KLHL40-Related Myopathy: A Systematic Review and Insight into a Follow-up Biomarker via a New Case Report.

BACKGROUND: Mutations in the KLHL40 gene are a common cause of severe or even lethal nemaline myopathy. Some cases with mild forms have been described, although the cases are still anecdotal. The aim of this paper was to systematically review the cases described in the literature and to describe a 12-year clinical and imaging follow-up in an Italian patient with KLHL40- related myopathy in order to suggest possible follow-up measurements. METHODS: Having searched through three electronic databases (PubMed, Scopus, and EBSCO), 18 articles describing 65 patients with homozygous or compound heterozygous KLHL40 mutations were selected. A patient with a KLHL40 homozygous mutation (c.1582G>A/p.E528K) was added and clinical and genetic data were collected. RESULTS: The most common mutation identified in our systematic review was the (c.1516A>C) followed by the (c.1582G>A). In our review, 60% percent of the patients died within the first 4 years of life. Clinical features were similar across the sample. Unfortunately, however, there is no record of the natural history data in the surviving patients. The 12-year follow-up of our patient revealed a slow improvement in her clinical course, identifying muscle MRI as the only possible marker of disease progression. CONCLUSIONS: Due to its clinical and genotype homogeneity, KLHL40-related myopathy may be a condition that would greatly benefit from the development of new gene therapies; muscle MRI could be a good biomarker to monitor disease progression.

Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness: A Two-Years Follow up Study.

Background: Becker muscular dystrophy (BMD) is a dystrophinopathy due to in-frame mutations in the dystrophin gene (DMD) which determines a reduction of dystrophin at muscle level. BMD has a wide spectrum of clinical variability with different degrees of disability. Studies of natural history are needed also in view of up-coming clinical trials. Objectives: From an initial cohort of 32 BMD adult subjects, we present a detailed phenotypic characterization of 28 patients, then providing a description of their clinical natural history over the course of 12 months for 18 and 24 months for 13 of them. Methods: Each patient has been genetically characterized. Baseline, and 1-year and 2 years assessments included North Star Ambulatory Assessment (NSAA), timed function tests (time to climb and descend four stairs), 6-minute walk test (6MWT), Walton and Gardner-Medwin Scale and Medical Research Council (MRC) scale. Muscle magnetic resonance imaging (MRI) was acquired at baseline and in a subgroup of 9 patients after 24 months. Data on cardiac function (electrocardiogram, echocardiogram, and cardiac MRI) were also collected. Results and conclusions: Among the clinical heterogeneity, a more severe involvement is often observed in patients with 45-X del, with a disease progression over two years. The 6MWT appears sensitive to detect modification from baseline during follow up while no variation was observed by MRC testing. Muscle MRI of the lower limbs correlates with clinical parameters.Our study further highlights how the phenotypic variability of BMD adult patients makes it difficult to describe an uniform course and substantiates the need to identify predictive parameters and biomarkers to stratify patients.

Congenital Myopathy as a Phenotypic Expression of CACNA1S Gene Mutation: Case Report and Systematic Review of the Literature.

BACKGROUND: Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is CACNA1S, which is recognized as the cause of Dihydropyridine Receptor Congenital Myopathy. METHODS: To better characterize the phenotypic spectrum of CACNA1S myopathy, we conducted a systematic review of cases in the literature through three electronic databases following the PRISMA guidelines. We selected nine articles describing 23 patients with heterozygous, homozygous, or compound heterozygous mutations in CACNA1S and we added one patient with a compound heterozygous mutation in CACNA1S (c.1394-2A>G; c.1724T>C, p.L575P) followed at our Institute. We collected clinical and genetic data, muscle biopsies, and muscle MRIs when available. RESULTS: The phenotype of this myopathy is heterogeneous, ranging from more severe forms with a lethal early onset and mild-moderate forms with a better clinical course. CONCLUSIONS: Our patient presented a phenotype compatible with the mild-moderate form, although she presented peculiar features such as a short stature, myopia, mild sensorineural hearing loss, psychiatric symptoms, and posterior-anterior impairment gradient on thigh muscle MRI.

Further characterization of NFIB-associated phenotypes: Report of two new individuals.

Nuclear Factor I B (NFIB) haploinsufficiency has recently been identified as a cause of intellectual disability (ID) and macrocephaly. Here we report on two new individuals carrying a microdeletion in the chromosomal region 9p23-p22.3 containing NFIB. The first is a 7-year 9-month old boy with developmental delays, ID, definite facial anomalies, and brain and spinal cord magnetic resonance imaging findings including periventricular nodular heterotopia, hypoplasia of the corpus callosum, arachnoid cyst in the left middle cranial fossa, syringomyelia in the thoracic spinal cord and distal tract of the conus medullaris, and a stretched appearance of the filum terminale. The second is a 32-year-old lady (the proband' mother) with dysmorphic features, and a history of learning disability, hypothyroidism, poor growth, left inguinal hernia, and panic attacks. Her brain magnetic resonance imaging findings include a dysmorphic corpus callosum, and a small cyst in the left choroidal fissure that marks the hippocampal head. Array-based comparative genomic hybridization identified, in both, a 232 Kb interstitial deletion at 9p23p22.3 including several exons of NFIB and no other known genes. Our two individuals add to the knowledge of this rare disorder through the addition of new brain and spinal cord MRI findings and dysmorphic features. We propose that NFIB haploinsufficiency causes a clinically recognizable malformation-ID syndrome.

A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing.

OBJECTIVE: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. METHODS: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. RESULTS: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. CONCLUSIONS: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants.

A Rare Case of Perrault Syndrome with Auditory Neuropathy Spectrum Disorder: Cochlear Implantation Treatment and Literature Review.

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in PRLTS3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In PRLTS3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in PRLTS3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided.

How to define and enhance diagnostic and assistance pathways in neuromuscular diseases during the COVID-19 pandemic: the concept of network.

The main consequence of the COVID-19 pandemic has been to increase the distance between patients and their doctors and to limit the opportunities to compare experiences and clinical cases in the medical community. Based on this, we adopted a strategy to create networks with the ambition to break down these distances and to unify the process of care and management. Here we report the results and perspectives of our efforts and studies. A summary of the presentations on the topic, held during the webinars organized for macro-areas by the Italian Association of Myology with the aim of raising awareness among "non-expert doctors" who deal with neuromuscular disorders in the era of COVID-19 was collected and here reported. Although the macro-areas responded in different way to the problems of neuromuscular patients in the era of COVID-19, they all have tried to create a network between doctors and opportunity for education and information, with the secondary outcome to have shared process of care and management. Telemedicine, virtual meetings and the strengthening of national and international networks, through research projects, were the nodal and common points. Due to their complexity, neuromuscular diseases had already taught clinicians the importance of multidisciplinary confrontation. COVID-19 has further strengthened the need to create links between clinicians and experts, even of different nationalities, in order to guarantee to patients the best possible care, but above all, access and continuity of care even in critical periods. Adequate answers have been given to these problems, though there is still a lot to improve.

Behavioural and Emotional Changes during COVID-19 Lockdown in an Italian Paediatric Population with Neurologic and Psychiatric Disorders.

On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5-18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t-tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5-5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6-18 years subpopulation. In the regression models, younger age in the 1.5-5 years subpopulation resulted as "protective" while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6-18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.