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1.
J Inherit Metab Dis ; 36(6): 1015-24, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23494656

ABSTRACT

BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.


Subject(s)
Enzyme Replacement Therapy , alpha-Mannosidase/administration & dosage , alpha-Mannosidosis/drug therapy , Adolescent , Child , Cognition/drug effects , Dose-Response Relationship, Drug , Enzyme Replacement Therapy/adverse effects , Enzyme Replacement Therapy/methods , Exercise Test , Follow-Up Studies , Humans , Psychomotor Performance/drug effects , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/immunology , Recombinant Proteins/pharmacokinetics , Treatment Outcome , alpha-Mannosidase/adverse effects , alpha-Mannosidase/immunology , alpha-Mannosidase/pharmacokinetics
2.
Eur J Neurol ; 16(12): 1336-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19486129

ABSTRACT

BACKGROUND AND PURPOSE: It is unknown whether prolonged training is a safe treatment to alleviate exercise intolerance in patients with mitochondrial DNA (mtDNA) mutations. METHODS: The effect of 3 and 12 months training and 3-12 months deconditioning was studied in four patients carrying different mtDNA mutations. RESULTS: Three-month moderate-intensity training increased oxidative capacity by 23%, which was sustained after 6-12 months of low-intensity training. Training and deconditioning did not induce adverse effects on clinical symptoms, muscle morphology and mtDNA mutation load in muscle. CONCLUSION: Long-term training effectively improves exercise capacity in patients with mitochondrial myopathy, and appears to be safe.


Subject(s)
Exercise Therapy/methods , Mitochondrial Myopathies/rehabilitation , Exercise Tolerance/physiology , Humans , Mitochondrial Myopathies/metabolism , Mitochondrial Myopathies/pathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Time
3.
J Inherit Metab Dis ; 32 Suppl 1: S235-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19517265

ABSTRACT

The pyruvate dehydrogenase (PDH) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. We report four novel PDHA1 mutations in patients with pyruvate dehydrogenase deficiency. Analysis of PDH activity showed decreased activity in fibroblasts from all four patients, around 16-52% of mean control, similar to what has been found in previous studies. Two of the mutations were missense mutations: c.616G>A (p.Glu206Lys) and c.457A>G (p.Met153Val), one was a 3 bp in-frame deletion: c.429_431delAGG (p.Gly143del), and one was a 65 bp duplication: c.900-6_958dup65. cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication. The small amount of normal transcript likely explains the survival of the patient, who was a boy. The duplication and one of the missense mutations were associated with decreased amounts of E(1)α And E(1)ß protein on western blot analysis, whereas the other two mutations were associated with normal amounts. This study adds four novel mutations to the around 90 reported mutations in PDHA1 (HGMD PDHA1 mutation database). The phenotypes of patients with PDH deficiency have been divided into three groups: a neonatal form with severe lactic acidosis, a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia, and an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor retardation, in some cases Leigh-like lesions and mild to moderate hyperlactataemia. The four patients reported here all belong to the latter group, which is the largest.


Subject(s)
Mutation , Pyruvate Dehydrogenase (Lipoamide)/deficiency , Pyruvate Dehydrogenase (Lipoamide)/genetics , Pyruvate Dehydrogenase Complex Deficiency Disease/enzymology , Pyruvate Dehydrogenase Complex Deficiency Disease/genetics , Adolescent , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Mitochondrial Proteins/deficiency , Mitochondrial Proteins/genetics , Molecular Sequence Data , Mutation, Missense , Phenotype , Pyruvate Dehydrogenase Complex Deficiency Disease/classification , Sequence Deletion
4.
Neurology ; 72(4): 317-23, 2009 Jan 27.
Article in English | MEDLINE | ID: mdl-19171827

ABSTRACT

OBJECTIVE: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage. METHODS: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo(2max)), maximal work capacity (W(max)), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. RESULTS: W(max) increased by 18%, and CS activity increased by 35%. There was no significant change in Vo(2max) or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. CONCLUSIONS: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.


Subject(s)
Bulbo-Spinal Atrophy, X-Linked/physiopathology , Bulbo-Spinal Atrophy, X-Linked/therapy , Exercise Therapy/methods , Exercise/physiology , Activities of Daily Living/psychology , Bulbo-Spinal Atrophy, X-Linked/psychology , Female , Humans , Male , Middle Aged , Muscular Atrophy, Spinal/physiopathology , Muscular Atrophy, Spinal/psychology , Muscular Atrophy, Spinal/therapy , Oxygen Consumption/physiology
5.
Neurology ; 65(6): 931-3, 2005 Sep 27.
Article in English | MEDLINE | ID: mdl-16186538

ABSTRACT

The authors report a 27-year-old man with B12-responsive mut- methylmalonic aciduria associated with pure muscle symptoms. Two mutations were found in the methylmalonyl-CoA mutase gene. An exercise test showed a reduced maximal workload and reduced oxygen uptake, and a muscle biopsy showed subsarcolemmal accumulation of mitochondria and normal respiratory chain enzyme activities. These findings may be caused by inhibition of mitochondrial energy metabolism by methylmalonate or its metabolites.


