Myotonic dystrophy type 1 - a multiorgan disorder. / Dystrofia myotonika type 1 ­ en multiorgansykdom.

Myotonic dystrophy type 1 is an autosomal dominant, inherited multiorgan disorder that can affect people of all ages. It is the most prevalent inherited muscular disease in adults. Late diagnosis points to limited knowledge among the medical community that symptoms other than typical muscular symptoms can dominate. The condition often worsens with each generation and some families are severely affected. Significantly delayed diagnosis means a risk of more serious development of the disorder and inadequate symptomatic treatment. We hope that this clinical review article may lead to more rapid diagnosis and better follow-up of this patient group.

A woman in her fifties with chronic muscle weakness. / En kvinne i 50-årene med langvarig muskelsvakhet.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a descriptive term that encompasses a group of congenital, aetiologically heterogeneous conditions characterised by multiple joint contractions. CASE PRESENTATION: As a teenager, the index patient was told she had AMC, as did one of her parents. Subsequently, she wondered how her condition might evolve over time, since her affected parent had become wheelchair- dependent. Her history and clinical findings led to genetic testing which identified a causative variant in the COL6A2 gene, revealing an underlying diagnosis of Bethlem myopathy. INTERPRETATION: Adults who have rare monogenic disorders may lack an aetiological diagnosis because of limited access to genetic laboratory testing in the past. Advances in genetic laboratory diagnostics during the last 10−15 years have made testing more widely available. As exemplified by this case, molecular genetic diagnosis may provide benefits such as information concerning prognosis and treatment options.

Pain in adult myotonic dystrophy type 1: relation to function and gender.

BACKGROUND: Pain is prevalent in myotonic dystrophy 1 (DM1). This study investigated whether CTG repeat size, disease duration, BMI and motor and psychological function were related to pain in adult patients with DM1, and if there were gender differences regarding intensity and location of pain. METHOD: Cross-sectional design. Pain was investigated in 50 genetically confirmed DM1 patients by combining clinical assessment and self-reports of pain intensity and locations. Pain scoring results were related to CTG size, disease duration, muscle strength, walking capacity measured by 6-min walk test, activity of daily life by Katz ADL Index, respiratory function by Forced Vital Capacity and BMI. In addition, the degree of reported pain was related to Quality of life measured by WHOQOL-BREF; fatigue was measured by Fatigue severity scale; psychological functions were measured by Beck Depression Inventory, Beck Anxiety Inventory, IQ and Autism spectrum Quotient. RESULTS: Pain was reported in 84% of the patients and was significantly correlated with CTG size (r = 0.28 p = 0.050), disease duration (r = 0.38 p = 0.007), quality of life (r = - 0.37 p = 0.009), fatigue (r = 0.33 p = 0.02) and forced vital capacity (r = - 0.51, p = 0.005). Significant gender differences, with higher scores for females, were documented. In male subjects the number of pain locations was significantly correlated with quality of life and the autism quotient. In females, pain intensity was significantly correlated with activity, respiratory function and BMI. CONCLUSIONS: Pain in DM1 was prevalent, with a strong association to lung function and other aspects of the disease. Significant gender differences were present for pain intensity and number of pain locations. How pain was related to other symptoms differed between male and female subjects. Our findings highlight the importance of assessments of pain in DM1 patients.

MRI of trunk muscles and motor and respiratory function in patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic Dystrophy 1 (DM1) causes progressive myopathy of extremity muscles. DM1 may also affect muscles of the trunk. The aim of this study was to investigate fat infiltration and muscle size in trunk muscles in DM1 patients, and in an age and gender matched control group. Further, explore how fat infiltration and degree of atrophy in these muscles are associated with motor and respiratory function in DM1 patients. METHOD: We measured fat infiltration and trunk muscle size by MRI in 20 patients with genetically confirmed classic form of DM1, and compared these cases with 20 healthy, age and gender matched controls. In the DM1 group, we investigated correlations between MRI findings and clinical measures of muscle strength, mobility and respiration. We used sum scores for fat infiltration and muscle size in trunk flexors and trunk extensors in the analysis of group differences and correlations. RESULTS: Significant differences between cases and controls were present for fat infiltration in trunk flexors (p = 0.001) and trunk extensors (p = < 0.001), and for muscle size in trunk flexors (p = 0.002) and trunk extensors (p = 0.030). Fat infiltration in trunk flexors were significant correlated to back extension strength (rho = - 0.523 p = 0.018), while muscle size in trunk flexors was significantly correlated to trunk flexion strength (rho = 0.506 p = 0.023). Fat infiltration in trunk flexors was significantly correlated with lower general mobility (rho = - 0.628, p = 0.003), reduced balance (rho = 0.630, p < 0.003) and forced vital capacity (rho - 0.487 p = 0.040). CONCLUSIONS: Trunk muscles in DM1 patients had significant higher levels of fat infiltration and reduced muscle size compared to age and gender matched controls. In DM1 patients, fat infiltration was associated with reduced muscle strength, mobility, balance and lung function, while muscle size was associated with reduced muscle strength and lung function. These findings are of importance for clinical management of the disease and could be useful additional outcome measures in future intervention studies.

