Trouble at the junction: When myopathy and myasthenia overlap.

Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co-occurrence of myasthenia gravis or Lambert-Eaton myasthenic syndrome with an immune-mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita.

KEY POINTS: Paramyotonia congenita is a hereditary channelopathy caused by missense mutations in the SCN4A gene, which encodes the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. Affected individuals suffered from myotonia and paralysis of muscles, which were aggravated by exposure to cold. We report a three-generation Chinese family with patients presenting paramyotonia congenita and identify a novel N1366S mutation of NaV1.4. Whole-cell electrophysiological recordings of the N1366S channel reveal a gain-of-function change of gating in response to cold. Modelling and molecular dynamic simulation data suggest that an arginine-to-serine substitution at position 1366 increases the distance from N1366 to R1454 and disrupts the hydrogen bond formed between them at low temperature. We demonstrate that N1366S is a disease-causing mutation and that the temperature-sensitive alteration of N1366S channel activity may be responsible for the pronounced paramyotonia congenita symptoms of these patients. ABSTRACT: Paramyotonia congenita is an autosomal dominant skeletal muscle channelopathy caused by missense mutations in SCN4A, the gene encoding the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. We report a three-generation family in which six members present clinical symptoms of paramyotonia congenita characterized by a marked worsening of myotonia by cold and by the presence of clear episodes of paralysis. We identified a novel mutation in SCN4A (Asn1366Ser, N1366S) in all patients in the family but not in healthy relatives or in 500 normal control subjects. Functional analysis of the channel protein expressed in HEK293 cells by whole-cell patch clamp recording revealed that the N1366S mutation led to significant alterations in the gating process of the NaV1.4 channel. The N1366S mutant displayed a cold-induced hyperpolarizing shift in the voltage dependence of activation and a depolarizing shift in fast inactivation, as well as a reduced rate of fast inactivation and accelerated recovery from fast inactivation. In addition, homology modelling and molecular dynamic simulation of N1366S and wild-type NaV1.4 channels indicated that the arginine-to-serine substitution disrupted the hydrogen bond formed between N1366 and R1454. Together, our results suggest that N1366S is a gain-of-function mutation of NaV1.4 at low temperature and the mutation may be responsible for the clinical symptoms of paramyotonia congenita in the affected family and constitute a basis for studies into its pathogenesis.

Splicing biomarkers of disease severity in myotonic dystrophy.

OBJECTIVE: To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). METHODS: In a discovery cohort, we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA. RESULTS: Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. INTERPRETATION: Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.

Alternative splicing of human insulin receptor gene (INSR) in type I and type II skeletal muscle fibers of patients with myotonic dystrophy type 1 and type 2.

INSR, one of those genes aberrantly expressed in myotonic dystrophy type 1 (DM1) and type 2 (DM2) due to a toxic RNA effect, encodes for the insulin receptor (IR). Its expression is regulated by alternative splicing generating two isoforms: IR-A, which predominates in embryonic tissue, and IR-B, which is highly expressed in adult, insulin-responsive tissues (skeletal muscle, liver, and adipose tissue). The aberrant INSR expression detected in DM1 and DM2 muscles tissues, characterized by a relative increase of IR-A versus IR-B, was pathogenically related to the insulin resistance occurring in DM patients. To assess if differences in the aberrant splicing of INSR could underlie the distinct fiber type involvement observed in DM1 and DM2 muscle tissues, we have used laser capture microdissection (LCM) and RT-PCR, comparing the alternative splicing of INSR in type I and type II muscle fibers isolated from muscle biopsies of DM1, DM2 patients and controls. In the controls, the relative amounts of IR-A and IR-B showed no obvious differences between type I and type II fibers, as in the whole muscle tissue. In DM1 and DM2 patients, both fiber types showed a similar, relative increase of IR-A versus IR-B, as also evident in the whole muscle tissue. Our data suggest that the distinct fiber type involvement in DM1 and DM2 muscle tissues would not be related to qualitative differences in the expression of INSR. LCM can represent a powerful tool to give a better understanding of the pathogenesis of myotonic dystrophies, as well as other myopathies.

Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies.

Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment.

Nuclear ribonucleoprotein-containing foci increase in size in non-dividing cells from patients with myotonic dystrophy type 2.

Myotonic dystrophies (DM) are genetically based neuromuscular disorders characterized by the accumulation of mutant transcripts into peculiar intranuclear foci, where different splicing factors (among which the alternative splicing regulator muscleblind-like 1 protein, MBNL1) are ectopically sequestered. The aim of the present investigation was to describe the dynamics of the DM-specific intranuclear foci in interphase nuclei and during mitosis, as well as after the exit from the cell cycle. Primary cultures of skin fibroblasts from DM2 patients were used, as a model system to reproduce in vitro, as accurately as possible, the in vivo conditions. Cycling and resting fibroblasts were investigated by immunocytochemical and morphometric techniques, and the relative amounts of MBNL1 were also estimated by western blotting. MBNL1-containing foci were exclusively found in the nucleus during most of the interphase, while being observed in the cytoplasm during mitosis when they never associate with the chromosomes; the foci remained in the cytoplasm at cytodieresis, and underwent disassembly in early G1 to be reformed in the nucleus at each cell cycle. After fibroblasts had stopped dividing in late-passage cultures, the nuclear foci were observed to progressively increase in size. Interestingly, measurements on muscle biopsies taken from the same DM2 patients at different ages demonstrated that, in the nuclei of myofibers, the MBNL1-containing foci become larger with increasing patient's age. As a whole, these results suggest that in non-dividing cells of DM2 patients the sequestration in the nuclear foci of factors needed for RNA processing would be continuous and progressive, eventually leading to the onset (and the worsening with time) of the pathological traits. This is consistent with the evidence that in DM patients the most affected organs or tissues are those where non-renewing cells are mainly present, i.e., the central nervous system, heart and skeletal muscle.

Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2.

The mutation that underlies myotonic dystrophy type 2 (DM2) is a (CCTG)n expansion in intron 1 of zinc finger protein 9 (ZNF9). It has been suggested that ZNF9 is of no consequence for disease pathogenesis. We determined the expression levels of ZNF9 during muscle cell differentiation and in DM2 muscle by microarray profiling, real-time RT-PCR, splice variant analysis, immunofluorescence, and Western blotting. Our results show that in differentiating myoblasts, ZNF9 protein was localized primarily to the nucleus, whereas in mature muscle fibers, it was cytoplasmic and organized in sarcomeric striations at the Z-disk. In patients with DM2, ZNF9 was abnormally expressed. First, there was an overall reduction in both the mRNA and protein levels. Second, the subcellular localization of the ZNF9 protein was somewhat less cytoplasmic and more membrane-bound. Third, our splice variant analysis revealed retention of intron 3 in an aberrant isoform, and fourth quantitative allele-specific expression analysis showed the persistence of intron 1 sequences from the abnormal allele, further suggesting that the mutant allele is incompletely spliced. Thus, the decrease in total expression appears to be due to impaired splicing of the mutant transcript. Our data indicate that ZNF9 expression in DM2 patients is altered at multiple levels. Although toxic RNA effects likely explain overlapping phenotypic manifestations between DM1 and DM2, abnormal ZNF9 levels in DM2 may account for the differences in DM1.

Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene.

