Insomnia and sleep-disordered breathing in FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020).

Limb-girdle muscular dystrophy R9 (LGMDR9) is a progressive and disabling genetic muscle disease. Sleep is relevant in the patient care as it impacts on health, functioning, and well-being. LGMDR9 may potentially affect sleep by physical or emotional symptoms, myalgia, or sleep-disordered breathing (SDB) through cardiorespiratory involvement. The objective was to investigate the occurrence of insomnia and unrecognized or untreated SDB in LGMDR9, associated factors, and relationships with fatigue and health-related quality of life (HRQoL). All 90 adults in a Norwegian LGMDR9 cohort received questionnaires on sleep, fatigue, and HRQoL. Forty-nine of them underwent clinical assessments and 26 without mask-based therapy for respiration disorders additionally underwent polysomnography (PSG) and capnometry. Among 77 questionnaire respondents, 31% received mask-based therapy. The prevalence of insomnia was 32% of both those with and without such therapy but was significantly increased in fatigued respondents (54% vs 21%). Insomnia levels correlated inversely with mental HRQoL. Among 26 PSG candidates, an apnea-hypopnea index (AHI) ≥ 5/h was observed in 16/26 subjects (≥ 15/h in 8/26) with median 6.8 obstructive apneas and 0.2 central apneas per hour of sleep. The AHI was related to advancing age and an ejection fraction < 50%. Sleep-related hypoventilation was detected in one subject. Fatigue severity did not correlate with motor function or nocturnal metrics of respiration or sleep but with Maximal Inspiratory Pressure (r = - 0.46). The results indicate that insomnia and SDB are underrecognized comorbidities in LGMDR9 and associated with HRQoL impairment and heart failure, respectively. We propose an increased attention to insomnia and SDB in the interdisciplinary care of LGMDR9. Insomnia and pulmonary function should be examined in fatigued patients.

Health-Related Quality of Life in FKRP-Related Limb-Girdle Muscular Dystrophy R9.

BACKGROUND: Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. OBJECTIVE: To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. METHODS: Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, and 14 months and measures of fatigue and sleep quality at 9 months. RESULTS: HRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p≤0.006) except mental health in males (p = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively. CONCLUSIONS: The 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9.

Epidemiology and natural history in 101 subjects with FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020).

We aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide. Of the 153 subjects, 134 (88 %) were homozygous for FKRP c.826C>A giving a carrier frequency for this variant of 1/101 in Norway. Clinical questionnaires and patient notes from 101 subjects, including 88 c.826C>A homozygotes, were reviewed, and 43/101 subjects examined clinically. Age of onset in c.826C>A homozygotes demonstrated a bimodal distribution. Female subjects showed an increased cumulative probability of wheelchair dependency and need for ventilatory support. Across the cohort, the need for ventilatory support preceded wheelchair dependency in one third of the cases, usually due to sleep apnea. In c.826C>A homozygotes, occurrence of cardiomyopathy correlated positively with male gender but not with age or disease stage. This study highlights novel gender differences in both loss of ambulation, need for ventilatory support and the development of cardiomyopathy. Our results confirm the need for vigilance in order to detect respiratory insufficiency and cardiac involvement, but indicate that these events affect males and females differently.

Novel mutations in the HADHB gene causing a mild phenotype of mitochondrial trifunctional protein (MTP) deficiency.

Mitochondrial trifunctional protein (MTP) deficiency is an ultrarare hereditary recessive disorder causing a broad spectrum of phenotypes with lethal infantile cardiomyopathy at the most severe end. Attenuated forms with polyneuropathy have been reported combined with myoglobinuria or rhabdomyolysis as key features. We here report three young adults (two siblings) in which three variants in the HADHB-gene were identified. All three cases had a similar mild phenotype with axonal neuropathy and frequent intermittent weakness episodes but without myoglobinuria. Special dietary precautions were recommended to minimize complications especially during infections and other catabolic states. MTP deficiency is therefore an important differential diagnosis in patients with milder fluctuating neuromuscular symptoms. Take­home message: Axonal neuropathy and recurrent muscular weakness without concomitant rhabdomyolysis may be due to MTP deficiency.

