Myofibrillar myopathy (MFM) type 8, caused by PYROXD1 gene variants, has recently been identified and has been rarely reported to date.Our aim was to report the first case of MFM type 8 from Tunisia with delayed diagnosis due to a non-specific clinical presentation.ResultsA 36-year-old North-African male presented to our neurology department with a 15-year history of progressive muscle weakness leading to difficulty in walking and standing without dysphagia or facial weakness. His family history was unremarkable, with no similar cases reported. His medical history was insignificant, with no previous or current medication.Neurological examination noted symmetrical proximal motor deficit in all four limbs with calf pseudohypertrophy and hyporeflexia in lower limbs. Proximal muscular dystrophy was suspected. Normal levels of blood creatine kinase (CK) and lactate dehydrogenase were noted, and the immunological work-up was negative. A muscle biopsy of the anterior tibialis was performed, revealing a histopathological pattern consistent with proximal muscle dystrophy suggestive of Limb-Girdle Muscle Dystrophy (LGMD).Whole exome sequencing (WES) was performed, revealing a homozygous variant NM_024854.3: c.464A > G on the PYROXD1 gene. The diagnosis of MFM type 8 was retained, and physical therapy was prescribed. At 2-year follow-up, a slight worsening of motor deficit was observed, but his modified Rankin’s scale remained stable at 3.ConclusionsWe reported the first Tunisian case of MFM type 8 associated with a well-known pathogenic variant in the PYROXD1 gene. This case mimics LGMD with a moderate deficit and slow progression. MFM type 8 can present with different phenotypes, making the diagnosis difficult.

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as a genetic cause of autosomal recessive axonal Charcot-Marie-Tooth disease 2 (CMT2) and distal hereditary motor neuropathy (dHMN).We herein review the main phenotypes associated with SORD mutations and report the case of a 16-year-old man who was referred to our outpatient clinic for a slowly worsening gait disorder with wasting and weakness of distal lower limbs musculature. Since creatine phosphokinase (CPK) values were persistently raised (1.5fold increased) and a Next-Generation Sequencing CMT-associated panel failed in identifying pathogenic variants, a muscle biopsy was performed with evidence of alterations suggestive of a protein surplus distal myopathy. Finally, Whole-Exome Sequencing (WES) identified two pathogenic SORD variants in the heterozygous state: c.458C > A (p.Ala153Asp) and c.757delG (p.Ala253Glnfs*27).This is an isolated report of compound heterozygosity for two SORD mutations associated with clinical and histological signs of skeletal muscle involvement, expanding the phenotypic expression of SORD mutations.

Improvement in clinical conditions allowed physicians to pay more attention to the cognitive function in DMD patients, leading to description of a cognitive impairment not only in affected males, but in female carriers as well.This study aimed to investigate the cognitive involvement in a cohort of DMD carriers and to summarize the current knowledge about the intellectual involvement and neuropsychological profile in DMD/BMD carriers.Our case series consisted of 22 carrier patients from two different centers (IRCCS Mondino, Pavia and Policlinico Gemelli, Rome), for whom we retrospectively collected cognitive, clinical and genetic data.For literature review, we selected 9 studies published in English language from 2011 to 2023 and cited in PubMed.We found that the average IQ of DMD carriers was lower (74; very low) than the average score on normal curve (100 as average standard score). Furthermore, about 50% of them fell in the “extremely low IQ” range, compared with 2-3% of general population. A higher incidence of intellectual disability was confirmed in symptomatic DMD carriers (mean IQ 66; extremely low) from IRCCS Mondino, but not in the asymptomatic ones (mean IQ 99; average), when compared to the general population.Current literature, albeit limited, seems to confirm the presence of a cognitive impairment in carriers, although milder than in affected males but with a similar neuropsychological profile. However, further studies are necessary to delve deeper into this issue and provide adequate educational support.

Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly.This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration.

Juvenile Myasthenia Gravis (JMG) is a neuromuscular disease, often characterized at onset by fatigue and fluctuating weakness. We report a case of a girl affected by severe mood disorder, in which the diagnosis of JMG and its treatment were challenged by the concomitant psychiatric condition. A 14-year-old girl, with a history of severe mood disorder and emotional dysregulation, had been treated with benzodiazepines, sertraline, and antipsychotics, reporting generalized fatigability, weakness, and drowsiness, first ascribed to her psychiatric condition and therapy. After a suicide attempt, she was hospitalized and a neurological assessment revealed a fluctuating ptosis and facial weakness, that improved with rest. The diagnosis of JMG was confirmed by repeated nerve stimulation test, and by the response to pyridostigmine. Antibodies anti-AChR and anti-MuSK were negative. JMG diagnosis may be harder in adolescents with psychiatric comorbidity. Moreover, the neurological condition limits the choice of the appropriate psychopharmacotherapy.

