Forensic age estimation at the University Center of Legal Medicine Lausanne-Geneva: a retrospective study over 12 years.

With the undeniable increase in asylum requests from unaccompanied alleged minors, age estimation of living individuals has become an essential part of the routine work in European forensic centers. This study aims to review the forensic age estimations performed in our center since 2010, to evaluate the state-of-the-art of this practice in Switzerland with the evolution of the methodology according to upcoming recommendations. Our institute's expert reports performed between 2010 and 2022 were retrospectively analyzed. We gathered the following parameters: demographic data, morphological characteristics, alleged age compared with the assessed minimum age, sexual maturation, dental and bone age. When available, we collected personal and family history, medical history, records of torture-related/self-inflicted injuries, and information about eating habits that might affect skeletal development. Data collection amounted to 656 cases. Forensic age estimations ordered by the Swiss Secretariat for Migration (SEM) represented 76.4% of cases, with 23.6% of them ordered by the Court/Public Prosecutor. Most alleged minors were male (94.5%) and came from Afghanistan (53.4%). Adjunction of CT scans of the sternoclavicular joints was necessary in 86.4% of cases. Only 25.2% of our reports concluded on most probable minority, with 55.6% of definite majors; in 19.2% of our cases, minority could not be excluded. This study aspires to further broaden our expertise regarding forensic age estimations. Given the increasing migratory flows, we can expect a notable increase in the frequency of these requests. Consequently, this study aims to promote a multidisciplinary approach and the international standardization of the methodology of these estimations.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype−phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype−phenotype correlations and improve prognostic outcomes.

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

Palliative Care for Patients with End-Stage, Non-Oncologic Diseases-A Retrospective Study in Three Public Palliative Care Departments in Northern Italy.

Patients with irreversible malignant and non-malignant diseases have comparable mortality rates, symptom burdens, and quality of life issues; however, non-cancer patients seldom receive palliative care (PC) or receive it late in their disease trajectory. To explore the characteristics of non-cancer patients receiving PC in northern Italy, as well as the features and outcomes of their care, we retrospectively analyzed the charts of all non-cancer patients initiating PC regimens during 2019 in three publicly funded PC departments in Italy's populous Lombardy region. We recorded the baseline variables (including data collected with the NECPAL CCOMS-ICO-derived questionnaire used since 2018 to evaluate all admissions to the region's PC network), as well as treatment features (setting and duration) and outcomes (including time and setting of death). Of the 2043 patients admitted in 2019, only 12% (243 patients­131 females; mean age 83.5 years) had non-oncological primary diagnoses (mainly dementia [n = 78], heart disease [n = 55], and lung disease [n = 30]). All 243 had Karnofsky performance statuses ≤ 40% (10−20% in 64%); most (82%) were malnourished, 92% had ≥2 comorbidities, and 61% reported 2−3 severe symptoms (pain, dyspnea, and fatigue). Fifteen withdrew or were discharged from the study PCN; the other 228 remained in the PCN and died in hospice (n = 133), at home (n = 9), or after family-requested transfer to an emergency department (n = 1). Most deaths (172/228, 75%) occurred <3 weeks after PC initiation. These findings indicate that the PCN network we studied cares for few patients with life-limiting non-malignant diseases. Those admitted have advanced-stage illness, heavy symptom burdens, low performance statuses, and poor survival. Additional efforts are needed to improve PCN accessibility for non-cancer patients.

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps.

Objective: To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants. Design: Observational study. Methods: Probands' phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports. Results: Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): -2.8 (0.9) and -3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: -4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference -3.0 (range: -4.7 to -1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process. Conclusions: Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort.

BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

Parents' dilemma: A therapeutic decision for children with spinal muscular atrophy (SMA) type 1.

