Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5-year follow-up study.

The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large- and small-fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty-nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z-scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow-up (54% vs. 37%). The overall mean NCS Z-score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z-scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 ± 4.8 to 4.3 ± 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.

Clinical and muscle biopsy findings in Norwegian paediatric patients with limb girdle muscular dystrophy 2I.

AIM: To describe patients diagnosed with limb girdle muscular dystrophy 2I (LGMD2I) in our paediatric departments between 2004 and 2012. METHODS: The hospital charts of 17 patients presenting for evaluation at a mean age of 7.8 years (range 1-13 years) were retrospectively reviewed. RESULTS: With one exception, all patients were homozygous for the common mutation c.826C>A in the FKRP gene. Three patients experienced transient pronounced weakness as toddlers. Fatigue and muscle pain were most prominent, weakness less so, in children presenting at an older age. The degree of severity varied substantially. In certain cases, increased creatine kinase was an incidental finding. All walked independently by 18 months. When last evaluated at a mean age of 14.3 years (range 3.5-18 years), five patients were part-time wheelchair users. One patient was then treated for a cardiomyopathy. Creatine kinase was consistently increased, except presymptomatic in one patient. Muscle biopsies showed focal acute and chronic myopathic changes and pathological expression of α-dystroglycan. No consistent relationship between clinical function and the degree of morphological pathology was found. CONCLUSION: LGMD2I is a relevant differential diagnosis when creatine kinase is increased in children presenting with fatigue, muscle pain and sometimes weakness.

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

OBJECTIVES: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. METHODS: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. RESULTS: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST. CONCLUSIONS: Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).

Cardiac resynchronization therapy improves minute ventilation/carbon dioxide production slope and skeletal muscle capillary density without reversal of skeletal muscle pathology or inflammation.

AIMS: We evaluated the effects of cardiac resynchronization therapy (CRT) on skeletal muscle pathology and inflammation in patients with heart failure. METHODS AND RESULTS: Stable patients (n = 21, 14 males, mean age 70 ± 7 years) with symptomatic heart failure (mean left ventricular ejection fraction 24 ± 6%) and an indication for CRT were included. Ergospirometry, skeletal muscle open biopsy, and blood sampling were performed prior to implantation and after 6 months of CRT. After CRT there was a reduction in both left ventricular end-diastolic diameter (LVEDD; 6.8 ± 0.8 vs. 6.3 ± 0.7 cm, P < 0.001) and native QRS duration (D) minus biventricular paced QRSD (172.9 ± 23 vs. 136.3 ± 23 ms, P ≤ 0.001). These changes were associated with an increase in peak slope oxygen uptake (consumption) (VO2) (13.3 ± 2.2 vs. 14.5 ± 2.6 mL/kg/min, P = 0.07) and an improvement in the minute ventilation/carbon dioxide production slope (VE/VCO2) slope (41.6 ± 7.4 vs. 39.1 ± 5.6, P = 0.012). There were no statistically significant changes in levels of pro-inflammatory cytokines, in mediators of mitochondrial biosynthesis or skeletal muscle pathology, except for an increase in skeletal muscle capillary density (4.5 ± 2.4 vs. 7.7 ± 3.3%, P = 0.002). Both the reduction of QRS duration and the increase in peak VO2 correlated significantly with the change in mitochondrial density (r = 0.57, P = 0.008 and r = 0.54, P = 0.027, respectively). CONCLUSION: Cardiac resynchronization therapy, with improved functional status and reduced LVEDD resulted in increased peak VO2, improvement in VE/VCO2 slope and capillary density in skeletal muscle, with no reduction in systemic pro-inflammatory cytokines, increase in intramuscular levels of mediators of mitochondrial biosynthesis or improvement in skeletal muscle ultrastructure per se. ClinicalTrials.gov Identifier: NCT01019915.

Surgical strategy in grade II astrocytoma: a population-based analysis of survival and morbidity with a strategy of early resection as compared to watchful waiting.

