The potential of a ketogenic diet to minimize effects of the metabolic fault in glycogen storage disease V and VII.

PURPOSE OF REVIEW: To explore the potential of a low carbohydrate ketogenic diet (LCKD) to counter physical activity intolerance, pain and muscle damage for glycogen storage disease (GSD) V and VII, and highlight the realistic possibility that nutrition could be key. RECENT FINDINGS: Carbohydrate (CHO) ingestion during physical activity in GSDV and a LCKD for GSDVII is common. For the latter, a long-term study demonstrated improvement in physiological markers while on a LCKD. This included improvement in aerobic power and activity tolerance. In GSDV, preliminary research on a LCKD suggest a diet of 75% fat, 15% protein, 10% CHO, is best for improved function and compliance. Ketones provide immediate fuel for acute physical activity, and have an epigenetic role, improving ketone and lipid use. Evidence from elite athletes found a LCKD can increase fat oxidation and is optimal at 70% VO2max. This suggests the need to also improve conditioning via exercise to maximize the benefit of a LCKD. SUMMARY: A high CHO diet in GSDV and VII comes with a restricted physical activity capacity alongside significant pain, muscle damage and risk of renal failure. Mounting evidence suggests a LCKD is efficacious for both disorders providing an immediate fuel source which may negate the need for a 'warm-up' prior to every activity and restore 'normal' function.

Exercise efficiency impairment in metabolic myopathies.

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O2 was measured breath-by-breath throughout the incremental test. The ∆V'O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O2/∆Work-Rate slope (mLO2.min-1.W-1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.

My Diagnostic Odyssey-A Call to Expand Access to Genomic Testing for the Next Generation.

I attended the NSIGHT Ethics and Policy Advisory Board's meeting on sequencing newborns as a research associate in a joint apprenticeship between the University of California, San Francisco, Institute for Human Genetics and the university's Program in Bioethics. But I also came to the meeting with a deeply personal perspective: I had spent nearly my entire childhood in search of a diagnosis and therefore was eager to hear the board's discussion on how to ethically include genomic sequencing early in life. Genomic sequencing in the newborn period could have helped me avoid my diagnostic odyssey by revealing the cause of my condition shortly after birth.

Metabolic Myopathies.

PURPOSE OF REVIEW: Metabolic myopathies are genetic disorders that impair intermediary metabolism in skeletal muscle. Impairments in glycolysis/glycogenolysis (glycogen-storage disease), fatty acid transport and oxidation (fatty acid oxidation defects), and the mitochondrial respiratory chain (mitochondrial myopathies) represent the majority of known defects. The purpose of this review is to develop a diagnostic and treatment algorithm for the metabolic myopathies. RECENT FINDINGS: The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or in adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing. SUMMARY: Accurate and early identification of metabolic myopathies can lead to therapeutic interventions with lifestyle and nutritional modification, cofactor treatment, and rapid treatment of rhabdomyolysis.

Infantile form of muscle phosphofructokinase deficiency in a premature neonate.

Muscle phosphofructokinase (PFK) deficiency is a rare autosomal recessive disease. We report the case of a preterm female infant who was diagnosed with the infantile form of phosphofructokinase deficiency due to a lack of PFK activity in her muscles, manifesting at a corrected age of 1 month as floppy infant syndrome, congenital joint contracture, cleft palate and duplication of the pelvicalyceal system. She died at a corrected age of 6 months due to respiratory failure. We further reviewed other infantile cases in the literature. Congenital hypotonia (78.6%), arthrogryposis (64.3%) and other systemic involvement including encephalopathy (35.7%) and cardiomyopathy (21.4%) are common presentations of the infantile form of PFK deficiency. The overall survival rate of the infantile form is low. The early recognition of multiple system involvement is essential to provide better clinical care for infants with the infantile form of PFK deficiency.

[Exercise-induced muscle pain due to phosphofrutokinase deficiency: Diagnostic contribution of metabolic explorations (exercise tests, 31P-nuclear magnetic resonance spectroscopy)]. / Intolérance musculaire à l'effort par déficit en phosphofructokinase : apport au diagnostic du bilan métabolique musculaire (tests d'effort, spectroscopie RMN du P31).