Subject(s)
Energy Metabolism/genetics , Metabolism, Inborn Errors/genetics , Methylmalonyl-CoA Mutase/deficiency , Mitochondrial Myopathies/enzymology , Mitochondrial Myopathies/genetics , Muscle, Skeletal/enzymology , Adult , Cell Respiration/genetics , DNA Mutational Analysis , Exercise Tolerance/genetics , Humans , Male , Methylmalonic Acid/metabolism , Methylmalonyl-CoA Mutase/genetics , Mitochondria/enzymology , Mitochondria/genetics , Mitochondria/pathology , Mitochondrial Diseases/enzymology , Mitochondrial Diseases/genetics , Mitochondrial Myopathies/physiopathology , Muscle Weakness/enzymology , Muscle Weakness/genetics , Muscle Weakness/physiopathology , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Mutation/genetics , Sarcolemma/enzymology , Sarcolemma/pathology
6.
Neurology ; 59(6): 926-9, 2002 Sep 24.
Article in English | MEDLINE | ID: mdl-12297582

ABSTRACT

Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.


Subject(s)
DNA, Mitochondrial/genetics , Gene Deletion , Mitochondrial Encephalomyopathies/genetics , Adult , DNA Mutational Analysis , Female , Humans , Male , Mitochondrial Encephalomyopathies/enzymology , Muscle, Skeletal/enzymology , Pedigree , Phenotype
7.
Ann Neurol ; 50(4): 540-3, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11601507

ABSTRACT

Mitochondrial cytochrome b mutations have been reported to have a homogenous phenotype of pure exercise intolerance. We describe a novel mutation in the cytochrome b gene of mitochondrial DNA (A15579G) associated with a selective decrease of muscle complex III activity in a patient who, besides severe exercise intolerance, also has multisystem manifestations (deafness, mental retardation, retinitis pigmentosa, cataract, growth retardation, epilepsy). The point mutation is heteroplasmic in muscle (88%) and leukocytes (15%), and changes a highly conserved tyrosine to cysteine at amino acid position 278.


Subject(s)
Cytochrome b Group/genetics , Hearing Loss, Bilateral/genetics , Intellectual Disability/genetics , Muscular Diseases/genetics , Mutation, Missense , Adult , DNA, Mitochondrial/genetics , Epilepsy/genetics , Female , Humans , Phenotype , Polymorphism, Restriction Fragment Length , Retinitis Pigmentosa/genetics
8.
Eur J Hum Genet ; 9(10): 805-9, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11781695

ABSTRACT

We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome. The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit. The patient was heteroplasmic for the mutation in both muscle and blood, but the mutation was not detected in the patient's mother. A marked reduction of complex I activity was found in the patient's muscular tissue. This is the first report of a mutation in the ND6 subunit causing MELAS. Our data confirm the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and confirms that MELAS can be caused by mutation in polypeptide-coding mtDNA genes.


Subject(s)
DNA, Mitochondrial/genetics , MELAS Syndrome/enzymology , MELAS Syndrome/genetics , Mutation/genetics , NADH Dehydrogenase/chemistry , NADH Dehydrogenase/genetics , Base Sequence , Child, Preschool , DNA Mutational Analysis , DNA, Mitochondrial/blood , Female , Humans , MELAS Syndrome/blood , Mitochondria, Muscle/enzymology , NADH Dehydrogenase/metabolism , Protein Subunits , Restriction Mapping
9.
Biochem J ; 299 ( Pt 2): 533-7, 1994 Apr 15.
Article in English | MEDLINE | ID: mdl-8172615

ABSTRACT

The lactate carrier was solubilized from purified rat skeletal-muscle sarcolemma with the detergent decanoyl-N-methyl-glucamide and the solubilized carrier was reconstituted into phospholipid vesicles. Reconstituted proteoliposomes showed a faster time course of L-lactate uptake than did protein-free liposomes. The rate of L-lactate uptake into the proteoliposomes was inhibited by the lactate-transport inhibitors p-chloromercuribenzenesulphonate, diethyl pyrocarbonate, alpha-cyano-4-hydroxycinnamate and quercetin. In contrast, the anion-exchange inhibitor DIDS (4,4'-di-isothiocyanostilbene-2,2'-disulphonate) had almost no effect on the uptake. The extent of L-lactate uptake at equilibrium was not affected by the presence of the transport inhibitors, but was sensitive to osmotic strength. L-Lactate and pyruvate, but not D-lactate, inhibited L-lactate uptake when present at 10-fold excess. The properties of L-lactate transport in reconstituted proteoliposomes were similar to those observed in native sarcolemmal vesicles, i.e. the lactate carrier seems to retain its transport characteristics during the solubilization and reconstitution steps.


