion within the thymus, suggesting hyperplasia or thymoma. FDG-PET confirmed the diagnosis whyendoscopic thymectomywas carried out in 8/2012,which excluded a thymoma. Since thymectomy and application of pyridostigmine maximally at 480 mg/day only partially and temporarily resolved dysarthria and dysphagia, myasthenia was ruled out. Next it was assumed that symptoms were triggered by N,N-diethyl m-toluamide (DEET), which worsens myasthenia. She used DEET as a repellent particularly for one of her three horses, which was allergic to the sun, black flies, and gadflies. Occasionally, she also used DEET for herself and sprayed it onto the upper arms and into the face. She used DEET since it was the only repellent with a beneficial effect after having tried various others. She administered 30–40 puffs per horse of either Leovet Phaser® or Leovet Power-Phaser® between April and October during the occurrence of black flies once a day for 7 days/week after grooming. Since discontinuation of DEET did not improve symptoms, DEET was excluded as causative. Clinical exam in 3/2013 revealed, in addition to the previous findings, weak head anteflexion (M4−) and retroflexion (M5−). Trans-cranial magnetic stimulation in 4/2013 revealed an increased motor latency to the right sternocleidomastoid muscle. Since her symptoms were slowly progressive, ALS was suspected despite normal needle EMG from three muscles in 10/2013. The family historywasnoteworthy for polymyalgia, polyarthralgia, short stature, thyroidectomy, cholecystectomy, and depression in her mother and transient speech disturbance during several weeks in 2009 in her monozygotic twin sister who also used DEET, but less extensively. In 4/2014 she reported that she had developed gait disturbance 9 months ago, that she stumbled 3–4 months ago, and that she experienced shortage of breathduringexercise. A clinical examrevealed, in addition to the previous abnormalities, an exaggerated masseter reflex, weak lid closure, tongue atrophy without fasciculations, diffuse weakness (M5−) of the lower limbs, and exaggerated tendon reflexes without fasciculations, ataxia, or pyramidal signs. Nerve conduction studieswere normal. On the contrary, needle electromyography showed chronic neurogenic changes in the brachial biceps and vastus lateralis muscles. Clinical cardiologic examination revealed leg edema, STabnormalities, and surprisingly left ventricular hypertrabeculation/noncompaction (LVHT) on echocardiography (Fig. 1). A previous echocardiography from 7/2012 did not show LVHT. The presented case is interesting for several aspects. First, establishing the correct diagnosis was delayed for 3 years because of several reasons. The patient had a history of a skull base fracturewith damage of the 6th, 7th, and 8th cranial nerves, a contusional bleeding, and a posttraumatic seizure. At the beginning of the diagnostic work-up it was assumed that progressive bulbar symptomswere causally related to the

  • Aborted sudden cardiac death and a mother with suspected Metabolic Myopathy.
    Clinical Medicine Insights. Cardiology, 2014
    Co-Authors: Josef Finsterer, Claudia Stöllberger, Hans Keller
    Abstract:

    Aborted sudden cardiac death (SCD) has not been reported as initial manifestation of cardiac involvement in Metabolic Myopathy (MM). A 20-year-old female with a previous history of three syncopes, hyperhidrosis, and recurrent tick bites experienced aborted SCD. Her mother presented with MM, and a history of pituitary adenoma, nephroptosis, arterial hypertension, depression, migraine, goiter, pancreatitis, osteoporosis, hyperhidrosis, multiple muscle ruptures, and hyperlipidemia. After a few days of disorientation and amnesia, the young female recovered completely. Clinical neurological examination was noticeable for partial ophthalmoparesis and mild hyperprolactinemia. She received an implantable cardioverter defibrillator, which did not discharge so far. Recurrent syncopes and aborted SCD may be the initial manifestation of MM with multiple organ involvement. The family history is important in cases with aborted SCD to guide the diagnostic work-up. Phenotypic heterogeneity between the family members may be an indicator of MM.