Kennedy disease in two sisters with biallelic CAG expansions of the androgen receptor gene.

We present a retrospective 21-year follow-up of two sisters with X-linked biallelic CAG expansions in the androgen receptor (AR) gene causing Kennedy disease. Two sisters inherited CAG expansions from their mother who was a carrier and their father who had Kennedy disease. Genetic testing revealed alleles comprising 43/45, and 43/43 CAG repeats in the younger and older sister, respectively. They were referred to a neurologist for further evaluation. Both reported similar symptoms with chronic backache, pain and cramps in upper- and lower extremities, and fasciculations in their faces and extremities. Neurological examination demonstrated postural hand tremor in both and EMG revealed chronic neurogenic changes. Reevaluation of the patients at ages 74 and 83 showed slight progression of clinical manifestations. As opposed to male patients, these two females showed minimal disease progression and have maintained normal level of function into old age.

The prevalence of hereditary neuromuscular disorders in Northern Norway.

AIM: To investigate the point prevalence of hereditary neuromuscular disorders on January 1, 2020 in Northern Norway. METHODS: From January 1, 1999, until January 1, 2020, we screened medical and genetic hospital records in Northern Norway for hereditary neuromuscular disorders. RESULTS: We identified 542 patients with a hereditary neuromuscular disorder living in Northern Norway, giving a point prevalence of 111.9/100,000 on January 1, 2020. The prevalence of children (<18 years old) and adults (≥18 years old) were 57.8/100,000 and 125.1/100,000, respectively. Inherited neuropathies had a prevalence of 38.8/100,000. Charcot-Marie-Tooth and hereditary neuropathy with liability to pressure palsies had a prevalence of 29.9/100,000 and 8.3/100,000, respectively. We calculated a prevalence of 3.7/100,000 for spinal muscular atrophies and 2.4/100,000 for Kennedy disease. Inherited myopathies were found in 67.7/100,000. Among these, we registered 13.4/100,000 myotonic dystrophy type 1, 6.8/100,000 myotonic dystrophy type 2, 7.3/100,000 Duchenne muscular dystrophy, 1.6/100,000 Becker muscular dystrophy, 3.7/100,000 facioscapulohumeral muscular dystrophy, 12.8/100,000 limb-girdle muscular dystrophy, 2.5/100,000 hypokalemic periodic paralysis and 11.4/100,000 myotonia congenita. CONCLUSION: Our total prevalence was higher than previously hypothesized in European population-based studies. The prevalence was especially high for myotonia congenita and limb-girdle muscular dystrophy. The prevalence of Charcot-Marie-Tooth polyneuropathy was higher than in most European studies, but lower than previously reported in epidemiological studies in other regions of Norway.

ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9.

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) is considered rare and phenotypic descriptions are scarce for the different subgroups. Mutations in the SH3TC2 gene, causing recessive demyelinating CMT type 4C have been found in several Norwegian CMT patients over the last years. We aimed to estimate a minimum prevalence and to study the genotypic and phenotypic variability of CMT4C in Norway. Patients were selected from diagnostic registries in medical genetic centers in Norway for cases of CMT4C. All patients were invited to complete a questionnaire and give medical consent to the use of clinical data from medical hospital records. A total of 35 patients from 31 families were found with CMT4C, which gives a minimum prevalence of 0.7/100,000 in Norway. Six new mutations were identified. Most patients had debut in the first decade with foot deformities, distal limb paresis, sensory ataxia and scoliosis. Proximal lower limb paresis and cranial nerve involvement was seen in about half of the patients. CMT4C is the most common recessive CMT in Norway. In addition to the classic distal limb affection, early debut, scoliosis, proximal paresis, cranial nerve affection and sensory ataxia are the most prominent features of CMT4C.

Population distribution of traditional and the emerging cardiovascular risk factors carotid plaque and IMT: the REFINE-Reykjavik study with comparison with the Tromsø study.