BACKGROUND: We recently demonstrated a survival benefit of early resection in unselected diffuse low-grade gliomas (LGG). However, heterogeneity within the LGG entity warrants investigation in a homogenous subgroup. Astrocytoma represents the largest subgroup of LGG, and is characterized by diffuse growth and inferior prognosis. We aimed to study the effects of early resection compared to biopsy and watchful waiting in this subgroup. METHODS: Patient data was retrospectively reviewed in two neurosurgical departments with regional referral practice. In one hospital, initial diagnostic biopsies and watchful waiting was favored, while early resections guided with three-dimensional (3D) ultrasound were advocated in the other hospital. This created a natural experiment with patient management heavy influenced by residential address. In the hospitals' histopathology databases, all adult patients diagnosed with supratentorial LGG from 1998 through 2009 were screened (n = 169) and underwent blinded histopathological review. Histopathological review concluded with 117 patients with grade II astrocytomas that were included in the present study. The primary end-point was overall survival assessed by a regional comparison. RESULTS: Early resections were performed in 51 (82 %) versus 12 (22 %) patients in the respective hospitals (p < 0.001). The two patient populations were otherwise similar. Median survival was 9.7 years (95 % CI 7.5-11.9) if treated in the hospital favoring early resections compared to 5.6 years (95 % CI 3.5-7.6) if treated at the hospital favoring biopsy and watchful waiting (p = 0.047). No difference in surgical-related neurological morbidity was seen (p = 0.843). CONCLUSIONS: Early 3D ultrasound guided resections improve survival, apparently without increased morbidity, compared to biopsy and watchful waiting in patients with diffuse World Health Organization (WHO) grade II astrocytomas.

Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas.

CONTEXT: There are no controlled studies on surgical treatment of diffuse low-grade gliomas (LGGs), and management is controversial. OBJECTIVE: To examine survival in population-based parallel cohorts of LGGs from 2 Norwegian university hospitals with different surgical treatment strategies. DESIGN, SETTING, AND PATIENTS: Both neurosurgical departments are exclusive providers in adjacent geographical regions with regional referral practices. In hospital A diagnostic biopsies followed by a "wait and scan" approach has been favored (biopsy and watchful waiting), while early resections have been advocated in hospital B (early resection). Thus, the treatment strategy in individual patients has been highly dependent on the patient's residential address. Histopathology specimens from all adult patients diagnosed with LGG from 1998 through 2009 underwent a blinded histopathological review to ensure uniform classification and inclusion. Follow-up ended April 11, 2011. There were 153 patients (66 from the center favoring biopsy and watchful waiting and 87 from the center favoring early resection) with diffuse LGGs included. MAIN OUTCOME MEASURE: The prespecified primary end point was overall survival based on regional comparisons without adjusting for administered treatment. Results Initial biopsy alone was carried out in 47 (71%) patients served by the center favoring biopsy and watchful waiting and in 12 (14%) patients served by the center favoring early resection (P < .001). Median follow-up was 7.0 years (interquartile range, 4.5-10.9) at the center favoring biopsy and watchful waiting and 7.1 years (interquartile range, 4.2-9.9) at the center favoring early resection (P=.95). The 2 groups were comparable with respect to baseline parameters. Overall survival was significantly better with early surgical resection (P=.01). Median survival was 5.9 years (95% CI, 4.5-7.3) with the approach favoring biopsy only while median survival was not reached with the approach favoring early resection. Estimated 5-year survival was 60% (95% CI, 48%-72%) and 74% (95% CI, 64%-84%) for biopsy and watchful waiting and early resection, respectively. In an adjusted multivariable analysis the relative hazard ratio was 1.8 (95% CI, 1.1-2.9, P=.03) when treated at the center favoring biopsy and watchful waiting. CONCLUSIONS: For patients in Norway with LGG, treatment at a center that favored early surgical resection was associated with better overall survival than treatment at a center that favored biopsy and watchful waiting. This survival benefit remained after adjusting for validated prognostic factors.

Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities.

BACKGROUND: To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). METHODS: Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. RESULTS: In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbA1c in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. CONCLUSIONS: The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy.

Neuropathological changes in the brain of pigs with acute liver failure.