Myotonia is characterized by hyperexcitability of the muscle cell membrane. Myotonic disorders are divided into two main categories: non-dystrophic and dystrophic myotonias. The non-dystrophic myotonias involve solely the muscle system, whereas the dystrophic myotonias are characterized by multisystem involvement and additional muscle weakness. Each category is further subdivided into different groups according to additional clinical features or/and underlying genetic defects. However, the phenotypes and the pathological mechanisms of these myotonic disorders are still not entirely understood. Currently, four genes are identified to be involved in myotonia: the muscle voltage-gated sodium and chloride channel genes SCN4A and CLCN1, the myotonic dystrophy protein kinase (DMPK) gene, and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP. Additional gene(s) and/or modifying factor(s) remain to be identified. In this study, we investigated a large Norwegian family with clinically different presentations of myotonic disorders. Molecular analysis revealed CCTG repeat expansions in the CNBP gene in all affected members, confirming that they have myotonic dystrophy type 2. However, a CLCN1 mutation c.1238C>G, causing p.Phe413Cys, was also identified in several affected family members. Heterozygosity for p.Phe413Cys seems to exaggerate the severity of myotonia and thereby, to some degree, contributing to the pronounced variability in the myotonic phenotype in this family.

Muscle pathology in myotonic dystrophy: light and electron microscopic investigation in eighteen patients.

Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Two known genetic subtypes include DM1 (myotonic dystrophy type 1) and DM2 (myotonic dystrophy type 2). Genetic testing is considered as the only reliable diagnostic criterion in myotonic dystrophies. Relatively little is known about DM1 and DM2 myopathology. Thus, the aim of our study was to characterise light and electron microscopic features of DM1 and DM2 in patients with genetically proven types of the disease. We studied 3 DM1 cases and 15 DM2 cases from which muscle biopsies were taken for diagnostic purposes during the period from 1973 to 2006, before genetic testing became available at our hospital. The DM1 group included 3 males (age at biopsy 15-19). The DM2 group included 15 patients (5 men and 10 women, age at biopsy 26-60). The preferential type 1 fibre atrophy was seen in all three DM1 cases in light microscopy, and substantial central nucleation was present in two biopsies. Electron microscopy revealed central nuclei in all three examined muscle biopsies. No other structural or degenerative changes were detected, probably due to the young age of our patients. Central nucleation, prevalence of type 2 muscle fibres, and the presence of pyknotic nuclear clumps were observed in DM2 patients in light microscopy. Among the ultrastructural abnormalities observed in our DM2 group, the presence of internal nuclei, severely atrophied muscle fibres, and lipofuscin accumulation were consistent findings. In addition, a variety of ultrastructural abnormalities were identified by us in DM2. It appears that no single ultrastructural abnormality is characteristic for the DM2 muscle pathology. It seems, however, that certain constellations of morphological changes might be indicative of certain types of myotonic dystrophy.

Shear wave velocity is sensitive to changes in muscle stiffness that occur independently from changes in force.

Clinical assessments for many musculoskeletal disorders involve evaluation of muscle stiffness, although it is not yet possible to obtain quantitative estimates from individual muscles. Ultrasound elastography can be used to estimate the material properties of unstressed, homogeneous, and isotropic materials by tracking the speed of shear wave propagation; these waves propagate faster in stiffer materials. Although elastography has been applied to skeletal muscle, there is little evidence that shear wave velocity (SWV) can directly estimate muscle stiffness since this tissue violates many of the assumptions required for there to be a direct relationship between SWV and stiffness. The objective of this study was to evaluate the relationship between SWV and direct measurements of muscle force and stiffness in contracting muscle. Data were collected from six isoflurane-anesthetized cats. We measured the short-range stiffness in the soleus via direct mechanical testing in situ and SWV via ultrasound imaging. Measurements were taken during supramaximal activation at optimum muscle length, with muscle temperature varying between 26°C and 38°C. An increase in temperature causes a decrease in muscle stiffness at a given force, thus decoupling the tension-stiffness relationship normally present in muscle. We found that increasing muscle temperature decreased active stiffness from 4.0 ± 0.3 MPa to 3.3 ± 0.3 MPa and SWV from 16.9 ± 1.5 m/s to 15.9 ± 1.6 m/s while force remained unchanged (mean ± SD). These results demonstrate that SWV is sensitive to changes in muscle stiffness during active contractions. Future work is needed to determine how this relationship is influenced by changes in muscle structure and tension.NEW & NOTEWORTHY Shear wave ultrasound elastography is a noninvasive tool for characterizing the material properties of muscle. This study is the first to compare direct measurements of stiffness with ultrasound measurements of shear wave velocity (SWV) in a contracting muscle. We found that SWV is sensitive to changes in muscle stiffness, even when controlling for muscle tension, another factor that influences SWV. These results are an important step toward developing noninvasive tools for characterizing muscle structure and function.