INTRODUCTION: Muscle phosphofructokinase deficiency, the seventh member of the glycogen storage diseases family, is also called Tarui's disease (GSD VII). METHODS: We studied two patients in two unrelated families with Tarui's disease, analyzing clinical features, CK level, EMG, muscle biopsy findings and molecular genetics features. Metabolic muscle explorations (forearm ischemic exercise test [FIET]; bicycle ergometer exercise test [EE]; 31P-nuclear magnetic resonance spectroscopy of calf muscle [31P-NMR-S]) are performed as appropriate. RESULTS: Two patients, a 47-year-old man and a 38-year-old woman, complained of exercise-induced fatigue since childhood. The neurological examination was normal or showed light weakness. Laboratory studies showed increased CPK, serum uric acid and reticulocyte count without anemia. There was no increase in the blood lactate level during the FIET or the EE although there was a light increase in the respiratory exchange ratio during the EE. 31P-NMR-S revealed no intracellular acidification or accumulated intermediates such as phosphorylated monoesters (PME) known to be pathognomic for GSD VII. Two new mutations were identified. DISCUSSION: FIET and EE were non-contributive to diagnosis, but 31P-NMR provided a characteristic spectra of Tarui's disease, in agreement with phosphofructokinase activity level in erythrocytes. Muscle biopsy does not always provide useful information for diagnosis. In these two cases, genetic studies failed to establish a genotype-phenotype correlation. CONCLUSION: The search for phosphofructokinase deficiency should be continued throughout life in adults experiencing fatigability or weakness because of the severe disability for daily life activities caused by the late onset form.

Miopatías metabólicas / Metabolic myopathies

Objetivo. Revisar las miopatías metabólicas manifestadas solamente por crisis de mialgias, calambres y rigidez musculares con dificultad para contraer los músculos afectados y el examen neurológico normal entre las crisis en niños y adolescentes. Desarrollo. Estas miopatías metabólicas se deben a déficits enzimáticos heredados en forma autosómica recesiva del metabolismo de los carbohidratos y lípidos. El resultado final es una reducción del trifosfato de adenosina principalmente a través de la fosforilación oxidativa mitocondrial con disminución de la energía disponible para la contracción muscular. Las secundarias a trastornos del metabolismo de los carbohidratos se producen por ejercicios de alta intensidad y breves (< 10 min) y las secundarias a trastornos de los lípidos, por ejercicios de baja intensidad y prolongados (> 10 min). Los déficits enzimáticos en el primer grupo son de miofosforilasa (glucogenosis V), fosfofructocinasa muscular (glucogenosis VII), fosfoglicerato mutasa 1 (glucogenosis X) y beta enolasa (glucogenosis XIII), y en el segundo, de carnitina palmitol transferasa tipo II y de acil-CoA deshidrogenasa de cadena muy larga. Conclusiones. Las características diferenciales de los pacientes en cada grupo y dentro de cada grupo permitirán el diagnóstico clínico presuntivo inicial en la mayoría y solicitar solamente los exámenes necesarios para corroborar el diagnóstico. El tratamiento de las crisis consiste en hidratación, glucosa y alcalinización de la orina. Las medidas preventivas son evitar el tipo de ejercicio que induce las crisis y el ayuno. No existe cura o tratamiento específico. El pronóstico es bueno con la excepción de casos raros de insuficiencia renal aguda debido a la elevación sanguínea de la mioglobina producto de una rabdomiólisis grave (AU)

To review the metabolic myopathies manifested only by crisis of myalgias, cramps and rigidity of the muscles with decreased voluntary contractions and normal inter crisis neurologic examination in children and adolescents. Development. These metabolic myopathies are autosomic recessive inherited enzymatic deficiencies of the carbohydrates and lipids metabolisms. The end result is a reduction of intra muscle adenosine triphosphate, mainly through mitochondrial oxidative phosphorylation, with decrease of available energy for muscle contraction. The one secondary to carbohydrates intra muscle metabolism disorders are triggered by high intensity brief (< 10 min) exercises. Those secondary to fatty acids metabolism disorders are triggered by low intensity prolonged (> 10 min) exercises. The conditions in the first group in order of decreasing frequency are the deficiencies of myophosforilase (GSD V), muscle phosphofructokinase (GSD VII), phosphoglycerate mutase 1 (GSD X) and beta enolase (GSD XIII). The conditions in the second group in order of decreasing frequency are the deficiencies of carnitine palmitoyl transferase II and very long chain acyl CoA dehydrogenase. Conclusions. The differential characteristics of patients in each group and within each group will allow to make the initial presumptive clinical diagnosis in the majority and then to order only the necessary tests to achieve the final diagnosis. Treatment during the crisis includes hydration, glucose and alkalinization of urine if myoglobin in blood and urine are elevated. Prevention includes avoiding exercise which may induce the crisis and fasting. The prognosis is good with the exception of rare cases of acute renal failure due to hipermyoglobinemia because of severe rabdomyolisis (AU)