OBJECTIVES: Population statistics for carotid plaque and cardiovascular risk factors reported in scientific journals are usually presented as averages for the population or age and sex adjusted, rather than sex and age groups. Important population differences about atherosclerosis and cardiovascular risk factors may thus be missed. We compare the distribution of cardiovascular risk factors, carotids plaque and carotid intima-media thickness (CIMT) in two population-based studies. METHODS: Carotid artery atherosclerotic plaque prevalence and risk factors levels for cardiovascular disease by sex in 5-year age groups from the Risk Evaluation For Infarct Estimates Reykjavik study (REFINE-Reykjavik study) were compared with data from the Tromsø 6 study. RESULTS: The threshold of carotid plaque presence in the Tromsø 6 study fell between minimal and moderate plaque defined in the REFINE-Reykjavik study reflecting carotid plaque prevalence. The prevalence of minimal carotid plaque in the REFINE-Reykjavik study was 47% in men (40-69 years old) and 38% in women and 11% in men and 7% in women of moderate plaque. The prevalence of any plaque in the Tromsø 6 study was 35% in men and 27% in women. The mean (CIMT) was similar in the studies. In the Tromsø 6 study mean systolic blood pressure was 8 mm Hg higher in men and 10 mm Hg higher in women, mean low-density lipoprotein was 0.5 mmol/L higher in men and 0.3 mmol/L higher in women and the prevalence of smoking was 4% higher in men and 9% higher in women. However, body mass index was 0.8 kg/m2 higher in men and 0.9 kg/m2 in women in the REFINE-Reykjavik study. CONCLUSION: Comparison between Iceland and Norway revealed differences in the prevalence of carotid plaque, which was assumed to be due to different definition of plaque. However, clinically significant differences in conventional cardiovascular risk factors were seen. This underscores the importance of detailed comparison of population data across different populations.

Joint Effect of Carotid Plaque and C-Reactive Protein on First-Ever Ischemic Stroke and Myocardial Infarction?

BACKGROUND: The joint effect of atherosclerosis and CRP (C-reactive protein) on risk of ischemic stroke (IS) and myocardial infarction (MI) has been sparsely studied. The aim of this study was to explore whether CRP mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether CRP and carotid plaque add to risk prediction beyond traditional risk factors. METHODS AND RESULTS: CRP and carotid total plaque area (TPA) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident IS (n=671) and MI (n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of MI and IS according to categories of CRP (<1, 1-3, and >3 mg/L) and plaque status (no plaque and TPA below and above median) in Cox proportional hazard models with time-varying covariates. Multivariable-adjusted CRP >3 versus <1 mg/L was associated with risk of IS (HR, 1.84; 95% confidence interval, 1.49-2.26) and MI (HR, 1.46; 95% confidence interval, 1.23-1.73). TPA above median versus no plaque was associated with risk for IS (HR, 1.65; 95% confidence interval, 1.36-2.01) and MI (HR, 1.64; 95% confidence interval, 1.41-1.92). In participants with plaque, adjustment for CRP minimally attenuated the risk estimates. The highest incidence rates for MI and IS were seen in the group with both CRP >3 mg/L and TPA is above the median. TPA and CRP combined added to risk prediction beyond traditional risk factors. CONCLUSIONS: The simultaneous presence of subclinical atherosclerosis and elevated CRP was associated with increased risk of IS and MI. The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification.

Interleukin-6 is an independent predictor of progressive atherosclerosis in the carotid artery: The Tromsø Study.