Spinal muscular atrophy is a progressive and severe hereditary (autosomal recessive) neuromuscular disease characterized by lower motor neuron degeneration in the spinal cord and brainstem causing a clinical picture of progressive muscle atrophy and weakness of skeletal and respiratory muscles. There is an ongoing discussion on the extent to which other tissues might be affected in patients with SMA. Several animal models and some case reports or small case series report involvement of other organ systems, such as peripheral nerve, brain, muscle, heart, vascular system, and pancreas. Recent literature reviews identified a number of cases with vascular abnormalities. We present two consecutive cases of patients diagnosed with SMA who developed peripheral circulation disturbances and combine the findings with a thorough review the literature.

The widespread use of magnetic resonance imaging (MRI) in the diagnosis of myopathies has made it possible to clarify the typical MRI pattern of dysferlinopathy. However, sufficient attention has not been given to the variability of MRI patterns in dysferlinopathy.Materials and methodsTwenty-five patients with the clinical manifestations of dysferlinopathy were examined. For all patients, creatine phosphokinase levels were measured and molecular genetics were examined. In two patients, immunohistochemical examinations of muscle biopsies were performed. MRI scanning was included T2 multi-slice multi-echo, T1 weighted, T2 weighted and Short Tau Inversion Recovery T2 weighted sequences. Quantitative and semi-quantitative evaluations of fatty replacement and swelling of the muscles were undertaken.ResultsVariability in the MRI patterns was lowest in the pelvis and leg muscles and highest in the thigh muscles. Three main types of MRI patterns were distinguished: posterior-dominant (80%), anterior-dominant (16%), and diffuse (4%). Among patients with the anterior-dominant pattern, the collagen-like variant (4%), proximal variant (4%) and pseudo-myositis (8%) were separately distinguished.ConclusionsAwareness of atypical MRI patterns in dysferlinopathy is important for increasing the efficiency of routine diagnostics and optimizing the search for causative gene mutations.

BackgroundRisdiplam has been approved for Compassionate Use (CUP) since 2019, for SMA type 1 and type 2 who could not receive the approved treatment for the disease. It’s an orally administered drug targeting SMN2 gene. More than 200 patients have had access to this program in Italy, up to June 2021.AimsTo describe the clinical and demographic features of patients included in CUP amongst the iSMAc’ Italian centers.MethodsThis is a retrospective study including demographic, neuromotor, respiratory and nutritional data, shifts, adverse events and dropouts.Results44 out of 576 Italian iSMAc patients (7.6%) are on risdiplam (8 SMA1, 36 SMA2). Age ranges: 0-10 yrs (n = 1, SMA2); 11-17 yrs (n = 13, 4 SMA1, 9 SMA2); 18-25 yrs (n = 15, 3 SMA1, 12 SMA2); 18-25 yrs (n = 15.3 SMA1, 12 SMA2) and older than 25 yrs (n=14 SMA2). The majority (73%) are non-sitters. Concerning respiratory status, 6 patients are in invasive-ventilation, 26 use NIV and 8 patients do not require respiratory support. Regarding the nutritional status, 11 have a PEG and 12 have dysphagia. About 20% of patients switched from nusinersen for difficulties in intrathecal administration. 3 dropped-out respectively for side-effects, subjective inefficacy, shift to gene therapy.ConclusionsConsidering the criteria to access risdiplam so far, all but one are older than 11 yrs, have severe motor, nutritional and respiratory conditions and are naive due to inaccessibility to nusinersen for technical difficulties. After open clinical use, further follow-up data will provide information on additional reasons and number of patients accessing risdiplam.

PurposeTo assess the reproducibility of a manual muscle MRI segmentation method that follows a specific set of recommendations developed in our center.Materials and methodsNine healthy volunteers underwent a muscle MRI examination that included a TSE T2 sequence of the thighs. Muscle segmentation was performed by three operators: an expert operator (OP1) with 3 years of experience and two radiology residents (OP2 and 3) who were both given basic segmentation instructions, whereas only OP2 underwent additional supervised training from OP1. Intra- and inter-operator Dice similarity coefficient (DSC) was calculated.ResultsOP1 showed the highest average intra-operator DSC values (0.885), whereas OP2 had higher average DSC (0.856) compared to OP3 (0.818). The highest inter-operator agreement was observed between Operators 1 and 2 (0.814) and the lowest between OP2 and OP3 (0.702). Confidence interval (CI) analysis showed that the most experienced operator also had the least variability in drawing the ROIs, whereas OP2 showed both higher intra-operator reproducibility compared to OP3 and higher inter-operator agreement with OP1. The muscles that showed the least reproducibility were the semimembranosus and the short head of the biceps femoris.DiscussionFollowing specific recommendations such as these ones derived from our single-center experience leads to an overall high reproducibility of manual muscle segmentation and is helpful in improving both intra-operator and inter-operator reproducibility in less experienced operators.

Patients with Duchenne muscular dystrophy may benefit from gastrostomy tube feeding due to progressive dysphagia and malnutrition. However, due to concomitant pathologies, they are often at high risk for anesthesiologic complications. We describe how the non-invasive mechanical ventilation has been an alternative successful respiratory support option during the gastrostomy tube placement in a patient with Duchenne muscular dystrophy, on continuous NIV treatment. This report confirms how the use of NIV can support alveolar ventilation, before, during and after mini-invasive procedures, and prevent respiratory complications.