OBJECTIVE: Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. MATERIALS AND METHODS: Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. RESULTS: Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. CONCLUSIONS: Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.

A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.

This report describes two brothers, both deceased in infancy, with severe depletion of mitochondrial DNA (mtDNA) in muscle tissue. Both had feeding difficulties, failure to thrive, severe muscular hypotonia and lactic acidosis. One of the boys developed a renal proximal tubulopathy. A novel homozygous c.686 G-->T missense mutation in the RRM2B gene, encoding the p53-inducible ribonucleotide reductase subunit (p53R2), was identified. This is the third report on mutations in RRM2B associated with severe mtDNA depletion, which further highlights the importance of de novo synthesis of deoxyribonucleotides (dNTPs) for mtDNA maintenance.

Clinicopathologic factors and nuclear morphometry as independent prognosticators in KIT-positive gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms found in the gastrointestinal tract. The purpose of this study was to evaluate whether morphometric measurements could complement tumor size and mitotic activity in risk evaluation. Nuclear roundness and ellipse axis ratio were found to correlate with tumor size, mitotic activity, nuclear atypia, and hemorrhage. Morphometric variables in 422 GISTs were significant for overall survival in univariate analyses but did not retain independent significance in multivariate analyses incorporating mitotic count and tumor size. Traditional variables, together with sex, location of primary tumor, and nuclear atypia, seem to be the best parameters for prognostic evaluation.

Limb girdle muscular dystrophy type 2I: No correlation between clinical severity, histopathology and glycosylated α-dystroglycan levels in patients homozygous for common FKRP mutation.

Limb girdle muscular dystrophy type 2I (LGMD2I) is a progressive disorder caused by mutations in the FuKutin-Related Protein gene (FKRP). LGMD2I displays clinical heterogeneity with onset of severe symptoms in early childhood to mild calf and thigh hypertrophy in the second or third decade. Patients homozygous for the common FKRP mutation c.826C>A (p.Leu276Ile) show phenotypes within the milder end of the clinical spectrum. However, this group also manifests substantial clinical variability. FKRP deficiency causes hypoglycosylation of α-dystroglycan; a component of the dystrophin associated glycoprotein complex. α-Dystroglycan hypoglycosylation is associated with loss of interaction with laminin α2, which in turn results in laminin α2 depletion. Here, we have attempted to clarify if the clinical variability seen in patients homozygous for c.826C>A is related to alterations in muscle fibre pathology, α-DG glycosylation levels, levels of laminin α2 as well as the capacity of α-DG to bind to laminin. We have assessed vastus lateralis muscle biopsies from 25 LGMD2I patients harbouring the c.826C>A/c.826C>A genotype by histological examination, immunohistochemistry and immunoblotting. No clear correlation was found between clinical severity, as determined by self-reported walking function, and the above features, suggesting that more complex molecular processes are contributing to the progression of disease.

A new non-craniotomy model of subarachnoid hemorrhage in the pig: a pilot study.

Subarachnoid hemorrhage (SAH) from rupture of an intracranial arterial aneurysm is a devastating disease affecting young people, with serious lifelong disability or death as a frequent outcome. Large animal models that exhibit all the cardinal clinical features of human SAH are highly warranted. In this pilot study we aimed to develop a non-craniotomy model of SAH in pigs suitable for acute intervention studies. Six Norwegian Landrace pigs received advanced invasive hemodynamic and intracranial pressure (ICP) monitoring. The subarachnoid space, confirmed by a clear cerebrospinal fluid (CSF) tap, was reached by advancing a needle below the ocular bulb through the superior orbital fissure and into the interpeduncular cistern. SAH was induced by injecting 15 mL of autologous arterial blood into the subarachnoid space. Macro- and microanatomical investigations of the pig brain showed a typical blood distribution consistent with human aneurysmal SAH (aSAH) autopsy data. Immediately after SAH induction ICP sharply increased with a concomitant reduction in cerebral perfusion pressure (CPP). ICP returned to near normal values after 30 min, but increased subsequently during the experimental period. Signs of brain edema were confirmed by light microscopy post-mortem. None of the animals died during the experimental period. This new transorbital injection model of SAH in the pig mimics human aSAH and may be suitable for acute intervention studies. However, the model is technically challenging and needs further validation.