BACKGROUND AND AIMS: Novel biomarkers are linked to cardiovascular disease (CVD). The aim of the present study was to investigate the association between 28 blood biomarkers and the formation and progression of carotid plaque. METHODS: In a nested case control study with 703 participants from the population based Tromsø Study, a large biomarker panel was measured in blood obtained at baseline. Carotid ultrasound was assessed both at baseline and at 6 years of follow-up. Four groups were defined: Group 1: no plaque at baseline or at follow-up (reference group); Group 2: novel plaque at follow-up; Group 3: stable plaque at follow-up; Group 4: progression of plaque at follow-up. By multinomial logistic regression analyses, we assessed the risk of being in the different plaque groups with regard to traditional cardiovascular risk factors and levels of biomarkers at baseline. RESULTS: Adjusted for traditional risk factors, interleukin-6 (IL-6) was an independent predictor of plaque progression (OR 1.44, 95% CI 1.12-1.85 per SD increase in IL-6 level). This result remained significant after inclusion of other novel biomarkers to the model, and when subjects with former CVD were excluded. Neopterin was protective of novel plaque formation (OR 0.73, 95% CI 0.57-0.93). Myeloperoxidase and Caspase-1 were independent predictors of plaque progression, but this effect disappeared when excluding subjects with former CVD. CONCLUSIONS: IL-6 is an independent predictor of plaque progression, suggesting that it may be a marker of progressive atherosclerosis in the general population and that its central role in CVD may be related to promotion of plaque growth.

Small and large vessel disease in persons with unrecognized compared to recognized myocardial infarction: The Tromsø Study 2007-2008.

BACKGROUND: Unrecognized myocardial infarction (MI) is a frequent condition with unknown underlying reason. We hypothesized the lack of recognition of MI is related to pathophysiology, specifically differences in underlying small and large vessel disease. METHODS: 6128 participants were examined with retinal photography, ultrasound of the carotid artery and a 12­lead electrocardiography (ECG). Small vessel disease was defined as narrower retinal arterioles and/or wider retinal venules measured on retinal photographs. Large vessel disease was defined as carotid artery pathology. We defined unrecognized MI as ECG-evidence of MI without a clinically recognized event. We analyzed the cross-sectional relationship between MI recognition and markers of small and large vessel disease, adjusted for age and sex. RESULTS: Unrecognized MI was present in 502 (8.2%) and recognized MI in 326 (5.3%) of the 6128 participants. Compared to recognized MI, unrecognized MI was associated with small vessel disease indicated by narrower retinal arterioles (OR 1.66, 95% CI 1.05-2.62, highest vs. lowest quartile). Unrecognized MI was less associated with wider retinal venules (OR 0.55, 95% CI 0.35-0.87, lowest vs. highest quartile). Compared to recognized MI, unrecognized MI was less associated with large vessel disease indicated by presence of plaque in the carotid artery (OR for presence of carotid artery plaque in unrecognized MI 0.51, 95% CI 0.37-0.69). No significant sex interaction was present. CONCLUSIONS: Unrecognized MI was more associated with small vessel disease and less associated with large vessel disease compared to recognized MI. These findings suggest that the pathophysiology behind unrecognized and recognized MI may differ.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

C-reactive protein in atherosclerosis - A risk marker but not a causal factor? A 13-year population-based longitudinal study: The Tromsø study.

BACKGROUND AND AIMS: CRP predicts cardiovascular disease (CVD) in large epidemiologic studies. The aim of the present study was to elucidate the role of CRP in atherosclerosis formation and progression in a prospective population-based study. METHODS: 6503 middle-aged subjects from The Tromsø study had serum CRP, carotid ultrasound and complete covariate data collected at baseline in 1994. Of these, 4730 and 2917 attended follow-up surveys with repeated assessments in 2001 and 2007, respectively. The cross-sectional associations between CRP and subclinical carotid atherosclerosis, and the longitudinal associations between baseline CRP and novel plaque formation and plaque progression were assessed in generalized estimating equations and linear mixed models stratified by sex. RESULTS: At baseline, traditional risk factors and plaque prevalence increased by CRP risk categories (<1 mg/L, 1-3 mg/L, and >3 mg/L) in both sexes. In cross-sectional analyses, multivariable-adjusted CRP was associated with plaque prevalence and total plaque area (TPA) in men and women. Age-adjusted baseline CRP >3 mg/L compared to CRP <1 mg/L predicted novel plaque formation (OR 1.44, CI 1.08-1.92) and TPA progression (ß = 0.0.029 (CI, 0.003-0.056)) in men, but not in women. In neither men nor women was baseline CRP a predictor of TPA-progression or novel plaque formation when adjusted for traditional risk factors. CONCLUSIONS: CRP was associated with plaque presence and TPA in cross-sectional analyses, but was not an independent predictor of novel plaque formation or plaque progression. Our findings suggest that CRP may link to CVD by other mechanisms than promoting formation and progression of atherosclerotic plaques.

