Chiara Terracciano

Preferential central nucleation of type 2 myofibers is an invariable feature of myotonic dystrophy type 2.

The clinical features of myotonic dystrophy type 1 (DM1) and type 2 (DM2) may present striking similarity, whereas, in some cases, the DM2 phenotype may be so mild that the diagnosis may be missed. Therefore, the identification of disease‐specific histopathological patterns for DM1 and DM2 may help clinicians to correctly address genetic studies. We performed a comparative morphological and morphometric analysis on muscle biopsies from 10 DM1 and 11 DM2 patients, comparing type 1 and type 2 fibers as to: fiber type predominance, transverse diameter, atrophy and hypertrophy factors, and prevalence of central nuclei. In DM1 cases we observed preferential type 1 fiber atrophy and a higher prevalence of central nucleation among type 1 fibers in all cases. In DM2 muscle biopsies, high rates of atrophic and hypertrophic type 2 fibers were observed in most cases, and preferential central nucleation in type 2 fibers was present in all cases. As opposed to DM1, in which type 1 fibers display most of the histological changes, preferential atrophy and hypertrophy of type 2 fibers may be considered as markers of DM2. A higher prevalence of central nuclei among hypertrophic type 2 fibers has a predictive value for the diagnosis of DM2. Thus, morphometric and fiber type‐based histological analysis of muscle biopsies may help differentiate between DM1 and DM2 and guide molecular analysis.

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

Mutations in the ALS5/SPG11/ KIAA1840 gene cause autosomal recessive hereditary spastic paraplegia or autosomal recessive juvenile amyotrophic lateral sclerosis. Montecchiani et al . show that KIAA1840 mutations can manifest also as recessive Charcot-Marie-Tooth disease. They describe 12 kindreds with 15 different mutations, two of which have not been reported previously.

Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity

Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, ptosis, ophthalmoplegia, and leukoencephalopathy with early onset and severe prognosis. Mutations in the TYMP/ECGF1 gene cause a loss of thymidine phosphorylase catalytic activity, disrupting the homeostasis of intramitochondrial nucleotide pool. We report a woman with a very late onset of MNGIE, lacking peripheral neuropathy. Thymidine phosphorylase activity was markedly reduced in cultured fibroblasts, but only mildly reduced in buffy coat, where the defect is usually detected, and plasma thymidine was mildly increased compared to typical MNGIE patients. TYMP/ECGF1 analysis detected two heterozygous mutations, including a novel missense mutation. These findings indicate that a partial loss of thymidine phosphorylase activity may induce a late-onset and incomplete MNGIE phenotype.

Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study and self-reported questionnaires.

There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep–wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients.

Recurrent hyperCKemia with normal muscle biopsy in a pediatric patient with neuromyelitis optica

Neuromyelitis optica (NMO) is a demyelinating disease of the CNS that preferentially affects the optic nerve and spinal cord.1 The presence of circulating autoantibodies (NMO–immunoglobulin G [IgG]) having the water channel aquaporin-4 (AQP-4) as their target antigen is associated with NMO.1 Outside the CNS AQP-4 is present in the distal collecting tubes of the kidney, in parietal cells of the stomach,2 and in fast-twitch fibers of skeletal muscle.3 Several findings support the idea that AQP-4 water channels may be associated to the dystrophin-glycoprotein complex (DGC) in skeletal muscle fibers and AQP-4 expression has been found altered in muscle diseases.4

Association of HLA-DQB1*05:02 and DRB1*16 Alleles with Late-Onset, Nonthymomatous, AChR-Ab-Positive Myasthenia Gravis

An association of several HLA alleles with myasthenia gravis (MG) has been reported. Aim of this work was to analyze the HLA allele profile in a survey of 76 unselected Italian MG patients and in a subgroup characterized by disease onset after the age of 50 years, absence of thymoma, and presence of antiacetylcholine receptor antibodies. We defined this subgroup by the acronym LOAb. Typing was performed at low resolution for HLA-A, -B, and -DRB1 loci with sequence-specific oligonucleotide probe (PCR-SSO); at high resolution for HLA-DQB1 locus by PCR with sequence-specific primers (PCR-SSPS). HLA allele frequencies were compared with 100 healthy controls. No correlation was observed between MG and the studied HLA class I alleles. On the contrary, a strong positive association was found for the HLA class II alleles DQB1∗05:02 (P c = 0.00768) and DRB1∗16 (P c = 0.0211) in the LOAb subgroup (n = 27) of MG patients. Association between DQB1∗05:02 and some subtypes of MG has been previously reported but not in patients with the LOAb characteristics. Therefore, the HLA allele DQB1∗05:02 might be considered as a susceptibility marker for LOAb among Italians.