[Metabolic myopathies]. / Miopatías metabólicas.

AIM: To review the metabolic myopathies manifested only by crisis of myalgias, cramps and rigidity of the muscles with decreased voluntary contractions and normal inter crisis neurologic examination in children and adolescents. DEVELOPMENT: These metabolic myopathies are autosomic recessive inherited enzymatic deficiencies of the carbohydrates and lipids metabolisms. The end result is a reduction of intra muscle adenosine triphosphate, mainly through mitochondrial oxidative phosphorylation, with decrease of available energy for muscle contraction. The one secondary to carbohydrates intra muscle metabolism disorders are triggered by high intensity brief (< 10 min) exercises. Those secondary to fatty acids metabolism disorders are triggered by low intensity prolonged (> 10 min) exercises. The conditions in the first group in order of decreasing frequency are the deficiencies of myophosforilase (GSD V), muscle phosphofructokinase (GSD VII), phosphoglycerate mutase 1 (GSD X) and beta enolase (GSD XIII). The conditions in the second group in order of decreasing frequency are the deficiencies of carnitine palmitoyl transferase II and very long chain acyl CoA dehydrogenase. CONCLUSIONS: The differential characteristics of patients in each group and within each group will allow to make the initial presumptive clinical diagnosis in the majority and then to order only the necessary tests to achieve the final diagnosis. Treatment during the crisis includes hydration, glucose and alkalinization of urine if myoglobin in blood and urine are elevated. Prevention includes avoiding exercise which may induce the crisis and fasting. The prognosis is good with the exception of rare cases of acute renal failure due to hipermyoglobinemia because of severe rabdomyolisis.

TITLE: Miopatias metabolicas.Objetivo. Revisar las miopatias metabolicas manifestadas solamente por crisis de mialgias, calambres y rigidez musculares con dificultad para contraer los musculos afectados y el examen neurologico normal entre las crisis en niños y adolescentes. Desarrollo. Estas miopatias metabolicas se deben a deficits enzimaticos heredados en forma autosomica recesiva del metabolismo de los carbohidratos y lipidos. El resultado final es una reduccion del trifosfato de adenosina principalmente a traves de la fosforilacion oxidativa mitocondrial con disminucion de la energia disponible para la contraccion muscular. Las secundarias a trastornos del metabolismo de los carbohidratos se producen por ejercicios de alta intensidad y breves (< 10 min) y las secundarias a trastornos de los lipidos, por ejercicios de baja intensidad y prolongados (> 10 min). Los deficits enzimaticos en el primer grupo son de miofosforilasa (glucogenosis V), fosfofructocinasa muscular (glucogenosis VII), fosfoglicerato mutasa 1 (glucogenosis X) y beta enolasa (glucogenosis XIII), y en el segundo, de carnitina palmitol transferasa tipo II y de acil-CoA deshidrogenasa de cadena muy larga. Conclusiones. Las caracteristicas diferenciales de los pacientes en cada grupo y dentro de cada grupo permitiran el diagnostico clinico presuntivo inicial en la mayoria y solicitar solamente los examenes necesarios para corroborar el diagnostico. El tratamiento de las crisis consiste en hidratacion, glucosa y alcalinizacion de la orina. Las medidas preventivas son evitar el tipo de ejercicio que induce las crisis y el ayuno. No existe cura o tratamiento especifico. El pronostico es bueno con la excepcion de casos raros de insuficiencia renal aguda debido a la elevacion sanguinea de la mioglobina producto de una rabdomiolisis grave.

Structure and allosteric regulation of eukaryotic 6-phosphofructokinases.