Carcinoid tumour metastatic to the orbit with infiltration to the extraocular orbital muscle.

Ninety-three percent of symptomatic patients with small intestinal carcinoid tumours have metastases. The most common sites of metastases are lymph nodes and liver. Orbital metastases have rarely been described and the majority of them involve the choroid rather than extraocular orbital structures. We report a patient who developed proptosis, impairment of vision and reduced ocular motility on the left side, eighteen months after operation for primary intestinal carcinoid tumour with hepatic metastases. CT and MR studies revealed the tumour mass infiltrating the inferior rectus muscle. Biopsy examined by imprint and frozen section showed tumour consistent with metastatic carcinoid. The tumour was removed. HE and staining for cytokeratin, chromogranin, NSE, serotonin, somatostatin and gastrin showed that the tumour tissue corresponded to that of the primary intestinal carcinoid tumour. Intramuscular orbital metastasis from a carcinoid tumour is a rare occurrence. Diagnosis may be difficult, especially where no evidence of primary carcinoid tumour is present. Metastatic orbital carcinoid should be suspected in patients with a clinical history of carcinoid tumour and who develop ocular complaints and mass lesion in the orbit. Complete surgical removal of the tumour is important for optimal restitution of vision and eye movements.

Statin-associated myopathy with normal creatine kinase levels. Case report from a Norwegian family.

Trøseid M, Henriksen OA, Lindal S. Statin-associated myopathy with normal creatine kinase levels - case report from a Norwegian family. APMIS 2005;113:635-7. Recent reports suggest that statins may cause myopathy with normal creatine kinase levels. We describe four related patients with statin-associated muscle symptoms and normal creatine kinase levels. In two out of the four patients (mother and son), pathological findings on EMG suggested myopathy, and muscle biopsies showed evidence of mitochondrial pathology. A third patient (daughter) had slight myopathic findings on EMG and muscle biopsy, but not enough to be classified as pathological. In a fourth patient, there were no pathological findings. Creatine kinase levels were normal and symptoms diminished after discontinuation of drugs in all four patients. Our findings are consistent with other reports of statin-associated myopathy with normal creatine kinase levels. An inherited vulnerability, possibly a mitochondrial pathology, might cause or aggravate symptoms in some patients.

Effect of exercise training on skeletal muscle fibre characteristics in men with chronic heart failure. Correlation between skeletal muscle alterations, cytokines and exercise capacity.

BACKGROUND: In patients with congestive heart failure (CHF) there is a shift from aerobic type I muscle fibres to less aerobic type II fibres. Exercise training has been shown to have beneficial effects on exercise performance, peripheral pathology and the neurohumoral profile in stable patients with CHF. This study evaluated the effect of a 3 month exercise training program on skeletal muscle characteristics and the correlation of these to cytokines and exercise capacity in CHF patients. METHODS: Skeletal muscle biopsies for enzyme-histochemical analysis were performed in 15 CHF patients in New York Heart Association classes II-III, with a mean ejection fraction of 33+/-5% before and after a 12 week training period. The patients were trained for 30 min, five times a week at 80% of the peak heart rate achieved at baseline ergometer cycle test. Fifteen healthy men were used as controls. Plasma samples were examined by enzyme immunoassays for levels of pro-inflammatory cytokines. RESULTS: (a) At baseline we found muscle atrophy in five of the patients. The percent area of type I fibres (40.7+/-12.0 vs. 56.4+/-11.0%, P<0.05) and the thickness of type IIA (56.10+/-7.8 vs. 71.6+/-11.9 microm, P<0.001) and B-fibres (49.0+/-8.9 vs. 63.9+/-10.6 microm, P<0.001) were reduced, whereas the percent area of type IIA fibres (52.1+/-13.3 vs. 36.4+/-9.9%, P<0.05) was increased in heart failure patients compared to healthy controls. There was a modest correlation between fibre thickness and the level of interleukin 6 (r=-0.657, P=0.008). (b) After exercise training there was a reduction in muscle area examined by light-microscopy, measured as a percentage of field (-2.7, P=0.003) with an concomitant increase in interstitium. This reduction correlated to the increase in the 6-min walk test (r=-0.558, P=0.031). The thickness of type IIB fibres increased (+5.6 microm, P=0.068) and the area of type I fibres decreased (-6.1%, P=0.062). CONCLUSIONS: Patients with CHF have a relatively increased area of type IIA fibres and a relatively decreased area of type I fibres compared to healthy individuals. The thickness of type IIA and type IIB fibres is decreased compared to normal individuals. A modest negative correlation between the level of interleukin 6 and fibre thickness at baseline, suggests that inflammatory cytokines may be involved in the pathogenesis of the CHF related myopathy. A significant correlation between the reduction of muscle area, with increased interstitum, and the increase in the 6-min walk test may indicate that the improvement is due to increased capillary density permitting better flow reserve to exercising muscles.