Background: SMA type 1 is a severe neurodegenerative disorder that, in the absence of curative treatment, leads to death before 1 year of age without ventilatory support. Three innovative therapies are available to increase life expectancy. Purpose: (i) To increase knowledge about parents' experiences with their decision to have opted for an innovative therapy; (ii) to assess the middle-term psychological consequences in the parents' lives. Methods: We used an in-depth interview; a self-administrated questionnaire and self-report scales (BDI-II, STAI-Y, PSI-SF, SOC-13, PBA, DAS 16 and FICD). We compared parents hesitant before the decision to parents who were not-hesitant and the group of parents whose child was treated with gene therapy (GT) to parents whose child received another innovative therapy. Main results: We included n = 18 parents of 13 children. Parent's mean age was 34.7 (±5.2), child's average age was 44.3 months (±38.0). Retrospectively, most parents felt involved by doctors in decision-making on treatment, they felt their point of view was considered and were satisfied with the effects of the treatment. The group of parents "non-hesitant" was more depressed (p < 0.001), more anxious (p = 0.022) and had higher parental stress (p = 0.026) than the group of "hesitant" parents; the group of "GT-treated" parents was more depressed (p = 0.036) than the group of parents with "other therapy". Qualitative data highlights revealed: the need to save the child's life at all costs; the fear of coping with end of life and palliative care, the high value of perceived physician confidence in the treatment, the hope that the child will acquire autonomy or be cured. At the time of the decision, no parents felt they fully understood all of the issues regarding therapy and the disease. Conclusion: Hesitating before making a decision did not predispose parents to depression and anxiety. The narratives suggest that the parents faced a dilemma regarding their child's health in an urgent context. The decision was not final, and parents will continue to think about it throughout the care process.

Species-Specific Inhibition of Necroptosis by HCMV UL36.

Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the Herpesviridae family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells of different species, others have species-specific functions, probably reflecting the co-evolution of the herpesviruses with their respective hosts. Human cytomegalovirus (HCMV) protein UL36 is a dual cell death pathway inhibitor. It blocks death receptor-dependent apoptosis by inhibiting caspase-8 activation, and necroptosis by binding to the mixed lineage kinase domain-like (MLKL) protein and inducing its degradation. While UL36 has been shown to inhibit apoptosis in human and murine cells, the specificity of its necroptosis-inhibiting function has not been investigated. Here we show that UL36 interacts with both human and murine MLKL, but has a higher affinity for human MLKL. When expressed by a recombinant mouse cytomegalovirus (MCMV), UL36 caused a modest reduction of murine MLKL levels but did not inhibit necroptosis in murine cells. These data suggest that UL36 inhibits necroptosis, but not apoptosis, in a species-specific manner, similar to ICP6 of herpes simplex virus type 1 and MC159 of molluscum contagiosum virus. Species-specific necroptosis inhibition might contribute to the narrow host range of these viruses.

International retrospective natural history study of LMNA-related congenital muscular dystrophy.

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum.

Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519) is an autosomal recessive disease caused by homozygous or compound heterozygous variants in SPTBN4 coding for type 4 ßIV-spectrin, a non-erythrocytic member of the ß-spectrin family. Variants in SPTBN4 disrupt the cytoskeletal machinery that controls proper localization of ion channels and the function of axonal domains, thereby generating severe neurological dysfunction. We set out to analyze the genetic causes and describe the clinical spectrum of suspected cases of NEDHND. Variant screening was done by whole exome sequencing; clinical phenotypes were described according to the human phenotype ontology, and histochemical analysis was performed with disease-specific antibodies. We report four families with five patients harboring novel homozygous and compound heterozygous SPTBN4 variants, amongst them a multi-exon deletion of SPTBN4. All patients presented with the key features of NEDHND; severe muscular hypotonia, dysphagia, absent speech, gross motor, and mental retardation. Additional symptoms comprised horizontal nystagmus, epileptiform discharges in EEG without manifest seizures, and choreoathetosis. Muscle histology revealed both characteristics of myopathy and of neuropathy. This report expands the SPTBN4 variant spectrum, highlights the spectrum of morphological phenotypes of NEDHND-patients, and reveals clinical similarities between the NEDHND, non-5q SMA, and congenital myopathies.

DOORS syndrome and a recurrent truncating ATP6V1B2 variant.

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.

Expanding the phenotype of X-linked SSR4-CDG: Connective tissue implications.

Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.