Upper motor neuron involvement in X-linked recessive bulbospinal muscular atrophy

OBJECTIVE Clinicopathological findings of X-linked recessive bulbospinal muscular atrophy (SBMA) are indicative of lower motor neuron and primary sensory neuron involvement. The aim of our study was to investigate the presence of subclinical upper motor neuron (UMN) dysfunction in this disease. METHODS Two siblings with clinical presentation, routine electrophysiological tests, histopathological features of muscle and nerve biopsies and genetic testing consistent with diagnosis of SBMA underwent transcranial magnetic stimulation (TMS). The analysed parameters were motor evoked potential (MEP) threshold, silent period (SP) and central motor conduction time. Intracortical inhibition with paired pulses from 1 to 6ms interstimulus intervals (ISIs) was evaluated in the older brother. RESULTS MEP parameters were significantly altered in limb and cranial muscles and MEP suppression after paired stimulation significantly reduced in the older brother. MEP abnormalities were present in one lower limb, but SP abolished in all limbs, in the younger brother. CONCLUSIONS Subclinical involvement of UMNs may be present in patients affected by SBMA. This finding suggests that the array of neuronal systems whose function may be affected by the pathogenic process of SBMA is larger than it was considered so far. SIGNIFICANCE TMS is a sensitive diagnostic tool for the identification of UMN dysfunction and should be included in the diagnostic evaluation of patients with SBMA.

Auto-reactions, autoimmunity and psoriatic arthritis.

Evidence from the literature suggests that autoimmune processes may drive features of psoriatic arthritis (PsA). Such hypothesis is supported by the evidence that class I major histocompatibility complex (MHC) genes are associated with susceptibility to develop PsA and auto-reactive cells, such as CD8 T cells, T helper (h) 17 and plasma cells, have been demonstrated in PsA. However, no autoantigens have ever been demonstrated in PsA. The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) patients. These autoantibodies have been associated with a worse disease progression independent of anti-citrulline antibodies (ACPA). In PsA, anti-CarP antibodies have not been evaluated yet. We aimed at analyzing, for the first time, the anti-CarP antibodies in sera of patients with active PsA who were negative for ACPA in order to explore both their presence and their relationship with disease activity. A total of 70 individuals, 30 patients with diagnosis of PsA (according to CASPAR criteria) and 40 healthy controls (HC) were enrolled. We found significantly increased levels of anti-CarP antibodies in PsA patients compared with HC (P<0.0001). Our findings indicate that anti-CarP antibodies are detectable with high specificity and sensibility in PsA patients suggesting an autoimmune background of PsA. Anti-CarP antibodies can be useful in improving the diagnosis of PsA and are correlated with disease activity.

Overexpression of ErbB2 and ErbB3 receptors in Schwann cells of patients with Charcot–Marie–Tooth disease type 1A

Axon‐derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal–glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot–Marie–Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage. Muscle Nerve, 2006

An Age-Standardized Prevalence Estimate and a Sex and Age Distribution of Myotonic Dystrophy Types 1 and 2 in the Rome Province, Italy

Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2) are not exhaustive or non-available. Our aim was to estimate the minimum prevalence of DM1 and DM2 in Italy in the Rome province, applying standards of descriptive epidemiology. Methods: All patients with a molecular diagnosis of DM1/DM2 and residents in the Rome province in 2013 have been enrolled, and the age-standardized prevalence has been calculated, assuming a Poisson distribution and adjusting for age. Results: We identified 395 DM1 patients: the age-standardized prevalence for total, females and males was 9.65, 8.35 and 11.07/100,000, respectively. The mean age of subjects differed considerably according to CTG repeat length (p = 0.001). Forty DM2 patients were identified. The age-standardized prevalence for total, females and males was 0.99, 1.07 and 0.90/100,000, respectively. The mean age was 57.05. Conclusions: We estimated for the first time the age-standardized prevalence and the sex and age distribution of DM1 and DM2 in a general population. A higher prevalence of males in DM1 and females in DM2 and a higher mean age of DM2 patients (+8 years) were ascertained. Prevalence of DM2 was 10% that of DM1. These prevalence values are probably lower than mutational rates due to the incomplete penetrance of DM1 mutations and to the clinical elusiveness of DM2. Our findings will be useful in designing cohort studies and for developing a disease registry.