  • Ischemic stroke and intestinal bleeding under dabigatran in Metabolic Myopathy.
    Cardiovascular Therapeutics, 2013
    Co-Authors: Josef Finsterer, Gernot Paul, Claudia Stöllberger, Adam Bastovansky
    Abstract:

    Summary Objectives The subsequent occurrence of an ischemic thromboembolic event and a bleeding shortly after discontinuation of dabigatran has not been published. Case report In an 89-year-old female with atrial fibrillation dabigatran had been started 11 days before admission, following a transitory ischemic attack. Phenprocoumon had been stopped 1 month earlier because of a hematoma after a fall. Although dabigatran was discontinued already on hospital day 1, she experienced an intestinal bleeding on hospital day three and an ischemic stroke on hospital day 6. As blood coagulation parameters were still abnormal on hospital day 2, intestinal bleeding was attributed to the prolonged antithrombotic effect or the interaction of dabigatran with the comedication. Stroke was attributed to the absence of a sufficient antithrombotic effect or a rebound effect 5 days after discontinuation of dabigatran. Clinical neurological examination additionally suggested a neuromuscular disorder. Conclusions Ischemic stroke and intestinal bleeding may consecutively occur shortly after stopping dabigatran. Coagulation parameters may remain abnormal even 2 days after discontinuation of dabigatran. Dabigatran should be applied with caution in elderly patients with renal insufficiency who also take drugs, which enhance the absorption of dabigatran.

  • acquired familial noncompaction and eccentric hypertrophic cardioMyopathy associated with Metabolic Myopathy and epilepsy
    International Journal of Cardiology, 2012
    Co-Authors: Josef Finsterer, Claudia Stöllberger
    Abstract:

    2008;359:1811–21. [6] SoMW, Lee SG, Kim YG, Lee CK, Yoo B. Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study. Scand J Rheumatol 2011;40:444–7. [7] McCarty DJ. Gout without hyperuricemia. JAMA 1994;271:302–3. [8] Schlesinger N, Baker DG, Schumacher Jr HR. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–6. [9] Schumacher Jr HR, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488–92. [10] Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004;50:598–606. [11] Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout. J Rheumatol 2009;36:1287–9. [12] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [13] Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–32. [14] Bertazzo A, Punzi L, Bertazzolo N, et al. Tryptophan catabolism in synovial fluid of various arthropathies and its relationship with inflammatory cytokines. Adv Exp Med Biol 1999;467:565–70. [15] Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357–61. [16] Inokuchi T, Moriwaki Y, Tsutsui H, et al. Plasma interleukin (IL)-18 (interferongamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. Cytokine 2006;33:21–7. [17] Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597–605.

  • Thrombolysis of ischemic stroke from noncompaction in Metabolic Myopathy.
    The neurologist, 2012
    Co-Authors: Josef Finsterer, Claudia Stöllberger, Gottfried Sodeck
    Abstract:

    BACKGROUND: Ischemic stroke has not been reported together with left ventricular hypertrabeculation/noncompaction (LVHT) and Metabolic Myopathy. METHODS AND RESULTS: In a 32-year-old woman with suspected Metabolic Myopathy, congenital AV-block, pacemaker implantation at the age of 20, and reduced systolic function, LVHT was detected on echocardiography. Shortly afterward, the patient had a left-sided ischemic stroke and underwent systemic thrombolysis with rTPA 3.5 hours after the onset. After the exclusion of potential causes of stroke, cerebral thromboembolism was attributed to LVHT. Oral anticoagulation was initiated and a cardiac resynchronization system was implanted. CONCLUSIONS: LVHT patients with systolic dysfunction or atrial fibrillation experiencing an ischemic stroke may benefit from oral anticoagulation.

