•Double seropositivity can occur in MG old patients with a benign course.•Clinicians should detect both AChR and MuSK Abs under certain conditions.•We discuss all the other cases of double positive ...MG reported in literature.
AChR and MuSK double positive myasthenia gravis has been rarely reported. Generally, it occurs in children and adults after thymectomy or immunotherapy. Furthermore, in a few patients with bulbar or respiratory involvement, MuSK antibodies might be detected after clinical deterioration. We report a man with a very late onset myasthenia gravis (86-year-old) and the coexistence of both antibodies at the time of the diagnosis. Despite the presence of MuSK antibodies, he manifested no bulbar symptoms and had a favorable clinical outcome. However, side effects related to low dose pyridostigmine were evident. Hence, double positivity can also occur in elderly and in more benign forms of myasthenia gravis. Other cases of AChR and MuSK double positive myasthenia gravis could allow a better definition of this condition.
Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on ...the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions.
As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps.
This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.
Background and purpose
The aim was to assess the value of insoluble PABPN1 muscle fibre nuclei accumulation in the diagnosis of atypical cases of oculopharyngeal muscular dystrophy (OPMD).
Methods
...Muscle biopsies from a selected cohort of 423 adult patients from several Italian neuromuscular centres were analysed by immunofluorescence: 30 muscle biopsies of genetically proven OPMD, 30 biopsies from patients not affected by neuromuscular disorders, 220 from genetically undiagnosed patients presenting ptosis or swallowing disturbances, progressive lower proximal weakness and/or isolated rimmed vacuoles at muscle biopsy and 143 muscle biopsies of patients affected by other neuromuscular diseases.
Results
The detection of insoluble nuclear PABPN1 accumulation is rapid, sensitive (100%) and specific (96%). The revision of our cohort allowed us to discover 23 new OPMD cases out of 220 patients affected with nonspecific muscle diseases.
Conclusions
Oculopharyngeal muscular dystrophy is often misdiagnosed leading to diagnosis delay, causing waste of time and resources. A great number of these cases present symptoms and histological findings frequently overlapping with other muscle diseases, i.e. inclusion body myositis and progressive external ophthalmoplegia. PABPN1 nuclear accumulation is a reliable method for diagnostic purposes and it is safe and useful in helping pathologists and clinicians to direct genetic analysis in the case of suspected OPMD, even when clinical and histological clues are deceptive.
Pompe disease is a rare metabolic disorder, due to mutations in the gene encoding acid alpha-glucosidase (GAA), of which infantile and late-onset forms may occur. Aim of the work was to analyze ...clinical and laboratory data of a cohort of late-onset Pompe disease (LOPD) patients, collected during the last 15 years and to point out unusual phenotypic/genotypic features as well as enzyme replacement therapy (ERT) responses. We diagnosed 30 LOPD patients; at follow-up, they underwent motor, respiratory, cardiac and muscle MRI evaluations. Motor performances were tested by Walton Gardner-Medwin, GSGC and 6MWT tests. Respiratory function was assessed as FVC % in upright/supine position. LOPD presentations were represented by presymptomatic hyperCKemia (37 %), proximal/axial muscle weakness (53 %) and respiratory impairment (10 %). Median diagnostic delay was 8.6 years (±8.8). Atypical features were observed in 4 patients: marked distal muscle weakness and severe hearing loss at onset, as well as leukoencephalopathy and mesial temporal sclerosis during the disease course. By
GAA
sequence analysis, two causing mutations were detected in 22/30 patients, only one in the remaining 8 subjects. Overall, 29/30 patients harbored the common c.−32−13T>G mutation (2 were homozygous). Two new DNA variations were discovered (c.2395C>G, c.1771C>T). 14 patients received ERT for up to 60 months. Our study confirms LOPD clinical and genetic heterogeneity: atypical features may contribute to expand the clinical phenotype highlighting its multi-systemic nature. A timely diagnosis could allow early ERT start. An accurate follow-up is recommended to evaluate treatment responses.
Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype ...correlation could be established to date.
We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations.
We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein.
Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.
Congenital myopathies (CMs) caused by mutation in cofilin‐2 gene (CFL2) show phenotypic heterogeneity ranging from early‐onset and rapid progressive forms to milder myopathy. Muscle histology is also ...heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss‐of‐function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2−/− knockout mouse model.
Hereditary inclusion-body myopathy or distal myopathy with rimmed vacuoles (h-IBM/DMRV) is due to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, which ...codes for an enzyme of the sialic acid biosynthetic pathway. By Western blot (WB) analysis, we have previously shown that in h-IBM/DMRV muscle, the neural cell adhesion molecule (NCAM) has increased electrophoretic mobility that reflects reduced sialylation of the protein.