Surgical strategies in low-grade gliomas and implications for long-term quality of life.

Reports on long-term health related quality of life (HRQL) after surgery for World Health Organization grade II diffuse low-grade gliomas (LGG) are rare. We aimed to compare long-term HRQL in two hospital cohorts with different surgical strategies. Biopsy and watchful waiting was favored in one hospital, while early resections guided with three-dimensional (3D) ultrasound was favored in the other. With a population-based approach 153 patients with histologically verified LGG treated from 1998-2009 were included. Patients still alive were contacted for HRQL assessment (n=91) using generic (EQ-5D; EuroQol Group, Rotterdam, The Netherlands) and disease specific (EORTC QLQ-C30 and BN20; EORTC Quality of Life Department, Brussels, Belgium) questionnaires. Results on HRQL were available in 79 patients (87%), 25 from the hospital that favored biopsy and 54 from the hospital that favored early resection. Among living patients there was no difference in EQ-5D index scores (p=0.426). When imputing scores defined as death (zero) in patients dead at follow-up, a clinically relevant difference in EQ-5D score was observed in favor of early resections (p=0.022, mean difference 0.16, 95% confidence interval 0.02-0.29). In EORTC questionnaires pain, depression and concern about disruption in family life were more common with a strategy of initial biopsy only (p=0.043, p=0.032 and p=0.045 respectively). In long-term survivors an aggressive surgical approach using intraoperative 3D ultrasound image guidance in LGG does not lower HRQL compared to a more conservative surgical approach. This finding further weakens a possible role for watchful waiting in LGG.

Clinical impact of persistent hyperCKemia in a Norwegian general population: a case-control study.

In this case-control study we assessed the clinical impact of persistent hyperCKemia in a Norwegian general population. HyperCKemia was defined according to the NORIP- references (women 35-210 U/L, men <50 years 50-400 U/L, and men ≥50 years 40-280 U/L). We compared the frequency of muscular symptoms and function, neuromuscular diseases and risk factors between 120 cases with persistent hyperCKemia and 130 age- and sex-matched controls with normal CK values, all recruited from the single-centre, population-based prospective Tromsø Study. The participants underwent a standardized interview assessing muscle symptoms, physical activity, use of statins and presence of other CK risk factors, prior to clinical neurological and neurophysiological examination. Knee extensor muscle strength (Cybex NORM dynamometer) and dominant hand grip strength (Martin Vigorimeter) was assessed. A total of 85 cases (71%) reported either muscle pain, muscle stiffness or cramps, compared to 70 controls (54%) (p=0.017) There were no differences in muscle strength between the groups. In men, weight, Body Mass Index and muscle symptoms were significantly higher in the group with persistent hyperCKemia. In women, no differences between the groups were detected. Use of statins was similar in cases and controls. We diagnosed 3 women with previously unknown myopathy, all in the group with persistent hyperCKemia. This study support that CK may be used as a marker of muscular symptoms in the general population.

A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with "idiopathic" camptocormia or bent spine syndrome (BSS).