Hematopoietic stem cell transplantation or enzyme replacement therapy in Gaucher disease type 3.

Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.

X-linked creatine transporter (SLC6A8) deficiency in females: Difficult to recognize, but a potentially treatable disease.

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.

The impact of phenylalanine levels during pregnancy on birth weight and later development in children born to women with phenylketonuria.

Strict metabolic control with dietary treatment during pregnancy is essential for women with phenylketonuria (PKU), as elevated levels of phenylalanine (Phe) are toxic to the developing fetus. Maternal delay in achievement of the recommended Phe level during pregnancy is associated with delayed development of the child. However, the extent to which risk is changed by later or less stringently performed dietary treatment is unclear. The aim of this study was to investigate the impact of Phe levels and time of initiation of a Phe-restricted diet in pregnant women with PKU on birth weight, head circumference and later development of their children. Birth data were obtained from the medical records of women with PKU giving birth in the period 1980-2020. Later development was investigated by interviewing the mothers about their children's development and health. We included 79 children of 41 women with PKU. The women showed good adherence with the diet and had mean blood Phe levels within target range (248 ± 62 µmol/L). The children's development was not affected by fluctuations in the women's Phe levels, that occurred especially in first trimester. Despite maternal Phe levels being within target range, 19 children (26.8%) had low birth weight below 10th percentile. This study indicates that with dietary treatment, the children are born with the same prospect for normal development and health as children born to non-PKU mothers. This is despite maternal fluctuations in the Phe levels during first trimester.

Low skeletal muscle mass and liver fibrosis in children with cerebral palsy.

The purpose of the study was to conduct a nutritional and metabolic assessment of children with cerebral palsy, including an investigation of liver status, body composition, and bone mineral density. In this cross-sectional study we included 22 children with cerebral palsy. By using ultrasound, transient elastography, dual x-ray absorptiometry (DXA) scan, blood samples, anthropometric measurements, and a three-day diet registration, the nutritional and metabolic status was evaluated. Liver fibrosis and steatosis were found in four patients (18.2%), all with severe motor impairments, low skeletal muscle mass, and epilepsy. All patients with liver involvement had normal liver-related blood samples. Decreased bone mineral density was found in 26.3%, and 91.0% had low skeletal muscle mass. Fat mass and muscle mass were significantly lower in the patients with severe motor impairments compared to the patients with less severe motor impairments. Within the children classified as 'underweight' or 'normal' according to body mass index, body fat determined by DXA scan was normal or high in 50% of these patients. CONCLUSIONS: This study is the first to report liver fibrosis and steatosis in children with cerebral palsy. Possible causes of liver fibrosis and/or steatosis are altered body composition with low skeletal muscle mass, decreased mobility and medical drug intake. Further investigations of liver involvement and risk factors are needed. WHAT IS KNOWN: • Children and adolescents with cerebral palsy are at risk of malnutrition and altered body composition, both of which can lead to fatty liver disease. • It is unknown whether children with cerebral palsy are at increased risk of metabolic disturbances such as fatty liver disease. WHAT IS NEW: • Altered body composition and low skeletal muscle mass, regardless of ambulation is present in 91% of the children with cerebral palsy. • Liver fibrosis and/or steatosis were found in 18.2% of the patients. Possible causes are altered body composition, decreased mobility and medical drug intake.

Metabolic assessment in children with neuromuscular disorders shows risk of liver enlargement, steatosis and fibrosis.

AIM: The aim of this study was to conduct a metabolic and nutritional assessment of children with neuromuscular disorders, including the investigation of the liver and bone mineral density. METHODS: In this observational study, we included 44 children with neuromuscular disorders. The nutritional status, bone health and liver were assessed by ultrasound, transient elastography, dual X-ray absorptiometry scan, blood samples, anthropometric measurements and 3-day diet registration. RESULTS: Liver involvement was found in 31.0%: liver enlargement in 7.1%, steatosis in 4.8%, fibrosis in 14.3% and liver enlargement together with steatosis or fibrosis was found in 4.8%. These changes were found in 9/23 patients with Duchenne muscular dystrophy, 4/9 patients with spinal muscular atrophy type II and 0/12 patients with other neuromuscular diagnoses. Low bone mineral density was found in 44.0% of the patients, though the majority used daily vitamin D and calcium supplements. Vitamin D insufficiency or deficiency was found in 22.6%. CONCLUSION: The metabolic assessment in children with neuromuscular disorders shows an increased risk of liver enlargement, steatosis and fibrosis. Possible causes are obesity, decreased mobility, low skeletal muscle mass and for a subgroup the use of glucocorticoids. The findings suggest that monitoring liver function should be part of the nutritional assessment in patients with neuromuscular disorders.