Impact of Venous Thromboembolism on the Formation and Progression of Carotid Atherosclerosis: The Tromsø Study.

Venous thromboembolism (VTE) is associated with increased risk of arterial cardiovascular diseases (CVD), and development of atherosclerosis secondary to VTE may be an intermediate between VTE and CVD. Therefore, we aimed to investigate whether incident VTE was associated with subsequent carotid atherosclerosis formation and progression in a population-based observational study. Subjects attending two or more ultrasound examinations of the right carotid artery, with measurement of total plaque area (TPA), in the Tromsø Study in 1994-1995, 2001-2002, and/or 2007-2008 were eligible. We identified 150 subjects diagnosed with first-lifetime VTE between the initial and follow-up visit, and randomly selected 600 age- and sex-matched subjects without VTE between the visits. Subjects with VTE and carotid plaque(s) at the first visit had 4.1 mm 2 (ß: 4.13, 95% CI: -1.72 to 9.98) larger change in TPA between the first and second visit compared with subjects without VTE after adjustment for change in high-sensitivity C-reactive protein (hs-CRP) and traditional atherosclerotic risk factors. The association remained after restricting the analyses to VTE events diagnosed in the first half of the time interval between the carotid ultrasounds (ß: 4.02, 95% CI: -3.66 to 11.70), supporting that the change in TPA occurred subsequent to the VTE. No association was found between VTE and novel carotid plaque formation. In conclusion, we found a possible association between VTE and atherosclerosis progression in those with already established carotid plaques, but not between VTE and novel plaque formation. The association between VTE and carotid plaque progression was not mediated by low-grade inflammation assessed by hs-CRP.

Estimated and Measured GFR Associate Differently with Retinal Vasculopathy in the General Population.

BACKGROUND/AIMS: Estimated glomerular filtration rate (eGFR) is used extensively in epidemiological research. Validations of eGFR have demonstrated acceptable performance, but the dependence of creatinine and cystatin C on non-GFR factors could confound associations with disease. Few studies have investigated this issue in direct comparison with measured GFR (mGFR). We compared the associations between eGFR and mGFR and retinal vasculopathy, a marker of systemic microvasculopathy. METHODS: Iohexol clearance and retinal photography were examined in the Renal Iohexol Clearance Survey in Tromsø 6, which consists of a representative sample of middle-aged persons from the general population. A total of 1,553 persons without self-reported kidney disease, cardiovascular disease or diabetes were investigated. Three eGFR equations based on creatinine and/or cystatin C from the Chronic Kidney Disease Epidemiology Collaboration were studied. Differences between eGFR and mGFR were analyzed with seemingly unrelated regression methods. RESULTS: mGFR in the lowest quartile was associated with an increased multivariable-adjusted odds ratio of retinopathy (OR 1.86, 95% CI 1.16-2.97), but not with retinal artery or vein diameters. eGFR based on cystatin C (eGFRcys) was consistently biased relative to mGFR in its associations with retinal vessel diameters across different models. eGFR based on creatinine (eGFRcrea) and eGFR based on both creatinine and cystatin C were also biased in several of these models (p < 0.05). For retinopathy, the differences between the 3 eGFR and mGFR measurements were not statistically significant. CONCLUSIONS: Low mGFR is associated with retinopathy in the general population. eGFR based on creatinine and/or cystatin C are not valid substitutes for mGFR in studies of the relationship between the retina and kidney function in healthy persons.