Hypokalemic periodic paralysis: a 3-year follow-up study.

BACKGROUND AND OBJECTIVES: Primary hypokalemic periodic paralysis (HypoPP) is an inherited channelopathy most commonly caused by mutations in CACNA1S. HypoPP can present with different phenotypes: periodic paralysis (PP), permanent muscle weakness (PW), and mixed weakness (MW) with both periodic and permanent weakness. Little is known about the natural history of HypoPP. METHODS: In this 3-year follow-up study, we used the MRC scale for manual muscle strength testing and whole-body muscle MRI (Mercuri score) to assess disease progression in individuals with HypoPP-causing mutations in CACNA1S. RESULTS: We included 25 men (mean age 43 years, range 18-76 years) and 12 women (mean age 42 years, range 18-76 years). Two participants were asymptomatic, 21 had PP, 12 MW, and two PW. The median number of months between baseline and follow-up was 42 (range 26-52). Muscle strength declined in 11 patients during follow-up. Four of the patients with a decline in muscle strength had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Fat replacement of muscles increased in 27 patients during follow-up. Eight of the patients with increased fat replacement had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. DISCUSSION: The study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis.

Quantitative Muscle MRI and Clinical Findings in Women With Pathogenic Dystrophin Gene Variants.

Objective: To explore fat replacement, muscle strength, and clinical features in women heterozygous for a pathogenic DMD variant, we prospectively examined 53 women, assuming that some of these women-despite of the recessive X-linked inheritance-manifested clinical symptoms. Methods: We performed a cross-sectional observational study using MRI and stationary dynamometry of lower extremities, extracted blood muscle biomarkers, and investigated subjective complaints. Results were compared with 19 healthy women. Results: DMD variant carriers were weaker and had higher fat fractions than controls in all investigated muscle groups (p < 0.02). Fat fractions were 18% in carriers vs. 11% in controls in thighs (p = 0.008), and 15 vs. 11% in calf muscles (p = 0.032). Seventy-two percent had fat fractions deviating from controls by two standard deviations (SDs) in one or more of the 16 investigated muscle groups. On strength testing, 40% of the carriers had results deviating from control muscle strength by two SDs in one or more dynamometry assessments. Forty-three carriers (81%) had either reduced muscle strength (<2 SDs from control mean) and/or elevated muscle fat fraction (>2 SDs from control mean). Thirty of these had subjective symptoms. Blood creatine kinase and myoglobin were elevated in 57% of the carriers. Conclusion: Using quantitative methods, this study shows that both clinically symptomatic and asymptomatic women with pathogenic DMD variants show a high prevalence of muscle affection. Longitudinal studies in female carriers of pathogenic DMD variants are needed to follow the evolution of these changes.

Energy metabolism during exercise in patients with ß-enolase deficiency (GSDXIII).

AIM: To investigate the in vivo skeletal muscle metabolism in patients with ß-enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion. METHODS: Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO2max) and a 1-hour submaximal cycle test at an intensity of 65% to 75% of VO2max. The patients repeated the submaximal exercise after 2 days, where they received a 10% iv-glucose supplementation. RESULTS: Patients had lower VO2max than healthy controls, and two of three patients had to stop prematurely during the intended 1-hour submaximal exercise test. During nonischemic forearm test, all patients were able to produce lactate in normal amounts. Glucose infusion had no effect on patients' exercise capacity. CONCLUSIONS: Patients with GSDXIII experience exercise intolerance and episodes of myoglobinuria, even to the point of needing renal dialysis, but still retain an almost normal anaerobic metabolic response to submaximal intensity exercise. In accordance with this, glucose supplementation did not improve exercise capacity. The findings show that GSDXIII, although causing episodic rhabdomyolysis, is one of the mildest metabolic myopathies affecting glycolysis.

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.

Contractile properties are impaired in congenital myopathies.

