Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome.

Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome.

Rehabilitation of the face and temporomandibular joint in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) alterations of the face and of the mouth cause aesthetic modifications and disability, impairing self-esteem and quality of life (QoL). The aim of this study was to verify the effects of two rehabilitation protocols on facial mimic and mouth opening. METHODS: A total of 47 SSc patients (40 females and 7 males, mean age ± SD 59.08 ± 10.31 years), were consecutively selected: 22 were randomly assigned to protocol 1 [home exercises for temporomandibular joint (TMJ), mimic, masticatory and cervical spine muscles] and 25 to protocol 2 (home exercises and combined physiotherapeutic procedures performed by a physiotherapist). Each treatment had a duration of 12 weeks with a follow up of 8 weeks. TMJ dysfunction, orofacial involvement, disability, QoL, and safety were assessed at enrollment (T0), at the end of the treatment (T1), and at follow up (T2). RESULTS: Both Protocol 1 and Protocol 2 induced significant improvements of some clinical and clinimetric parameters, but better results were obtained with Protocol 2. In the comparison between the effects of Protocol 1 and Protocol 2 at T1 and T2, a significant difference was observed only for Mouth Handicap in SSc [MHISS; Total (p = 0.00178] and for MHISS Mouth opening (p = 0.0098) at T1. No significant difference of indices of short-form 36 was observed. CONCLUSION: The present data suggest that TMJ involvement in SSc may be managed by rehabilitation treatments. The action of a physiotherapist prescribing and personalizing exercises may induce better therapeutic effects.

Epidemiology and Genetics of Mucopolysaccharidosis Type VI in Russia.

Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB) and consequent deficient activity of ARSB, a lysosomal enzyme involved in the glycosaminoglycan (s) (GAGs) metabolism. Here, we present the results of the study of ARSB DNA analysis in MPS VI patients in the Russian Federation (RF) and other republics of the Former Soviet Union. In a cohort of 68 patients (57 families) with MPS VI, a total of 28 different pathogenic alleles were found. The most prevalent nucleotide changes included NM_000046.5:c.194C>T and NM_000046.5:c.454C>T. Five pathogenic alleles were novel, not previously reported (NM_000046.5:c.304C>G, NM_000046.5:c.533A>G, NM_000046.5:c.941T>C, NM_000046.5:c.447_456del10, and NM_000046.5:c.990_10003del14). The nucleotide variant NM_000045.6:c.454C>T was the prevalent allele among Slavic Russian patients. The nucleotide variant NM_000045.6:c.194C>T was found only in MPS VI families from the Republic of Dagestan. Based on the analysis of dry blood spots (DBSs) collected from newborns in this RF region, we showed the frequency of this mutant allele in the Republic of Dagestan to be 0.01 corresponding to the MPS VI frequency of nearly 1:10,000, which is one of the highest worldwide. This may eventually make the selective asymptomatic carrier test and newborn screening highly feasible in this region of the country.

Plasma FGF-21 and GDF-15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders.

Recently, the plasma cytokines FGF-21 and GDF-15 were described as cellular metabolic regulators. They share an endocrine function and are highly expressed in the liver under stress and during starvation. Several studies found that these markers have high sensitivity and specificity for the diagnosis of mitochondrial diseases, especially those with prominent muscular involvement. In our study, we aimed to determine whether these markers could help distinguish mitochondrial diseases from other groups of inherited diseases. We measured plasma FGF-21 and GDF-15 concentrations in 122 patients with genetically confirmed primary mitochondrial disease and 127 patients with non-mitochondrial inherited diseases. Although GDF-15 showed better analytical characteristics (sensitivity = 0.66, specificity = 0.64, area under the curve [AUC] = 0.88) compared to FGF-21 (sensitivity = 0.51, specificity = 0.76, AUC = 0.78) in the pediatric group of mitochondrial diseases, both markers were also elevated in a variety of non-mitochondrial diseases, especially those with liver involvement (Gaucher disease, galactosemia, glycogenosis types 1a, 1b, 9), organic acidurias and some leukodystrophies. Thus, the overall positive and negative predictive values were not acceptable for these measurements to be used as diagnostic tests for mitochondrial diseases (FGF-21 positive predictive value [PPV] = 34%, negative predictive value [NPV] = 73%; GDF-15 PPV = 47%, NPV = 28%). We suggest that FGF-21 and GDF-15 increase in patients with metabolic diseases with metabolic or oxidative stress and inflammation.

