Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Measuring Outcomes in Adults with Spinal Muscular Atrophy - Challenges and Future Directions - Meeting Report.

Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease which affects 1 in 6,000-10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1). A major focus of therapeutic developments has been on increasing the full-length SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene.In June 2017, FDA and EMA have approved the antisense oligonucleotide Nusinersen as the first treatment for all SMA subtypes without age restriction. While prominent treatment effects have been observed in the earlier stages of the disease and in patients up to 15 years of age, there is only limited data from clinical trials in adult SMA patients. First real-world data from neuromuscular clinical centers suggest a therapeutic benefit of nusinersen with a favourable safety profile also in adult SMA patients: in several cases, relevant improvements of motor function is achieved, which might lead to enhanced autonomy in daily life activities and improved quality of life. Systematic follow-up of the motor status with validated instruments is crucial for an adequate monitoring of the therapeutic effects but most of the widely used scales and scores have been developed and evaluated for the pediatric population only. International neuromuscular experts have met in Frankfurt/Main, Germany in May 2019 to discuss relevant aspects of the diagnostic pathway and patient management in adult SMA. The recommendations and challenges in this patient population are discussed.

Fragility fractures and bone mineral density in male patients affected by type 1 and type 2 myotonic dystrophy.

Myotonic dystrophy is a multisystemic disorder affecting skeletal muscle. Male patients have an increased risk of fractures and develop a number of endocrine/metabolic impairments known to adversely affect bone health. The aim of this study was primarily to determine the occurrence of fragility fractures and the bone mineralization status (lumbar spine, hip and total body by dual X-ray absorptiometry) in 36 male patients affected with type 1 myotonic dystrophy and 13 male patients affected with type 2 myotonic dystrophy. Fragility fractures occurred in 15 type 1 and 7 type 2 myotonic dystrophy in non-classical osteoporotic sites, such as metatarses. Hip osteopenia was the most frequent finding, particularly in type 2 (n = 6) than type 1 myotonic dystrophy patients (n = 1), while osteoporosis was rare. Patients with type 1 myotonic dystrophy presented higher total body bone mass density than patients with type 2 myotonic dystrophy and healthy controls and lumbar spine was associated positively with the severity of the disease. Gonadic failure, with low testosterone and reduced INSL3 levels, visceral adiposity and insulin resistance correlated with reduced body mass index in both type 1 and type 2 myotonic dystrophic patients. The independent determinant of fragility fractures were low total body mass index, low blood testosterone and low global muscle mass.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype.

BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; -1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF.

Vitamin D, parathyroid hormone and muscle impairment in myotonic dystrophies.

Parathyroid function in Myotonic Dystrophy (DM) patients has been poorly investigated. Parathyroid and muscle parameters were assessed in 31 male DM1 (44±2 years), 13 male DM2 (56±2 years) and 32 healthy controls. Hyperparathyroidism was diagnosed in 18% of patients without differences between DM types. In all DM patients, hyperparathyroidism was associated with normocalcemia but one with hypercalcemia. DM patients presented significantly higher PTH and lower vitamin D (25OHD) compared with controls, also considering seasonality. Severe vitamin D deficiency (25OHD<10 ng/ml) was diagnosed in 40% and hypovitaminosis D (25OHD<30 ng/ml) occurred in 88% of DM patients. About one-third of DM1 presented hypophosphatemia associated with elevated PTH levels. Serum 25OHD levels negatively correlated with PTH and with body fat mass. Considering DM1 patients, serum PTH levels positively correlated with CTG triplet repeats. Furthermore, PTH levels negatively correlated with total modified Medical Research Council (MRC) and positively with Muscular Impairment Rating Scale (MIRS). By contrast, in DM2 patients muscle assessment did not show any correlation with parathyroid function. In conclusion, we arrived at the following: 1) severe vitamin D deficiency is common in DM patients and it is associated with secondary hyperparathyroidism; 2) primary hyperparathyroidism, though rare, may occur; 3) increased adiposity in DM may be a risk factor for hypovitaminosis D; and 4) high serum PTH levels may indicate a muscle impairment, at least in DM1.

The frequency and severity of cardiac involvement in myotonic dystrophy type 2 (DM2): long-term outcomes.