The ratio between muscle strength and muscle cross-sectional area is called the specific force. Fatty replacement of muscles is seen in many myopathies, affecting the specific force, without necessarily affecting the ability of the remaining muscle fibers to contract. This ability is called the contractility and is the ratio between muscle strength and the lean muscle cross-sectional area, i.e. the contractile cross-sectional area. We hypothesized that contractility is disrupted in patients with congenital myopathy, because of defects in contractile proteins of the sarcomere. Peak torque across ankle and knee joints was measured by isokinetic dynamometry in 16 patients with congenital myopathy and 13 healthy controls. Five patients only participated partially in the dynamometer measurements due to severe muscle weakness. Dixon MRI technique was used to quantify muscle fat fractions and calculate cross-sectional area. Patients with congenital myopathy had lower cross-sectional area in all muscle groups (P<0.01), higher fat fraction (P<0.01) and less strength (P<0.005) in all studied muscle groups. Their fat content was more than doubled and peak torque lower than half that in healthy controls. Muscle contractility was reduced (P<0.01) in three of four patient muscle groups. In conclusion, muscle contractility was reduced in patients with congenital myopathy, across different diagnoses, and was independent of the level of muscle fat fraction, suggesting that intrinsic defects of the myocyte are responsible for reduced contractility.

Permanent muscle weakness in hypokalemic periodic paralysis.

OBJECTIVE: To map the phenotypic spectrum in 55 individuals with mutations in CACNA1S known to cause hypokalemic periodic paralysis (HypoPP) using medical history, muscle strength testing, and muscle MRI. METHODS: Adults with a mutation in CACNA1S known to cause HypoPP were included. Medical history was obtained. Muscle strength and MRI assessments were performed. RESULTS: Fifty-five persons were included. Three patients presented with permanent muscle weakness and never attacks of paralysis. Seventeen patients presented with a mixed phenotype of periodic paralysis and permanent weakness. Thirty-one patients presented with the classical phenotype of periodic attacks of paralysis and no permanent weakness. Four participants were asymptomatic. Different phenotypes were present in 9 of 18 families. All patients with permanent weakness had abnormal replacement of muscle by fat on MRI. In addition, 20 of 35 participants with no permanent weakness had abnormal fat replacement of muscle on MRI. The most severely affected muscles were the paraspinal muscles, psoas, iliacus, the posterior muscles of the thigh and gastrocnemius, and soleus of the calf. Age was associated with permanent weakness and correlated with severity of weakness and fat replacement of muscle on MRI. CONCLUSIONS: Our results show that phenotype in individuals with HypoPP-causing mutations in CACNA1S varies from asymptomatic to periodic paralysis with or without permanent muscle weakness or permanent weakness as sole presenting picture. Variable phenotypes are found within families. Muscle MRI reveals fat replacement in patients with no permanent muscle weakness, suggesting a convergence of phenotype towards a fixed myopathy with aging.

Growth and differentiation factor 15 as a biomarker for mitochondrial myopathy.

OBJECTIVE: We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other myopathies. METHODS: Serum GDF-15 was measured in 28 patients with mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls. RESULTS AND CONCLUSIONS: Our findings indicate that elevated GDF-15 can distinguish patients with mitochondrial myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect.

Fat oxidation is impaired during exercise in lipin-1 deficiency.

OBJECTIVE: To investigate substrate metabolism during exercise in an adult with lipin-1 deficiency, an inherited defect in lipid homeostasis, and to study the effect of glucose supplementation on his exercise tolerance. METHODS: We studied a 48-year-old man with lipin-1 deficiency and 2 healthy men. The patient has exercise intolerance and monthly episodes of rhabdomyolysis. All participants performed a submaximal exercise test while total fatty acid oxidation (FAO) and palmitate oxidation rate were assessed by stable isotope technique and indirect calorimetry. On another day, the patient was infused with 10% glucose (410 mL/h) and repeated the exercise. On the third and fourth visits, he was randomized in a double-blind manner to drink a supplement of glucose (soft drink 2% concentration) or placebo (soft drink: aspartame, acesulfame-K) before and during exercise. RESULTS: Mean FAO and palmitate oxidation rate during exercise were lower in the patient vs controls: 431 vs 1,271 and 1912 µmol/min and 122 vs 191 and 212 µmol/min. Plasma fatty acid concentration was lower in the patient during exercise than in controls: 477 vs 643 and 630 µmol/L. The patient's exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale). CONCLUSION: In this adult lipin-1-deficient patient, FAO was reduced, which was associated with no increase in plasma free fatty acids during submaximal exercise, and his exercise capacity improved with continuous ingestion of high-dose glucose. CLINICALTRIALSGOV IDENTIFIER: NCT02635269.

Expanding the phenotype of filamin-C-related myofibrillar myopathy.

We report three patients with a rare filamin C myofibrillar myopathy. They present with atypical symptoms that expand the phenotype of filaminopathy. The new findings are progressive contractures of muscles surrounding the temporomandibular joint, detailed single myofiber histology findings and demonstration of severe affection of paraspinal muscles on MRI.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.