Management Strategies for CLN2 Disease.

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease.

Efficacy of rehabilitation with Tai Ji Quan in an Italian cohort of patients with Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia Syndrome (FMS) is characterized by musculoskeletal pain, muscle tenderness leading to disability, impaired quality of life (QoL), fatigue and it is accompanied by sleep disorders and psychological distress. Mind body therapies (MBT), such as Tai Ji Quan (TJQ), use different techniques to facilitate the ability of the mind to influence disease characteristics and symptoms. Some studies showed that TJQ, in patients with rheumatic diseases, particularly FMS, improved QoL, disability and psychological distress. OBJECTIVES: To evaluate the efficacy of TJQ on disability, QoL, fatigue, sleep and psychological distress in an Italian cohort of FMS patients. METHODS: We enrolled 44 FMS patients: 22 patients (Experimental Group) participated to a course of Tai Ji Quan style of (2/week for 16 weeks); 22 patients (Control Group) participated to an educational course about FMS (2/week for 16 weeks). At baseline (T0) and at the end of treatment (T1), patients were assessed for disability [Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ)], Quality of Life [Short-Form 36 (SF36)], fatigue [Functional Assessment of Chronic Illness-Fatigue (FACIT-F)], pain [Widespread Pain Index (WPI)], tenderness [Tender Points (TP)], Sleep Quality [Pittsburgh Sleep Quality Index (PSQI)] and mood disorders [Hospital Anxiety and Depression Scale (HADS)]. RESULTS: At T1 versus T0, patients of the Experimental Group showed a significant improvement in FIQ, FACIT, SF36 (Summary Physical Index, Physical activity, physical role, bodily pain, general health, vitality, emotional role limitations), in WPI, TP, PSQI (total, sleep duration, and sleep disturbance) and HADS (total score and anxiety subscale), while Patients in the Control Group did not improve in any parameter. CONCLUSIONS: In FMS patients TJQ, if performed by an expert physiotherapist, should be regarded as an effective rehabilitation method.

A comparison of two podiatric protocols for metatarsalgia in patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVES: In rheumatoid arthritis (RA) and osteoarthritis (OA) forefoot involvement causes disability and metatarsalgia. Our objective was to evaluate, in RA and OA patients, the efficacy of two protocols combining insoles in polypropylene terephtalate (PPT) and custom silicone orthoses for toes on disability and metatarsalgia. METHODS: Twenty-four women (13 with OA, 11 with RA) with metatarsalgia were treated with two protocols: group A (protocol A) wore PPT insoles (T1) for 30 days and for another 30 days silicone orthosis for toes were added (T2). Group B (protocol B) wore PPT insoles and silicone orthosis (T1) for 30 days and in the following 30 days only insoles (T2). At T0, T1 and T2, pain, disability and function (Foot Function Index - FFI), pressure (KPA) and plantar contact areas (cm2) (baropodometer), and gait spatial-temporal parameters (GAITRite®) were assessed. RESULTS: At T0 versus T2, both protocols reduced FFI-pain, -disability and -functional limitation (p<0.05), with better results of protocol A than protocol B (p<0.05) for FFI-pain and -disability. Both protocols reduced baropodometer foot plantar pressures (p<0.001), with better results for protocol A for right foot pressures (p<0.05) and increased foot contact areas (p<0.05), with no difference between them (p=NS). Gait parameters were not significantly changed by both protocols (p=NS). CONCLUSIONS: In patients with RA and OA with metatarsalgia, the synergic action of silicone toe orthosis and PPT insoles improves FFI, reduces foot plantar pressures and increases foot plantar contact areas. Protocol A, using firstly insoles and then adding silicone toe orthoses, is the more efficacious.

