Myotonic dystrophy type 1 (DM1), commonly known as Steinert's disease (OMIM #160900), is the most common muscular dystrophy among adults, caused by an unstable expansion of a CTG trinucleotide repeat ...in the 3' untranslated region (UTR) of
. Besides skeletal muscle, central nervous system (CNS) involvement is one of the core manifestations of DM1, whose relevant cognitive, behavioral, and affective symptoms deeply affect quality of life of DM1 patients, and that, together with muscle and heart, may profoundly influence the global disease burden and overall prognosis. Therefore, CNS should be also included among the main targets for future therapeutic developments in DM1, and, in this regard, identifying a cost-effective, easily accessible, and sensitive diagnostic and monitoring biomarker of CNS involvement in DM1 represents a relevant issue to be addressed. In this mini review, we will discuss all the papers so far published exploring the usefulness of both cerebrospinal fluid (CSF) and blood-based biomarkers of CNS involvement in DM1. Globally, the results of these studies are quite consistent on the value of CSF and blood Neurofilament Light Chain (NfL) as a biomarker of CNS involvement, with less robust results regarding levels of tau protein or amyloid-beta.
Sporadic late-onset nemaline myopathy (SLONM) is a rare acquired myopathy characterized by rapid-onset proximal weakness in late adulthood, and the presence of nemaline bodies on muscle biopsy. In ...recent years, several therapeutic interventions, including immunomodulating agents and autologous stem cell transplantation, have shown variable degrees of efficacy in different patients, but no consensus has been reached to allow an effective tailoring of treatments in this severe disease. We performed a retrospective evaluation of clinical, pathological, laboratory, muscle MRI, and follow-up data of SLONM patients diagnosed in the period 2010–2015 in our neuromuscular center. Six patients (three males and three females) were identified. Average time elapsed from the onset of symptoms to referral to the neuromuscular specialist was 23.7 months. Monoclonal gammopathy was detectable in five patients. Nemaline bodies were detected in all the patients, and their abundance correlated with clinical severity. Signs of cardiac involvement were present in all the patients to different extents. Muscle MRI showed a preferential involvement of neck extensors, paraspinal, gluteal, hamstring and soleus muscles. All patients were treated with prednisone and repeated courses of intravenous immunoglobulins, and a favorable outcome was reached in five patients. Our experience confirms that SLONM is clinically characterized by subacute proximal and axial muscle weakness. Time to referral was relatively long and should be reduced with increasing awareness of the disease. Muscle MRI could be of help as a diagnostic tool to identify this potentially treatable myopathy. Cardiac evaluation should be warranted in all SLONM patients to detect subclinical heart involvement.
•Few studies evaluated the retinal involvement in Myotonic dystrophy type 1 (DM1).•We describe retinal findings in 61 eyes of 31 DM1 patients.•DM1 patients showed a higher central macular thickness ...than controls.•DM1 patients had a higher prevalence of retinal pigment epithelium abnormalities.•A premature aging of the retina in DM1 patients has been postulated.
The purpose of the study is to evaluate retinal involvement in a cohort of patients affected by Myotonic Dystrophy type 1 (DM1). Both eyes of 30 patients and one eye of a 31st patient with genetically proven diagnosis of DM1 and both eyes of 20 healthy age- and gender-matched subjects were enrolled. All patients underwent complete ophthalmologic examination including best-corrected visual acuity, intraocular pressure measurement, fundoscopy, fundus autofluorescence, infrared imaging and spectral-domain optical coherence tomography with central macular thickness measurement. DM1 patients showed statistically significant higher central macular thickness values than controls. In the DM1 group, butterfly (14.8%) and reticular (13.1%) pigment abnormalities were found with corresponding drusenoid deposit and focal disruption of photoreceptor and retinal pigment epithelium layers. Compared with the controls, DM1 group had higher prevalence of epiretinal membrane. In the DM1 group, the prevalence of epiretinal membrane and retinal pigment epithelium alterations were directly correlated with age, whereas no correlation was found with disease duration, CTG expansion and MIRS score. In conclusion, in addition to the typical retinal pigment epithelium changes, DM1 is also associated with abnormalities of the vitreoretinal interface, particularly epiretinal membrane, resulting in central macular thickness increase. Both inner and outer retinal alterations were associated with increasing age, suggesting that DM1 may cause a premature aging of the retina.
Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). ...However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion of Drosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscles from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.
Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 ...can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life.
We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. ...The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), revealed a triple diagnosis: autosomal dominant polycystic kidney disease (ADPKD) due to a pathogenic variant, c.2152C>T-p.(Gln718Ter), in the
gene; late-onset phenylketonuria due to the presence of two missense variants, c.842C>T-p.(Pro281Leu) and c.143T>C-p.(Leu48Ser) in the
gene; and a 915 Kb duplication on chromosome 15. Few patients with multiple concurrent genetic diagnoses are reported in the literature; in this ADPKD patient, genome-wide analysis allowed for the diagnosis of adult-onset phenylketonuria (which would have otherwise gone unnoticed) and a 15q11.2 duplication responsible for cognitive and behavioral impairment with incomplete penetrance. This case underlines the importance of clinical genetics for interpreting complex results obtained by genome-wide techniques, and for diagnosing concurrent late-onset monogenic conditions.
Introduction
Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in
PRKCG,
a ...gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development.
Methods
We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.
Results
We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in
PRKCG
, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype.
Conclusions
Our study broadens the genetic and clinical spectrum of SCA14.
To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.
The primary measure of disease severity was the ...Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.
The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74,
< 0.0001) and disease duration (0.22 ± 0.06 per additional year,
= 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8,
= 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2,
= 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.
Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.
NCT02701036.
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