Prolonged fasting-induced hyperketosis, hypoglycaemia and impaired fat oxidation in child and adult patients with spinal muscular atrophy type II.

AIM: This study explored hypoglycaemia and metabolic crises, including hyperketosis, in patients with spinal muscular atrophy (SMA). METHODS: The study comprised four adolescents aged 15-17 and six adults aged 19-37 with SMA type II and eight adult controls aged 21-41, who were recruited by the Rigshospitalet, Denmark, from May 1st to October 30th 2017. We used stable isotope technique and indirect calorimetry to investigate fat and glucose metabolism during a 24-h fast or until hypoglycaemia occurred. RESULTS: All patients with SMA II developed moderate to severe hyperketosis and 60% had symptoms of hypoglycaemia or blood glucose levels below 3 mmol/L. None of the controls developed hyperketosis or hypoglycaemia. Plasma bicarbonate decreased, in line with increased ketone bodies, indicating the start of metabolic acidosis in patients with SMA II. Increased fat production and utilisation were seen in healthy controls during the fasting period, but were absent in patients with SMA II, indicating blunted fat oxidation. CONCLUSION: Low skeletal muscle mass was the best explanation for why patients with SMA II had an increased risk of hypoglycaemia, hyperketosis, metabolic acidosis and disturbed fat and glucose metabolism during fasting. These risks have implications for children facing surgery and those with severe illnesses.

Exercise in muscle disorders: what is our current state?

PURPOSE OF REVIEW: Regular exercise improves muscle and cardiovascular function, which is why exercise is used as an adjuvant treatment in myopathies. In this review, we provide an update on recent exercise studies (from 2016) performed in humans with inherited myopathy. RECENT FINDINGS: Several studies provide new and interesting insight in the field of exercise in myopathies. A retrospective cohort study suggests that exercise may actually increase rate of disease progression in dysferlinopathy, and high intensity exercise, which is normally discouraged in muscle disorders because of the risk of muscle damage, is demonstrated to be an efficient time saving mode of exercise to train patients with facioscapulohumeral muscular dystrophy. Exoskeletons and antigravity trainers are examples of new devices, which provide an opportunity for very weak patients to train. Finally, several studies, including two randomized controlled trials, support the beneficial role of exercise as treatment of myopathy. SUMMARY: The reviewed studies extend previous knowledge about exercise, indicating that exercise is generally safe and well tolerated, and improves functional outcomes in patients with inherited muscle disease. However, recent studies also highlight the fact that the effect of exercise differs with mode of exercise and exercise prescriptions should be disease specific.

Fat and carbohydrate metabolism during exercise in late-onset Pompe disease.

Pompe disease is caused by absence of the lysosomal enzyme acid alpha-glucosidase. It is generally assumed that intra-lysosomal hydrolysis of glycogen does not contribute to skeletal muscle energy production during exercise. However, this hypothesis has never been tested in vivo during exercise. We examined the metabolic response to exercise in patients with late-onset Pompe disease, in order to determine if a defect in energy metabolism may play a role in the pathogenesis of Pompe disease. We studied six adult patients with Pompe disease and 10 healthy subjects. The participants underwent ischemic forearm exercise testing, and peak work capacity was determined. Fat and carbohydrate metabolism during cycle exercise was examined with a combination of indirect calorimetry and stable isotope methodology. Finally, the effects of an IV glucose infusion on heart rate, ratings of perceived exertion, and work capacity during exercise were determined. We found that peak oxidative capacity was reduced in the patients to 17.6 vs. 38.8 ml kg(-1) min(-1) in healthy subjects (p = 0.002). There were no differences in the rate of appearance and rate of oxidation of palmitate, or total fat and carbohydrate oxidation, between the patients and the healthy subjects. None of the subjects improved exercise tolerance by IV glucose infusion. In conclusion, peak oxidative capacity is reduced in Pompe disease. However, skeletal muscle fat and carbohydrate use during exercise was normal. The results indicate that a reduced exercise capacity is caused by muscle weakness and wasting, rather than by an impaired skeletal muscle glycogenolytic capacity. Thus, it appears that acid alpha-glucosidase does not play a significant role in the production of energy in skeletal muscle during exercise.