The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

Calidad de vida en niños y adolescentes con Atrofia Muscular Espinal / Quality of life in children and adolescents with Spinal Muscular Atrophy

INTRODUCCIÓN: La calidad de vida (CV) es un aspecto fundamental del tratamiento en pacientes con Atrofia Muscular Espinal (AME). Existe escasa información a nivel local e internacional. OBJETIVO: Caracterizar la CV en una muestra de niños y adolescentes chilenos con AME. SUJETOS Y MÉTODO: Estudio observacional, transversal. Se aplicó un cuestionario y el módulo neuromuscular 3.0 de la encuesta PedsQLtm, a padres de niños con AME de 2-18 años. Ésta consta de 3 ámbitos: Enfermedad, Comunicación y Familia. Se consideró el puntaje >60 como CV buena, 30-60 regular y <30, deficiente. Se utilizó el programa MINITAB-17®, considerando significativo p ≤ 0,05. RESULTADOS: Se reclutaron 38 pacientes, con edad mediana 8 años (2-18), 52,7% hombres, y 17 (44,7%) AME I. Todos con confirmación genética. El puntaje total fue 51,92 ± 17, correspondiendo 31% a CV buena, 55% regular y 14% baja. En AME I fue 46,5 ± 15,2 y en AME II-III, 56,3 ± 17,4 (p = 0,071). Para el ámbito de Enfermedad fue 53,83 ± 18,1, de Familia 48,6 ± 23,14 y Comunicación 33,3 (RIC: 0,0-83,33). En este último, tuvieron mayor puntaje los pacientes con AME II o III, los mayores de 6 años, los con menor apoyo ventilatorio y los residentes en regiones. Sin embargo, en el análisis multivariado solamente el tipo de AME fue significativo, explicando 40,9% de la variación del puntaje del área de comunicación. Conclusiones: En esta muestra de pacientes con AME, la calidad de vida fue regular a buena en la mayoría. El área más baja fue la de Comunicación, con mayor puntaje en aquellos con mayor capacidad motora funcional.

INTRODUCTION: Quality of life (QoL) is a key aspect in the treatment of patients with Spinal Muscular Atrophy (SMA). International information regarding QoL in SMA is scarce, and is not available in our country. OBJECTIVE: To characterize QoL in a sample of Chilean children and adolescents with SMA. SUBJECTS AND METHOD: Observational, cross-sectional study. A general questionnaire and the PedsQLTM 3.0 Neuromuscular Module Inventory were applied to parents of children with SMA aged 2 to 18 years. It has three areas: Disease, Communication, and Family. A score >60 was considered as good QoL, 30-60 as regular, and <30 as low. MINITAB-17® software was used, considering significant a p <0.05 value. RESULTS: We recruited 38 patients, with median age 8 years (2-18), 52.63% were male, and 17 (44.7%) with SMA I. All had genetic confirmation. The total score of QoL was 51.92 ± 17, representing 31% good, 55% regular, and 14% low. Regarding SMA I, it was 46.5 ± 15.2 and SMA II-III, 56.3 ± 17.4 (p = 0.071). Concerning the area of Disease, it was 53.83 ± 18.1, Family 48.6 ± 23.14, and Communication 33.3 (IQR: 0.0; 83.33). In this last area, children with SMA II-III, older than 6 years., with non-invasive ventilatory support, or living out of the metropolitan area had hig her scores, however, in multivariate analysis, only SMA type was significant, which explained 40,9% of the variation in the communication area score. CONCLUSIONS: In this sample of SMA pediatric patients, the QoL was regular or good in most of them. The lowest area was communication, with a higher score in those children with higher motor function.

Sobrecarga del cuidador de pacientes con atrofia muscular espinal / Caregiver burden in spinal muscular atrophy