Although the crystal structures of prokaryotic 6-phosphofructokinase, a key enzyme of glycolysis, have been available for almost 25 years now, structural information about the more complex and highly regulated eukaryotic enzymes is still lacking until now. This review provides an overview of the current knowledge of eukaryotic 6-phosphofructokinase based on recent crystal structures, kinetic analyses and site-directed mutagenesis data with special focus on the molecular architecture and the structural basis of allosteric regulation.

Altered allosteric regulation of muscle 6-phosphofructokinase causes Tarui disease.

Tarui disease is a glycogen storage disease (GSD VII) and characterized by exercise intolerance with muscle weakness and cramping, mild myopathy, myoglobinuria and compensated hemolysis. It is caused by mutations in the muscle 6-phosphofructokinase (Pfk). Pfk is an oligomeric, allosteric enzyme which catalyzes one of the rate-limiting steps of the glycolysis: the phosphorylation of fructose 6-phosphate at position 1. Pfk activity is modulated by a number of regulators including adenine nucleotides. Recent crystal structures from eukaryotic Pfk displayed several allosteric adenine nucleotide binding sites. Functional studies revealed a reciprocal linkage between the activating and inhibitory allosteric binding sites. Herein, we showed that Asp(543)Ala, a naturally occurring disease-causing mutation in the activating binding site, causes an increased efficacy of ATP at the inhibitory allosteric binding site. The reciprocal linkage between the activating and inhibitory binding sites leads to reduced enzyme activity and therefore to the clinical phenotype. Pharmacological blockage of the inhibitory allosteric binding site or highly efficient ligands for the activating allosteric binding site may be of therapeutic relevance for patients with Tarui disease.

Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog.

Hereditary muscle-type phosphofructokinase (PFK) deficiency causing intermittent hemolytic anemia and exertional myopathy due to a single nonsense mutation in PFKM has been previously described in English Springer and American Cocker Spaniels, Whippets, and mixed breed dogs. We report here on a new missense mutation associated with PFK deficiency in Wachtelhunds. Coding regions of the PFKM gene were amplified from genomic DNA and/or cDNA reverse-transcribed from RNA of EDTA blood of PFK-deficient and clinically healthy Wachtelhunds and control dogs. The amplicons were sequenced and compared to the published canine PFKM sequence. A point mutation (c.550C>T, in the coding sequence of PFKM expressed in blood) was found in all 4 affected Wachtelhunds. This missense mutation results in an amino acid substitution of arginine (Arg) to tryptophan (Trp) at position 184 of the protein expressed in blood (p.Arg184Trp). The mutation is located within an alpha-helix, and based on the SIFT analysis, this amino acid substitution is not tolerated. Amplifying the region around this mutation and digesting the PCR fragment with the restriction enzyme MspI, produces fragments that readily differentiate between PFK-deficient, carrier, and normal animals. Furthermore, we document 2 additional upstream PFKM exons expressed in canine testis but not in blood. Despite their similar phenotypic appearance and use for hunting, Wachtelhunds and English Springer Spaniels are not thought to have common ancestors. Thus, it is not surprising that different mutations are responsible for PFK deficiency in these breeds. Knowledge of the molecular basis of PFK deficiency in Wachtelhunds provides an opportunity to screen and control the spread of this deleterious trait.

Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency.

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

Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII).

Muscle phosphofructokinase (PFKM) deficiency, a rare disorder of glycogen metabolism also known as glycogen storage disease type VII (GSDVII), is characterized by exercise intolerance, myalgias, cramps and episodic myoglobinuria associated with compensated hemolytic anaemia and hyperuricemia. We studied five patients with PFKM deficiency coming from different Italian regions. All probands showed exercise intolerance, hyperCKemia, cramps and myoglobinuria. One patient had a mild hypertrophic cardiomyopathy. Biochemical studies revealed residual PFK activity ranging from 1 to 5%. Molecular genetic analysis identified four novel mutations in the PFKM gene. In our series of patients, clinical and laboratory features were similar in all but one patient, who had an unusual phenotype characterized by 25 ears disease history, high CK levels, hypertrophic cardiomyopathy with paroxysmal atrial fibrillation without fixed muscle weakness.

Phosphofructokinase deficiency and portal and mesenteric vein thrombosis.