Paramyotonia Congenita with Persistent Distal and Facial Muscle Weakness: A Case Report with Literature Review.

BACKGROUND: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. CASE REPORT: We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. CONCLUSIONS: PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.

Absence of a differentiation defect in muscle satellite cells from DM2 patients.

Myotonic dystrophy type 1 (DM1) and type II (DM2) are dominantly inherited multisystemic disorders. DM1 is triggered by the pathological expansion of a (CTG)(n) triplet repeat in the DMPK gene, whereas a (CCTG)(n) tetranucleotide repeat expansion in the ZNF9 gene causes DM2. Both forms of the disease share several features, even though the causative mutations and the loci involved differ. Important distinctions exist, such as the lack of a congenital form of DM2. The reason for these disparities is unknown. In this study, we characterized skeletal muscle satellite cells from adult DM2 patients to provide an in vitro model for the disease. We used muscle cells from DM1 biopsies as a comparison tool. Our main finding is that DM2 satellite cells differentiate normally in vitro. Myotube formation was similar to unaffected controls. In contrast, fetal DM1 cells were deficient in that ability. Consistent with this observation, the myogenic program in DM2 was intact but is compromised in fetal DM1 cells. Although expression of the ZNF9 gene was enhanced in DM2 during differentiation, the levels of the ZNF9 protein were substantially reduced. This suggests that the presence of a large CCTG tract impairs the translation of the ZNF9 mRNA. Additionally, DM2 muscle biopsies displayed the altered splicing of the insulin receptor mRNA, correlating with insulin resistance in the patients. Finally, CUGBP1 steady-state protein levels were unchanged in DM2 cultured muscle cells and in DM2 muscle biopsies relative to controls, whereas they are increased in DM1 muscle cells. Our findings suggest that the myogenic program throughout muscle development and tissue regeneration is intact in DM2.

Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.

OBJECTIVE: To verify the diagnosis of channelopathies in two families and explore the mechanism of the overlap between periodic paralysis (PP) and paramyotonia congenita (PMC). METHODS: We have studied two cases with overlapping symptoms of episodic weakness and stiffness in our clinical center using a series of assessment including detailed medical history, careful physical examination, laboratory analyses, muscle biopsy, electrophysiological evaluation, and genetic analysis. RESULTS: The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A. The second proband and part of his family with the overlap of PMC and hypokalemic periodic paralysis type 2 (HypoPP2) has been identified as c.4343G > A (R1448H) substitution of the gene SCN4A. In addition, one member of the second family with overlapping symptoms has been identified as a novel mutation c.2111C > T without the mutation c.4343G > A. CONCLUSIONS: SCN4A gene mutations can cause the overlap of PMC and PP (especially the HypoPP2). The clinical symptoms of episodic weakness and stiffness could happen at a different time or temperature. Based on diagnosis assessments such as medical history and muscle biopsy, further evaluations on long-time exercise test, genetic analysis, and patch clamp electrophysiology test need to be done in order to verify the specific subtype of channelopathies. Furthermore, the improvement of one member in the pregnancy period can be used as a reference for the other female in the child-bearing period with T704M.

[Eulenburg's paramyotonia congenita]. / Paramyotonie congénitale d'Eulenburg.