Subject(s)
Carrier Proteins/metabolism , Lactates/metabolism , Muscles/metabolism , Sarcolemma/metabolism , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , 4-Chloromercuribenzenesulfonate/pharmacology , Animals , Carrier Proteins/drug effects , Carrier Proteins/isolation & purification , Electrophoresis, Polyacrylamide Gel , Kinetics , Liposomes , Male , Monocarboxylic Acid Transporters , Proteolipids/metabolism , Rats , Rats, Wistar
10.
Am J Physiol ; 264(2 Pt 1): E156-60, 1993 Feb.
Article in English | MEDLINE | ID: mdl-8447380

ABSTRACT

The effect of training on lactate transport capacity was studied in giant vesicles obtained with collagenase treatment of rat skeletal muscles. Marker enzyme analyses demonstrated that these vesicles are predominantly of sarcolemmal origin. Treadmill training induced significant adaptations in the capacity of rat skeletal muscles to transport lactate but swimming [low-intensity training, approximately 50% of maximal oxygen consumption (VO2 max)] did not. After 7 wk of moderate (90% of VO2max)- and high-intensity (112% of VO2max) interval treadmill training the carrier-mediated equilibrium exchange flux with 30 mM lactate was increased by 58 and 76%, respectively. During 5 wk of detraining the capacity to transport lactate decreased to near control level. It is concluded that physical training can increase the capacity to transport lactate in rat skeletal muscles and that the training intensity is of great importance. The adaptation appears to include both an increased number of transport proteins and a higher affinity of the individual transporters.


Subject(s)
Lactates/metabolism , Physical Conditioning, Animal , Sarcolemma/metabolism , Animals , Biological Transport , Body Weight , Lactic Acid , Male , Physical Endurance , Rats , Rats, Wistar , Running , Swimming
11.
Proc Natl Acad Sci U S A ; 89(11): 5133-7, 1992 Jun 01.
Article in English | MEDLINE | ID: mdl-1594622

ABSTRACT

The vasorelaxing K+ channel opener P1060 (a pinacidil analog), gonadotropins, and cAMP were shown to activate a glibenclamide-sensitive 86Rb+ efflux from fully grown follicle-enclosed Xenopus oocytes. Glibenclamide-sensitive K+ channels are located in follicular cells. Glibenclamide (i) depressed the gonadotropin- but not the progesterone-induced maturation and (ii) did not significantly modify progesterone production in oocytes exposed to Xenopus gonadotropin. In follicle-enclosed oocytes, the opener P1060 very significantly enhanced the oocyte sensitivity to progesterone. This increased sensitivity to the hormone induced by the K+ channel opener was reversed by glibenclamide. Thus these results suggest that the opening of glibenclamide-sensitive K+ channels in follicular cells by gonadotropins (and other activators of this channel) induces a hyperpolarization in the oocyte that greatly facilitates maturation by increasing the oocyte sensitivity to progesterone.


Subject(s)
Oogenesis , Ovarian Follicle/physiology , Potassium Channels/physiology , Xenopus laevis/physiology , Animals , Female , Glyburide/pharmacology , Ion Channel Gating/drug effects , Meiosis/drug effects , Pituitary Hormones/pharmacology , Potassium Channels/drug effects , Progesterone/pharmacology , Progesterone/physiology
12.
Acta Physiol Scand ; 137(1): 33-9, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2552749

ABSTRACT

Lactate transport across the sarcolemma of isolated mouse muscles was studied with a 14C tracer technique. The cellular tracer uptake could be inhibited by unlabelled L-lactate (and pyruvate) and to a lesser extent by D-lactase. The stereospecific fraction had a Km of 3.5 mM, and made up 50% of the total transport. The tracer uptake was unaffected by 0.05 mM DIDS and 0.2 mM amiloride, but was inhibited by cinnamate (Ki = 8 mM) and PCMBS (Ki = 0.8 mM). With high concentrations of the latter inhibitor compounds or with high concentrations of unlabelled L-lactate, the tracer uptake was inhibited 80%, which indicates that the main part of the transport involves facilitated diffusion. The remaining fraction (20%) was non-saturable, reduced at high pH, and could not be inhibited; it is probably mediated by diffusion of undissociated lactic acid. Lactate transport was pH-dependent, which is consistent with a lactate-H+ symport. The maximal transport capacity, as calculated from the pH changes measured with pH-sensitive micro-electrodes while the lactate gradient was 30 mM, was 11.8 mmol kg-1 min-1 (pH 6.2).


Subject(s)
Lactates/pharmacokinetics , Muscles/metabolism , 4-Chloromercuribenzenesulfonate/pharmacology , Animals , Cinnamates/pharmacology , Hydrogen-Ion Concentration , Lactates/metabolism , Mice , Pyruvates/pharmacology
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