Barry J. Byrne - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Gene Therapy Trials for Pompe Disease
    Muscle Gene Therapy, 2019
    Co-Authors: Cristina Liberati, Stephanie Salabarria, Manuela Corti, Barry J. Byrne
    Abstract:

    Pompe disease is a Metabolic Myopathy which leads to severe and progressive weakness due to glycogen storage in striated muscle and neurons. Generalized weakness leads to cardiopulmonary insufficiency and early mortality. The spectrum of disease ranges from a fatal early-onset form to a more slowly progressive intermediate and adult-onset type. The severity of disease depends on the amount of residual acid α-glucosidase (GAA) activity which is determined by the nature of the two mutant alleles. The lack of GAA leads to accumulation of glycogen in lysosomes of neurons and striated muscle (especially skeletal and cardiac muscle). Lysosomal dysfunction and cellular autophagy result in neuronal cell loss over time. Enzyme replacement therapy (ERT) is the only currently approved treatment for Pompe disease; however, ERT does not effectively address the neural deficits; therefore, alternative approaches using gene therapy must be considered. The principal objective of gene therapy in Pompe disease is to increase the intrinsic ability of the cells to produce GAA. A variety of recombinant adeno-associated viral vectors (rAAV) are being studied to complete this task. The efficacy of gene therapy not only depends on the efficiency of the gene therapy agent but also on the host's immune response. The most critical immunological challenges are anti-AAV capsid antibodies and anti-GAA antibodies. In this chapter, we review the current status of AAV-mediated gene therapy for Pompe disease.

  • Preclinical Gene Therapy Studies for Metabolic Myopathy
    Muscle Gene Therapy, 2019
    Co-Authors: Stephanie Salabarria, Cristina Liberati, Barry J. Byrne, Manuela Corti
    Abstract:

    The application of adeno-associated virus (AAV) and adenovirus (AdV) gene therapy has become increasingly important as a therapeutic modality since its first application in humans in 1990. However, over the past 20 years, the field has matured, and tangible clinical outcomes have been achieved in a limited number of studies. Establishing proof of concept and overcoming some of the technical challenges and establishing safety are the focus of preclinical studies on gene therapy to date. Gene therapy has been extensively investigated for some Metabolic myopathies such as Pompe, but it has just begun for many others. This chapter will evaluate animal models for future research in Metabolic myopathies as well as preclinical gene therapy trials for glycogen storage diseases (GSD) I, III, and V, Barth syndrome, Friedreich’s ataxia, and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency . These animal models will provide a great opportunity to test novel forms of gene editing and gene replacement therapies.

  • Adeno-associated virus-mediated gene therapy for Metabolic Myopathy.
    Human gene therapy, 2013
    Co-Authors: Cathryn Mah, Manuela Corti, Meghan S. Soustek, A. Gary Todd, Angela L. Mccall, Barbara K. Smith, Darin J. Falk, Barry J. Byrne
    Abstract:

    Abstract Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into three major types of Metabolic disease: mitochondrial, lipid, or glycogen. Treatment varies greatly depending on the biochemical nature of the disease, and unfortunately no definitive treatments exist for Metabolic Myopathy. Since this group of diseases is inherited, gene therapy is being explored as an approach to personalized medical treatment. Adeno-associated virus–based vectors in particular have shown to be promising in the treatment of several forms of Metabolic Myopathy. This review will discuss the most recent advances in gene therapy efforts for the treatment of Metabolic myopathies.

  • rescue of enzyme deficiency in embryonic diaphragm in a mouse model of Metabolic Myopathy pompe disease
    Development, 2004
    Co-Authors: Mary B Rucker, Thomas J Fraites, Stacy Porvasnik, Melissa A Lewis, Irene Zolotukhin, Denise A Cloutier, Barry J. Byrne
    Abstract:

    Several human genetic diseases that affect striated muscle have been modeled by creating knockout mouse strains. However, many of these are perinatal lethal mutations that result in death from respiratory distress within hours after birth. As the diaphragm muscle does not contract until birth, the sudden increase in diaphragm activity creates permanent injury to the muscle causing it to fail to meet respiratory demands. Therefore, the impact of these mutations remains hidden throughout embryonic development and early death prevents investigators from performing detailed studies of other striated muscle groups past the neonatal stage. Glycogen storage disease type II (GSDII), caused by a deficiency in acid α-glucosidase (GAA), leads to lysosomal accumulation of glycogen in all cell types and abnormal myofibrillogenesis in striated muscle. Contractile function of the diaphragm muscle is severely affected in both infantile-onset and late-onset individuals, with death often resulting from respiratory failure. The knockout mouse model of GSDII survives well into adulthood despite the gradual weakening of all striated muscle groups. Using this model, we investigated the delivery of recombinant adeno-associated virus (rAAV) vectors encoding the human GAA cDNA to the developing embryo. Results indicate specific high-level transduction of diaphragm tissue, leading to activity levels up to 10-fold higher than normal and restoration of normal contractile function. Up to an estimated 50 vector copies per diploid genome were quantified in treated diaphragms. Histological glycogen staining of treated diaphragms revealed prevention of lysosomal glycogen accumulation in almost all fibers when compared with untreated controls. This method could be employed with disease models where specific rescue of the diaphragm would allow for increased survival and thus further investigation into the impact of the gene deletion on other striated muscle groups.

R L Wortmann - One of the best experts on this subject based on the ideXlab platform.

  • Metabolic myopathies.
    Current opinion in rheumatology, 1991
    Co-Authors: R L Wortmann
    Abstract:

    The term Metabolic Myopathy refers to a heterogeneous group of conditions that have in common abnormalities of muscle energy metabolism that result in skeletal muscle dysfunction. Most recognized Metabolic myopathies are considered primary, represent inborn errors of metabolism, and are associated with known or postulated defects that affect the ability of muscle fibers to maintain adequate ATP concentrations. Traditionally, these diseases are grouped into abnormalities of glycogen, lipid, purine, and mitochondrial biochemistry. This discussion reviews the basic Metabolic pathways that regulate normal muscle function; recent observations involving glycogen storage diseases, carnitine deficiency states, and myoadenylate deaminase deficiencies; and lastly, newer techniques available to assess patients with myopathic disorders.

Masatoshi Hagiwara - One of the best experts on this subject based on the ideXlab platform.

  • Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy.
    iScience, 2019
    Co-Authors: Motoyasu Hosokawa, Akihide Takeuchi, Jun Tanihata, Kei Iida, Shin'ichi Takeda, Masatoshi Hagiwara
    Abstract:

    Summary Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. How long-distance transcription is achieved is a fundamental question to be elucidated. In previous study, we had discovered that RNA-binding protein SFPQ preferentially binds to long pre-mRNAs and specifically regulates the cluster of neuronal genes >100 kbp. Here we investigated the roles of SFPQ for long gene expression, target specificities, and also physiological functions in skeletal muscle. Loss of Sfpq selectively downregulated genes >100 kbp including Dystrophin, which is 2.26 Mbp in length. Sfpq knockout (KO) mice showed progressive muscle mass reduction and Metabolic Myopathy characterized by glycogen accumulation and decreased abundance of mitochondrial oxidative phosphorylation complexes. Functional clustering analysis identified energy metabolism pathway genes as SFPQ's targets. These findings indicate target gene specificities and tissue-specific physiological functions of SFPQ in skeletal muscle.

  • Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy
    Elsevier, 2019
    Co-Authors: Motoyasu Hosokawa, Akihide Takeuchi, Jun Tanihata, Kei Iida, Shin'ichi Takeda, Masatoshi Hagiwara
    Abstract:

    Summary: Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. How long-distance transcription is achieved is a fundamental question to be elucidated. In previous study, we had discovered that RNA-binding protein SFPQ preferentially binds to long pre-mRNAs and specifically regulates the cluster of neuronal genes >100 kbp. Here we investigated the roles of SFPQ for long gene expression, target specificities, and also physiological functions in skeletal muscle. Loss of Sfpq selectively downregulated genes >100 kbp including Dystrophin, which is 2.26 Mbp in length. Sfpq knockout (KO) mice showed progressive muscle mass reduction and Metabolic Myopathy characterized by glycogen accumulation and decreased abundance of mitochondrial oxidative phosphorylation complexes. Functional clustering analysis identified energy metabolism pathway genes as SFPQ's targets. These findings indicate target gene specificities and tissue-specific physiological functions of SFPQ in skeletal muscle. : Molecular Biology; Molecular Mechanism of Gene Regulation; Pathophysiology Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Pathophysiolog