BACKGROUND: Frequency and severity of cardiac involvement in DM2 are still controversial. The aims of our study were to determine the frequency and progression of cardiac and muscle involvement in a relatively large cohort of patients with DM2 throughout Italy and Germany and to provide long-term outcomes in this disorder. METHODS: 104 DM2 and 117 DM1 patients underwent baseline and follow-up assessments of, ECG, 24h Holter monitoring, 2D echocardiography and electrophysiological study (EPS) when appropriate, and manual muscle strength testing (mean follow-up: 7.4 ± 4.1 for DM2 and 5.7 ± 4 years for DM1). RESULTS: Overall, 10% of DM2 patients vs 31% of DM1 patients had PR ≥ 200 ms and 17% of DM2 patients vs 48% of DM1 patients had QRSD ≥ 100 ms. Six patients with DM2 vs 28 patients with DM1 required PM/ICD implantations. DM2 patients were stronger than DM1 patients at baseline, but muscle strength worsened significantly over time (p<0.0001), just as in DM1, although at a slower annual rate. CONCLUSION: Our data demonstrate that the frequency and severity of cardiac involvement and of muscle weakness are reduced in DM2 compared to DM1 and that progression is slower and less severe. Nonetheless, careful cardiac evaluation is recommended in this patient population to identify patients at risk for potential major cardiac arrhythmias.

Measuring quality of life impairment in skeletal muscle channelopathies.

BACKGROUND AND PURPOSE: Fatigue and pain have been previously shown to be important determinants for decreasing quality of life (QoL) in one report in patients with non-dystrophic myotonia. The aims of our study were to assess QoL in skeletal muscle channelopathies (SMC) using INQoL (individualized QoL) and SF-36 questionnaires. METHODS: We administered INQoL and SF-36 to 66 Italian patients with SMC (26: periodic paralysis, 36: myotonia congenita and 4: Andersen-Tawil) and compared the results in 422 patients with myotonic dystrophies (DM1: 382; and DM2: 40). RESULTS: (i) INQoL index in SMC is similar to that in DMs (P = 0.79). (ii) Patients with myotonia congenita have the worst perception of QoL. (iii) Myotonia has the most detrimental effect on patients with myotonia congenita, followed by patients with DM2 and then by patients with DM1 and hyperkalemic periodic paralysis. (iv) Pain is a significant complaint in patients with myotonia congenita, hypokalemic periodic paralysis and DM2 but not in DM1. (v) Fatigue has a similar detrimental effect on all patient groups except for patients with hyperkalemic periodic paralysis in whom muscle weakness and myotonia more than fatigue affect QoL perception. (vi) Muscle symptoms considered in INQoL correlate with physical symptoms assessed by SF-36 (R from -0.34 to -0.76). CONCLUSIONS: QoL perception in patients with SMC is similar to that of patients with DMs, chronic multisystem disabling conditions. Our results provide information to target treatment and health care of these patients. The sensitivity of INQoL to changes in QoL in the SMC needs to be further explored in longitudinal studies.

Italian validation of INQoL, a quality of life questionnaire for adults with muscle diseases.

BACKGROUND AND PURPOSE: A quality of life (QoL) questionnaire for neuromuscular diseases was recently constructed and validated in the United Kingdom in a sample of adult patients with a variety of muscle disorders. Preliminary results suggested it could be a more relevant and practical measure of QoL in muscle diseases than generic health measures of QoL. The purpose of our work was: (i) To validate INQoL in Italy on a larger sample of adult patients with muscle diseases (ii) to compare INQoL to SF-36. METHODS: We have translated into Italian and applied language adaptations to the original UK INQoL version. We studied 1092 patients with different muscle disorders and performed (i) test-retest reliability (n = 80); (ii) psychometric (n = 345), known-group (n = 1092), external criterion (n = 70), and concurrent validity with SF-36 (n = 183). RESULTS: We have translated and formally validated the Italian version of INQoL confirming and extending results obtained in the United Kingdom. In addition to good results in terms of reliability, known-group and criterion validity, a comparison with the SF-36 scales showed a stronger association between INQoL total index and SF-36 physical (r = -0.72) than mental (r = -0.38) summary health indexes. When considering comparable domains of INQoL and SF-36 with respect to an objective measure of muscle strength assessment (MMRC), regression analysis showed a stronger correlation using INQoL rather than SF-36 scores. CONCLUSIONS: INQoL is recommended to assess QoL in muscle diseases because of its ability to capture physical limitations that are specifically relevant to the muscle condition.