Treatment Opportunities in Patients With Metabolic Myopathies.

Metabolic myopathies are disorders affecting utilization of carbohydrates or fat in the skeletal muscle. Adult patients with metabolic myopathies typically present with exercise-induced pain, contractures or stiffness, fatigue, and myoglobinuria. Symptoms are related to energy failure. Purpose of review In this review, the current treatment options, including exercise therapy, dietary treatment, pharmacological supplementation, gene transcription, and enzyme replacement therapy, are described. Recent findings Recognition of the metabolic block in the metabolic myopathies has started the development of new therapeutic options. Enzyme replacement therapy with rGAA has revolutionized treatment of early onset Pompe disease. Supplements of riboflavin, carnitine, and sucrose show promise in patients with respectively riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, primary carnitine deficiency, and McArdle disease. Treatment with citric acid cycle intermediates supply by triheptanoin seems promising in patients with glucogenoses, and studies are ongoing in patients with McArdle disease. Summary Treatment of metabolic myopathies primarily relies on avoiding precipitating factors and dietary supplements that bypass the metabolic block. Only a few of the used supplements are validated, and further studies are needed to define efficacious treatments. Further potential treatment targets are molecular therapies aimed at enzyme correction, such as chaperone therapy, gene therapy, gene expression therapy, and enzyme replacement therapies.

Substrate kinetics in patients with disorders of skeletal muscle metabolism.

The main purpose of the following studies was to investigate pathophysiological mechanisms in fat and carbohydrate metabolism and effect of nutritional interventions in patients with metabolic myopathies and in patients with severe muscle wasting. Yet there is no cure for patients with skeletal muscle disorders. The group of patients is heterozygous and this thesis is focused on patients with metabolic myopathies and low muscle mass due to severe muscle wasting. Disorders of fatty acid oxidation (FAO) are, along with myophosphorylase deficiency (McArdle disease), the most common inborn errors of metabolism leading to recurrent episodes of rhabdomyolysis in adults. Prolonged exercise, fasting, and fever are the main triggering factors for rhabdomyolysis in these conditions, and can be complicated by acute renal failure. Patients with low muscle mass are in risk of loosing their functional skills and depend on a wheel chair and respiratory support. We used nutritional interventions and metabolic studies with stable isotope technique and indirect calorimetry in patients with metabolic myopathies and patients with low muscle mass to get information of the metabolism of the investigated diseases, and to gain knowledge of the biochemical pathways of intermediary metabolism in human skeletal muscle. We have shown that patients with fat metabolism disorders in skeletal muscle affecting the transporting enzyme of fat into the mitochondria (carnitine palmitoyltransferase II deficiency) and affecting the enzyme responsible for breakdown of the long-chain fatty acids (very long chain acyl-CoA dehydrogenase deficiency) have a normal fatty acid oxidation at rest, but enzyme activity is too low to increase fatty acid oxidation during exercise. Furthermore, these patients benefit from a carbohydrate rich diet. Oppositely is exercise capacity worsened by a fat-rich diet in these patients. The patients also benefit from IV glucose, however, when glucose is given orally just before exercise, exercise capacity is worsened, most likely due to the sympatho-adrenergt response, that increases heart rate and blocks gluconeogenesis. Substrate turnover studies in patients with McArdle disease and phosphorylase b kinase deficiency showed that palmitate lipolysis, utilization and plasma concentration was higher and total CHO lower in the patients during exercise vs. healthy subjects. In patients with low muscle mass glucose homeostasis is impaired, and our findings showed that these patients are prone to develop hypoglycaemia during prolonged fasting. The following studies emphasize the importance of skeletal muscle in production of energy, both when skeletal muscle lack important metabolic enzymes (metabolic myopathies), and when skeletal muscle mass is low.

Lactate and Energy Metabolism During Exercise in Patients With Blocked Glycogenolysis (McArdle Disease).