Loss of haptic feedback impairs control of hand posture: a study in chronically deafferented individuals when grasping and lifting objects.

Previous work has highlighted the role of haptic feedback for manual dexterity, in particular for the control of precision grip forces between the index finger and thumb. It is unclear how fine motor skills involving more than just two digits might be affected, especially given that loss of sensation from the hand affects many neurological patients, and impacts on everyday actions. To assess the functional consequences of haptic deficits on multi-digit grasp of objects, we studied the ability of three rare individuals with permanent large-fibre sensory loss involving the entire upper limb. All three reported difficulties in everyday manual actions (ABILHAND questionnaire). Their performance in a reach-grasp-lift task was compared to that of healthy controls. Twenty objects of varying shape, mass, opacity and compliance were used. In the reach-to-grasp phase, we found slower movement, larger grip aperture and less dynamic modulation of grip aperture in deafferented participants compared to controls. Hand posture during the lift phase also differed; deafferented participants often adopted hand postures that may have facilitated visual guidance, and/or reduced control complexity. For example, they would extend fingers that were not in contact with the object, or fold these fingers into the palm of the hand. Variability in hand postures was increased in deafferented participants, particularly for smaller objects. Our findings provide new insights into how the complex control required for whole hand actions is compromised by loss of haptic feedback, whose contribution is, thus, highlighted.

Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor.

INTRODUCTION: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT). MATERIAL AND METHODS: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17). RESULTS: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy. CONCLUSIONS: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy.

Proprioceptive loss and the perception, control and learning of arm movements in humans: evidence from sensory neuronopathy.

It is uncertain how vision and proprioception contribute to adaptation of voluntary arm movements. In normal participants, adaptation to imposed forces is possible with or without vision, suggesting that proprioception is sufficient; in participants with proprioceptive loss (PL), adaptation is possible with visual feedback, suggesting that proprioception is unnecessary. In experiment 1 adaptation to, and retention of, perturbing forces were evaluated in three chronically deafferented participants. They made rapid reaching movements to move a cursor toward a visual target, and a planar robot arm applied orthogonal velocity-dependent forces. Trial-by-trial error correction was observed in all participants. Such adaptation has been characterized with a dual-rate model: a fast process that learns quickly, but retains poorly and a slow process that learns slowly and retains well. Experiment 2 showed that the PL participants had large individual differences in learning and retention rates compared to normal controls. Experiment 3 tested participants' perception of applied forces. With visual feedback, the PL participants could report the perturbation's direction as well as controls; without visual feedback, thresholds were elevated. Experiment 4 showed, in healthy participants, that force direction could be estimated from head motion, at levels close to the no-vision threshold for the PL participants. Our results show that proprioceptive loss influences perception, motor control and adaptation but that proprioception from the moving limb is not essential for adaptation to, or detection of, force fields. The differences in learning and retention seen between the three deafferented participants suggest that they achieve these tasks in idiosyncratic ways after proprioceptive loss, possibly integrating visual and vestibular information with individual cognitive strategies.

Small and large fiber neuropathy in adults with myotonic dystrophy type 1.

Introduction: Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder that affects multiple organs. In this study, we investigated symptoms of pain and presence of small and large fiber neuropathy in the juvenile and adult form of DM1. Method: Twenty genetically verified DM1 patients were included. Pain was assessed, and neurological examination and investigations of the peripheral nervous system by quantification of small nerve fibers in skin biopsy, quantitative sensory testing and nerve conduction studies were performed. Results from skin biopsies were compared to healthy controls. Result: Seventeen patients reported chronic pain. Large and/or small fiber abnormalities were present in 50% of the patients. The intraepidermal nerve fiber density was significantly lower in the whole group of patients compared to healthy controls. Conclusion: Small-fiber neuropathy might be an important cause of pain in DM1.

A scoping review of health literacy in rare disorders: key issues and research directions.