Phosphofructokinase deficiency is a rare disorder with less than 100 reported cases; the contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. The authors present a unique case of portal and mesenteric vein thrombosis in a 43-year-old man with a known case of phosphofructokinase deficiency.

Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis.

Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exercise intolerance. PFKM deficiency is considered as a skeletal muscle glycogenosis, but the relative contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. To elucidate this issue, we have generated mice deficient for PFKM (Pfkm(-/-)). Here, we show that Pfkm(-/-) mice had high lethality around weaning and reduced lifespan, because of the metabolic alterations. In skeletal muscle, including respiratory muscles, the lack of PFK activity blocked glycolysis and resulted in considerable glycogen storage and low ATP content. Although erythrocytes of Pfkm(-/-) mice preserved 50% of PFK activity, they showed strong reduction of 2,3-biphosphoglycerate concentrations and hemolysis, which was associated with compensatory reticulocytosis and splenomegaly. As a consequence of these haematological alterations, and of reduced PFK activity in the heart, Pfkm(-/-) mice developed cardiac hypertrophy with age. Taken together, these alterations resulted in muscle hypoxia and hypervascularization, impaired oxidative metabolism, fiber necrosis, and exercise intolerance. These results indicate that, in GSDVII, marked alterations in muscle bioenergetics and erythrocyte metabolism interact to produce a complex systemic disorder. Therefore, GSDVII is not simply a muscle glycogenosis, and Pfkm(-/-) mice constitute a unique model of GSDVII which may be useful for the design and assessment of new therapies.

Progressive mitral valve thickening and progressive muscle cramps as manifestations of glycogenosis VII (Tarui's Disease).

Progressive heart valve thickening and shrinkage, and progressive muscle cramps have not been reported as manifestations of glycogenosis type VII (Tarui's disease). In a 72-year-old female, Tarui's disease was diagnosed in 1997, initially manifesting as simple partial seizures since 1977, anginal chest pain since 1982 and muscle cramps since 1983. During the following years, low voltage ECG, ectopic supraventricular tachycardia, thickening of the mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy and diastolic dysfunction also developed. Neurological manifestations progressed to complex partial seizures, double vision, reduced tendon reflexes, central facial palsy, bradydiadochokinesia, distal weakness of the upper extremities and worsening muscle cramps. Thickening and shrinkage of the heart valves had further increased at 72 years of age. Progression of Tarui's disease may manifest as progressive thickening of the heart valves due to glycogen storage. Valve thickening may consecutively lead to valve insufficiency, enlargement of the atrium and atrial fibrillation. Progression of neurological manifestations may manifest as worsening muscle cramps.

Tissue-dependent loss of phosphofructokinase-M in mice with interrupted activity of the distal promoter: impairment in insulin secretion.

Phosphofructokinase is a key enzyme of glycolysis that exists as homo- and heterotetramers of three subunit isoforms: muscle, liver, and C type. Mice with a disrupting tag inserted near the distal promoter of the phosphofructokinase-M gene showed tissue-dependent differences in loss of that isoform: 99% in brain and 95-98% in islets, but only 50-75% in skeletal muscle and little if any loss in heart. This correlated with the continued presence of proximal transcripts specifically in muscle tissues. These data strongly support the proposed two-promoter system of the gene, with ubiquitous use of the distal promoter and additional use of the proximal promoter selectively in muscle. Interestingly, the mice were glucose intolerant and had somewhat elevated fasting and fed blood glucose levels; however, they did not have an abnormal insulin tolerance test, consistent with the less pronounced loss of phosphofructokinase-M in muscle. Isolated perifused islets showed about 50% decreased glucose-stimulated insulin secretion and reduced amplitude and regularity of secretory oscillations. Oscillations in cytoplasmic free Ca(2+) and the rise in the ATP/ADP ratio appeared normal. Secretory oscillations still occurred in the presence of diazoxide and high KCl, indicating an oscillation mechanism not requiring dynamic Ca(2+) changes. The results suggest the importance of phosphofructokinase-M for insulin secretion, although glucokinase is the overall rate-limiting glucose sensor. Whether the Ca(2+) oscillations and residual insulin oscillations in this mouse model are due to the residual 2-5% phosphofructokinase-M or to other phosphofructokinase isoforms present in islets or involve another metabolic oscillator remains to be determined.