Sexual function in Italian women with systemic sclerosis is affected by disease-related and psychological concerns.

OBJECTIVE: In patients with systemic sclerosis (SSc), sexual function is somewhat impaired. Our aim was to evaluate sexual function in women with SSc in comparison to controls, and to investigate the association with sociodemographic and disease characteristics, and physical and psychological variables. METHODS: Forty-six women with SSc and 46 healthy women were assessed for sociodemographic characteristics and gynecological development and administered the Female Sexual Function Index (FSFI), Medical Outcomes Study Short Form-36 (SF-36), Health Assessment Questionnaire (HAQ), Hospital Anxiety and Depression Scale (HADS), Rosenberg Self-Esteem Scale, Coping Orientation to Problems Experienced-New Italian Version, and Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Patients were also assessed for disease duration and subset, Female Sexual Function in SSc, Hand Mobility in Scleroderma test (HAMIS), Cochin Hand Functional Disability Scale, Mouth Handicap in Systemic Sclerosis Scale (MHISS), Disability Sexual and Body Esteem Scale (PDSBE); and fist closure, hand opening, and mouth opening. RESULTS: In patients with SSc, only FSFI desire subscale score was significantly lower (p = 0.035) versus controls. Total FSFI score, similar to controls, was related with Medical Outcomes Study Short Form-36 mental component, HAQ (p = 0.022), MHISS (p = 0.038), and HAMIS (p = 0.037). In SSc, the main factors independently associated with sexual functioning were vaginal dryness [regression coefficient (B) = -0.72; p < 0.001], PDSBE (B = 0.42; p = 0.001), and HADS depression scale (B = -0.23; p = 0.035). Together, these variables explained 70% of the variance in the FSFI total score. CONCLUSION: In SSc, sexual function, although not different from controls, is influenced by specific disease-related and psychological concerns. Thus it should be included in patient evaluations and assessed in daily clinical practice.

In systemic sclerosis, anxiety and depression assessed by hospital anxiety depression scale are independently associated with disability and psychological factors.

BACKGROUND: Anxious and depressive symptoms are frequent in Systemic Sclerosis (SSc). Our objective is to assess their prevalence and association with district and global disability and psychological variables. METHODS: 119 SSc patients were assessed by Hospital Anxiety Depression Scale (HADS). Clinical depression and anxiety were defined for HADS score cutoff ≥ 8. Patients were assessed for psychological symptoms (RSES, COPE-NIV), hand (HAMIS, CHFDS, fist closure, and hand opening) and face disability (MHISS, mouth opening), global disability, and fatigue (HAQ, FACIT). RESULTS: Both depression and anxiety in SSc are 36%. Depressive patients with comorbid anxiety have higher HADS-D score than patients with depression only (P = 0.001). HADS-A and -D are positively correlated with global disability, hands and mouth disability, fatigue, self-esteem and avoidance coping strategy, and, only HADS-A, also with social support (P < 0.05). By multiple regression, HADS-D is independently associated with FACIT-F (P < 0.001), RSES (P < 0.001), and MHISS total score (P = 0.016), together explaining 50% of variance. HADS-A is independently associated with RSES (P = 0.006), COPE-NIV SA (P = 0.003), COPE-NIV SS (P = 0.008), FACIT-F (P = 0.022), and MHISS mouth opening (P = 0.029), explaining 41% of variance. CONCLUSIONS: In SSc depression and anxiety correlate to local and global disabilities and psychological characteristics. Depressive patients with comorbid anxiety have higher level of depressive symptoms.

Immunological aspects of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months, in the absence of a medical diagnosis that would otherwise explain the clinical presentation. Other common symptoms include headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years. The estimated worldwide prevalence of CFS is 0.4-1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK. No physical examination signs are specific to CFS and no diagnostic tests identify this syndrome. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people. The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed. This review discusses the immunological aspects of CFS and offers an immunological hypothesis for the disease processes.