INTRODUCTION: Paramyotonia congenita is an autosomal dominant sodium channelopathy, caused by mutations in gene coding for muscle voltage-gated sodium channel alpha subunit. CASE REPORT: We report the case of a 38-year-old man who described since childhood muscle stiffness with attacks ok weakness induced by two provocative stimuli: cold exposure and exercise. It primarily concerned eyelids and hands, occasionally limbs. Family history suggested an autosomal dominant mode of transmission. Clinical examination revealed myotonia at the thenar eminence percussion. Generalized myotonic discharges were observed on electromyography. Molecular diagnosis reported an Arg1448Cys mutation in exon 24 in gene coding for muscle voltage-gated sodium channel alpha subunit (SCN4A) in chromosome 17. CONCLUSION: Paramyotonia congenita is not evolutive. Treatment is essentially preventive. Some medications could be proposed: membrane stabilizing agents like antiarrhythmic drugs (mexiletine, tocainide), or the carbonic anhydrase inhibitor (acetazolamide). Precautions may be taken during general anaesthesia because of diaphragm myotonia risk.

Proximal myotonic dystrophy associated with parkinsonism.

Although mental changes and cognitive disorders are seen frequently in myotonic dystrophy (MD) there are only three cases of MD associated with parkinsonism reported in the literature. We report another case of this extremely rare combination.

A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24.

The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 +/- 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy-both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.

Hyperparathyroidism in a patient with proximal myotonic myopathy (PROMM).

We describe a 60-year-old woman with progressive proximal leg weakness and dystrophic changes of the quadriceps and the adductor muscles on magnetic resonance imaging. She also suffered from primary hyperparathyroidism. A biopsy of the left deltoid muscle showed vacuoles as an unusual histopathological finding.

Intolerance to neuroleptics and susceptibility for malignant hyperthermia in a patient with proximal myotonic myopathy (PROMM) and schizophrenia.

We report a patient with proximal myotonic myopathy who was treated with neuroleptics because of exacerbating schizophrenia. Under therapy with fluanxol, the patient developed muscle stiffness and oculogyric cramps. Treatment with both amisulpride and olanzapine lead to markedly elevated serum creatine kinase levels. An in-vitro contracture test was positive for halothane. Thus, in patients with all kinds of multisystemic myotonic myopathies, a susceptibility for malignant hyperthermia and intolerance towards neuroleptics should be taken into account.

Proximal myotonic myopathy and proximal myotonic dystrophy: two different entities? The phenotypic variability of proximal myotonic syndromes.

Multisystemic myotonic myopathies are characterised by a variable pattern of symptoms and signs and a variable degree of disease severity. Proximal myotonic dystrophy has been described as an entity distinct from proximal myotonic myopathy because of severe proximal muscle weakness and dystrophic changes on magnetic reasonace imaging and on muscle histopathology. We describe two siblings, one of them presenting with a proximal myotonic myopathy phenotype, the other with a proximal myotonic dystrophy-like phenotype. The variability of disease expression in these two siblings suggests that a proximal myotonic dystrophy-like variant may occur in proximal myotonic myopathy.

Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study.

Myotonic dystrophy (DM1) and proximal myotonic myopathy (PROMM or DM2) are two distinct muscular disorders with multisystemic involvement. Both have previously been reported to be associated with cognitive impairment and white matter lesions detected by cerebral magnetic resonance imaging (MRI). In this study, the extent of brain atrophy was investigated in vivo in ten DM1 and nine PROMM patients in comparison to age-matched healthy controls for each group. The diagnosis was confirmed by DNA analysis of all patients. As a quantitative marker, the ratio of brain parenchymal to intracranial volume, called brain parenchymal fraction (BPF), was calculated from 3-dimensional MRI data using an automated analysis technique. Compared to age-matched healthy controls (mean BPF 0.852 +/- 0.032), the BPF in DM1 patients (0.713 +/- 0.031) was highly significantly decreased (P < 0.001). In contrast, the PROMM patients (mean BPF 0.792 +/- 0.029) showed only slightly decreased BPF values (P < 0.05). BPF was not significantly correlated to any of the clinical or genetic parameters in both diseases (disease duration, motor score, educational level, and number of CTG repeats in the expanded allele). In summary, global brain atrophy was demonstrated to occur in both diseases, but was more severely manifestated in DM1 patients.