To identify patients with h-IBM/DMRV with atypical clinical or pathologic phenotype using NCAM analysis and the possible cellular mechanism associated with the overall abnormal sialylation of NCAM observed in this disorder.
WB analysis of NCAM was performed on muscle biopsies of 84 patients with an uncharacterized muscle disorder who were divided in the following 2 groups: 1) 46 patients with a proximal muscle weakness in whom the main limb-girdle muscular dystrophy syndromes had been ruled out; and 2) 38 patients with a distal distribution of weakness in whom a neurogenic affection had been excluded. Patients in whom a reduced sialylation of NCAM was suspected were studied for the presence of GNE mutations.
In 3 patients, we found that NCAM had increased electrophoretic mobility, thus suggesting an abnormal sialylation of the protein. The genetic study demonstrated that they all carried pathogenic GNE mutations. Further studies demonstrated that hyposialylated NCAM, showing increased electrophoretic mobility on WB, is expressed by nonregenerating fibers in h-IBM/DMRV muscle.
WB analysis of NCAM may be instrumental in the identification of h-IBM/DMRV with atypical clinical or pathologic features.
•We report the first Italian family with TRPV4 related scapuloperoneal atrophy.•Skeletal deformities could support the clinical suspicion.•An early diagnosis is crucial to prevent the more severe ...congenital form.•We provide a literature review on this rare disease.
Scapuloperoneal spinal muscular atrophy (SPSMA) is a rare autosomal dominant disorder caused by heterozygous mutations in the transient receptor potential cation channel (TRPV4) gene, characterized by progressive scapuloperoneal atrophy and weakness. Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur. We report the first Italian family with SPSMA, harboring the c.806G>A mutation in TRPV4 gene (p. R269H). The pattern of expression was variable: the father showed a mild muscular involvement, while the son presented at birth skeletal dysplasia and a progressive course. We reinforce the concept that the disease can be more severe in the following generations. The disorder should be considered in scapuloperoneal syndromes with autosomal dominant inheritance and a neurogenic pattern. The presence of skeletal deformities strongly supports this suspicion. An early diagnosis of SPSMA may be crucial in order to prevent the more severe congenital form.
Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are ...2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P–Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP–Lambert-Eaton myasthenic syndrome). Lambert-Eaton myasthenic syndrome is a very rare disorder in children younger than age 12 years. Herein, we report a 25-year-old man with NP–Lambert-Eaton myasthenic syndrome, which onset was at the age of 10 years. To date, this is the most long-term follow-up of NP–Lambert-Eaton myasthenic syndrome in childhood. In our patient, the only symptomatic treatment with 3,4-diaminopyridine phosphate has been sufficient to guarantee him a good quality of life. Our data remind physicians to keep in mind the diagnosis of Lambert-Eaton myasthenic syndrome in children with a proximal myopathic pattern and they confirm the specificity of compound muscle action potential incremental pattern after brief maximal effort in Lambert-Eaton myasthenic syndrome.
We report a 44-years-old man, who presented, since the age of 20, recurrent episodes of rhabdomyolysis after exercise or prolonged fasting; he also showed a mild mental retardation and sporadic ...choreo-athetoid movements. His 14-years-old son had a psychomotor developmental delay with episodes of drowsiness and head drops, occurring mainly at fasting, and exercise-induced choreo-athetoid movements but no history of pigmenturia. Neurological examination revealed microcephaly, mild spastic ataxia and mental retardation. EEG was normal in the proband but in the son showed, during fasting, diffuse spike-wave discharges disappearing after food intake. Brain MRI was normal in both. CSF analysis in the son revealed hypoglycorrhachia (40 mg/dl). Clinical and laboratory findings suggested a search for mutations in SCL2A1 (GLUT-1) gene that revealed in both subjects, an already reported pathogenic heterozygous mutation (R333W). GLUT-1 Deficiency Syndrome (DS) is a rare encephalopathy, caused by impaired glucose transport into the brain, presenting with early-onset epilepsy, movement disorders, developmental delay and microcephaly but rhabdomyolysis has never been reported in similar cases. To better define the origin of recurrent exercise-induced rhabdomyolysis in the father, he underwent forearm ischemic test (normal), EMG (myopathic pattern) and muscle biopsy that evidenced unspecific changes. Muscle biochemical studies excluded the most common metabolic causes of recurrent rhabdomyolysis, but VLCAD gene analysis in the father showed two known heterozygous mutations (p.G185S and p.R385W) whereas his son carried only the p.G185S. Nowadays, it is evident that cases of “double trouble” are increasing and, when a known phenotype is accompanied by some atypical features, we should think of an alternative explanation of unusual presentations.
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