INTRODUCCIÓN La sobrecarga del cuidador ha sido ampliamente descrita en gerontología, pocos estudios la abordan en niños con enfermedades neuromusculares. El cuidado de pacientes con atrofia muscular espinal (AME), requiere atención continua de un tercero, pudiendo afectar la salud del cuidador y la calidad de atención y bienestar del paciente. El objetivo del estudio fue determinar el nivel de sobrecarga de los cuidadores de pacientes AME, identificando factores protectores y de riesgo asociados MÉTODOS Estudio observacional analítico transversal en padres de pacientes con AME, de un hospital privado de Santiago de Chile. Se analizaron datos demográficos clínicos y encuesta Zarit autoreportada por los padres de los pacientes con AME, realizada entre septiembre de 2017 y febrero de 2018. Se usó estadística descriptiva y regresión logística uni y multivariada para identificar factores asociados a sobrecarga RESULTADOS De los 50 padres encuestados, 14 (28%) eran de pacientes non-sitters, con sobrecarga intensa, mediana de puntaje 59 (37-76), 29 (58%) de pacientes sitters sobrecarga ligera, mediana 48 (32-79) y 7(14%) de pacientes walkers, ausencia de sobrecarga mediana 38 (23-54). Se identificaron como factores protectores de sobrecarga los años de enfermedad OR 0,9 (0,8-0,95) P=0,037 y la mayor edad de los pacientes OR 0,9(08,0,98) p=0,018. Factores de riesgo el uso de silla de ruedas OR 7,2(1,2-4,3) p=0,029 y la vía de alimentación artificial OR 9,2(1-78,8) p=0,040 CONCLUSIÓN Los padres de pacientes con AME tienen un significativo nivel de sobrecarga y existen factores que la aumentan y disminuyen. El equipo multidisciplinario debe integrar la medición periódica del nivel de sobrecarga, para intervenir oportunamente y procurar el cuidado integral de la familia.

Caregiver burden has been widely described in gerontology, few studies address it in children with neuromuscular diseases. The care of patients with spinal muscular atrophy (SMA) requires permanent care from a third person, which may affect the caregiver health, quality of care and well-being of the patient. The aim of the study was to determine the burden of SMA patient's caregivers, identifying associated protective and risk factors METHODS Descriptive cross-sectional analytical study in SMA patient's parents, from a private hospital in Santiago de Chile., demographic Clinical and self-reported Zarit survey data, parents self reported, conducted between September 2017 and February 2018, were analyzed. Descriptive statistics and uni and multivariate logistic regression were used to identify factors associated with overloading RESULTS Parents of non-sitter patients showed a median of 59 (37-76), corresponding to intense burden and those of sitters, a light burden, with a median score of 48 (32-79) Walkers patient's parents, presented a median score of 38 (23-54) that corresponds to an absence of burden. The years of illness and the higher age of the patients were identified as protective factors of overload. As risk factors of burden, the use of a wheelchair and artificial airway. Of the 50 parents surveyed, 14 (28%) were non-sitter patients, with intense overload, median 59(37-76), 29(58%) sitters patients, light overload, median 48 (32-79) and 7(14%) walker patients, absence of overload, median 38 (23-54). Protective factors of overload were years of disease OR 0,9(0,8-0,95) p=0.037 and the patients major age OR 0.9(0.8-0.98) p=0.018. Risk factors were the use of wheelchair OR 7,2(1,2-4,3) p=0.029 and artificial feeding support OR 9,2(1-78.8) p=0.040 CONCLUSION SMA patient's parents have a significant level of overload and there are factors that increase and decrease it. The multidisciplinary team must integrate the periodic measurement of the burden level, to make on time interventions and to ensure the integral care in the family.

Spontaneous symptomatic improvement in a pediatric patient with anti-3-hydroxy-3-methylglutraryl-coenzyme A reductase myopathy.

Immune-mediated necrotizing myopathy with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase is a subgroup of idiopathic inflammatory myopathies mainly described in adults and requiring long term immunomodulatory therapy for remission. Pediatric patients have been reported as small series or sporadic cases. We report an eight-year-old girl with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, presenting with subacute proximal limb weakness, high creatine kinase and a muscle biopsy displaying necrotizing pattern, initially diagnosed as limb-girdle muscular dystrophy, but subsequently negative genetic testing. A noteworthy spontaneous improvement in her weakness suggested the possibility of an acquired autoimmune myopathy, confirmed by positive testing of anti-HMGCR antibodies titers. After four years of follow-up, she maintains normal strength with high levels of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody. This patient shows that spontaneous fluctuations and spontaneous long-lasting symptomatic remission can occur in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy. Some patients could present a wane and wax clinical course, an important aspect when assessing response to therapy.