BACKGROUND: The ability to find, understand, appraise and utilise health information is crucial among individuals living with rare disorders. The aim of this study was to give a comprehensive overview of the literature on health literacy in adult persons with rare disorders. METHODS: We applied a scoping review methodology and performed a systematic search in 2021 in bibliographic databases. Searches were conducted in Medline (Ovid), Embase (Ovid), PsycInfo (Ovid), CINAHL (ebsco), and ERIC (Ovid). References were sorted and evaluated for inclusion using EndNote and Covidence. This review was guided by the question "What are the characteristics of research on health literacy in rare disorders?" RESULTS: The database searches yielded 75 eligible reports. A total of 6223 individuals with rare disorders were represented alongside 1707 caregivers. The reports in this review have included study participants representing a total of 80 different rare disorders with unique ORPHA and ICD-10 codes. The results revealed that persons with rare disorders often exhibit gaps in health literacy through a lack of knowledge and access to information related to self-management, their own diagnosis and health, as well as daily coping and social rights. In addition, the importance of aid and information from healthcare personnel and the significance of getting social support from others in the same situation were accentuated. CONCLUSION: This review emphasizes the importance of reinforcing health literacy among persons with rare disorders through peer support and education. This is the first review to give a comprehensive and state-of-the-art overview of literature investigating health literacy among persons with rare disorders and offers a basis for further research.

Type 1 spinal muscular atrophy treated with nusinersen in Norway, a five-year follow-up.

BACKGROUND: New treatments for 5q spinal muscular atrophy (SMA) have led to changes in the disease phenotype. Questions about long-term efficacy, however, persist. We present the results from five-year follow-up of the first ten Norwegian patients with SMA type1 treated with nusinersen. METHODS: - Ten patients referred to the expanded access program were included. Standardized assessments with Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), the Hammersmith Infant Neurological Examination (HINE-2), compound muscle action potential (CMAP) examination and cerebrospinal fluid analysis of neurofilament light chain (cNfL) were performed. RESULT: Age at baseline ranged from three months to 11 years and eight months. Nine patients were alive and continued to receive treatment at 62 months of follow-up. CHOP INTEND scores increased significantly up to 38 months. Any further increase from 38 to 50 months was not statistically significant, and scores remained almost unchanged from 50 to 62 months. HINE-2 scores increased but the difference from baseline never reached statistical significance. The youngest patients showed the best motor outcome. The changes in CMAP scores were not statistically significant. cNfL values were significantly reduced after 18 months compared with baseline; the largest difference occurred between baseline and 6 months. There was a significant negative correlation between log cNfL and CHOP INTEND (p = 0.042). Bulbar and respiratory function did not improve during the observation period. CONCLUSION: Our findings support previously reported results on efficacy and safety of nusinersen. All patients have shown improvement in motor function. The need of respiratory and nutritional support did not improve.

[Small-fibre neuropathy]. / Tynnfibernevropati.

BACKGROUND: Small-fibre neuropathy is a neuropathy that mainly affects the small nerve fibres. Owing to doctors' inadequate knowledge of the condition and limited diagnostic methods, this type of neuropathy is probably under-diagnosed. Small-fibre neuropathy has many causes, but the symptoms are often relatively similar. This review article is intended to give doctors insight into the clinical expressions and diagnosis of the condition. METHOD: The article is based on literature searches in PubMed and the authors' clinical and scientific experience of the subject. RESULTS: Small-fibre neuropathy generates a characteristic distribution of symptoms, particularly pain, and is associated with a number of common illnesses. Specific tests for small fibre neuropathy, such as skin biopsy and thermal testing, can be used to confirm the diagnosis. The treatment targets the symptoms, but complete pain relief is often difficult to achieve. INTERPRETATION: The clinical neurological examination will not generally be able to detect small-fibre neuropathy, but will contribute primarily to excluding a more general polyneuropathy. Supplementary tests are often necessary to make a final diagnosis.

[Microneurography and research on peripheral neuropathic pain]. / Mikronevrografi og forskning på perifer nevropatisk smerte.

BACKGROUND: Microneurography is a neurophysiological technique which enables recording from single peripheral nerve fibres in persons who are awake. The method is only used in research. We discuss how microneurography has been used to map nerve-fibre functions under normal circumstances and in chronic pain conditions. METHOD: The article is based on a literature search in PubMed and on the authors' own knowledge and experience of the method from their research. RESULTS: Microneurography has contributed to the understanding of pain under physiological conditions and in chronic pain conditions, in particular peripheral neuropathic pain. For example, signs of hyperexcitability have been found in peripheral nerve fibres in connection with neuropathies and peripheral neuropathic pain conditions, and the proportion of hyperexcitable nerve fibres has been shown to be greater in neuropathy patients with chronic pain than in neuropathy patients without pain. Findings indicate that so-called CMi nociceptors play an important role in chronic neuropathic pain. INTERPRETATION: In the longer term we hope that research using microneurography will help to reveal mechanisms of direct importance for the development of targeted treatment of neuropathic pain.