CONTEXT: Patients with blocked muscle glycogen breakdown (McArdle disease) have severely reduced exercise capacity compared to healthy individuals and are not assumed to produce lactate during exercise. OBJECTIVES: The objectives were: 1) to quantify systemic and muscle lactate kinetics and oxidation rates and muscle energy utilization during exercise in patients with McArdle disease; and 2) to elucidate the role of lactate formation in muscle energy production. DESIGN AND SETTING: This was a single trial in a hospital. PARTICIPANTS: Participants were four patients with McArdle disease and seven healthy subjects. INTERVENTION: Patients and healthy controls were studied at rest, which was followed by 40 minutes of cycle-ergometer exercise at 60% of the patients' maximal oxygen uptake (∼35 W). MAIN OUTCOME MEASURES: Main outcome measures were systemic and leg skeletal muscle lactate, alanine, fatty acid, and glucose kinetics. RESULTS: McArdle patients had a marked decrease in plasma lactate concentration at the onset of exercise, and the concentration remained suppressed during exercise. A substantial leg net lactate uptake and subsequent oxidation occurred over the entire exercise period in patients, in contrast to a net lactate release or no exchange in the healthy controls. Despite a net lactate uptake by the active leg, a simultaneous unidirectional lactate release was observed in McArdle patients at rates that were similar to the healthy controls. CONCLUSION: Lactate is an important energy source for contracting skeletal muscle in patients with myophosphorylase deficiency. Although McArdle patients had leg net lactate consumption, a simultaneous release of lactate was observed at rates similar to that found in healthy individuals exercising at the same very low workload, suggesting that lactate formation is mandatory for muscle energy generation during exercise.

[Juvenile asymmetrical segmental spinal muscular atrophy]. / Juvenil asymmetrisk segmental spinal muskelatrofi. En sjaelden form for motorneuronsygdom.

We report the case of a man who had an insidious onset of asymmetrical distal muscle weakness of the upper extremity at the age of 17. Objective findings were 1) muscular atrophy of calf and forearm flexor muscles and intrinsic hand muscles; 2) fasciculations; and 3) hand tremor. EMG and muscle biopsy showed neurogenic changes. MRI of the medulla and plasma creatine kinase were normal. Genetic testing for SMA-III was negative.

[Incomplete Kawasaki syndrome with a coronary artery aneurysm in an infant].

We report a four-month-old boy with incomplete Kawasaki syndrome. He developed a coronary artery aneurysm. Incomplete Kawasaki syndrome is rare in Denmark, and only reported in five patient cases in the past 25 years. It is difficult to diagnose Kawasaki disease; early diagnosis and treatment reduces the risk for cardiac sequel. In lack of diagnostic test, we recommend that the algorithm from the American Heart Association to diagnose incomplete Kawasaki is implemented in Denmark. The algorithm is based on classic clinical features, echocardiography and laboratory findings.

Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial.

OBJECTIVE: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. METHODS: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise. RESULTS: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise. CONCLUSION: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.

Fat metabolism during exercise in patients with mitochondrial disease.

OBJECTIVE: To determine whether patients with defects of the respiratory chain have metabolic adaptations that promote a preferential use of fats or carbohydrates, similar to what is observed in metabolic myopathies affecting glycolysis or fat oxidation. DESIGN: Causation and case-control study. Fat metabolism was determined by means of indirect calorimetry and stable isotope technique in patients and healthy subjects. Patients carried various types and loads (mean [SE], 72% [5%]) of mitochondrial DNA (mtDNA) mutations in skeletal muscle. All subjects exercised at the same absolute workload (mean [SE], 65 [10] W), corresponding to 72% (in patients) and 30% (in healthy subjects) of maximum oxygen consumption. SETTING: Neuromuscular research unit. PARTICIPANTS: Ten patients with mtDNA mutations and 10 sex-matched healthy subjects. MAIN OUTCOME MEASURES: Fat turnover, plasma concentrations of palmitate and total free fatty acids, glucose mobilization, and total carbohydrate oxidation. RESULTS: Fat turnover and plasma concentrations of palmitate and total free fatty acids were similar in patients and healthy subjects at rest and during exercise. In line with the higher relative workload of the patients, glucose mobilization and total carbohydrate oxidation were higher in the patients compared with the healthy subjects. CONCLUSION: During moderate-intensity exercise, the balance between fat and carbohydrate use in patients with mtDNA mutations matches that seen in healthy subjects, indicating that manipulating dietary fat and carbohydrate content is not a feasible therapeutic option to improve exercise intolerance in these disorders.

Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy.

Exercise programs have been shown to increase strength and endurance in patients with myopathic disorders. The authors investigated the effect of aerobic training in patients with facioscapulohumeral dystrophy (FSHD). Twelve weeks of low-intense aerobic exercise improved maximal oxygen uptake and workload with no signs of muscle damage. The authors conclude that aerobic training is a safe method to increase exercise performance in patients with FSHD.