Sporadic Myotonic Dystrophy Type 2 in a Japanese Patient.

We herein report a Japanese patient with myotonic dystrophy type 2 (DM2), which is rare in Japan. A 64-year-oldman had proximal muscle weakness and grip myotonia. Electromyography showed myotonic discharges, but dystrophia-myotonica protein kinase (DMPK) was negative for CTG repeats. A muscle biopsy revealed increased central nuclei, pyknotic nuclear clumps and muscle fiber atrophy, mainly in type 2 fibers, raising the possibility of DM2. The diagnosis was genetically confirmed by the abnormal CCTG repeat size in cellular nucleic acid-binding protein (CNBP) on repeat-primed polymerase chain reaction, which was estimated to be around 4,500 repeats by Southern blotting.

A Case of Oculopharyngeal Muscular Dystrophy Caused by a Novel PABPN1 c.34G > T (p.Gly12Trp) Point Mutation without Polyalanine Expansion.

Immediately after the initial methionine codon, the PABPN1 gene encodes a stretch of 10 alanines, 1 glycine, and 2 alanines. Oculopharyngeal muscular dystrophy (OPMD) is caused by the expansion of the first 10 alanine stretches. The only exception is the missense mutation of glycine at the 12th residue into alanine, which elongates the stretch to 13 alanines by connecting the first and second stretch with the addition of one alanine in between, indicating that the expansion or elongation of the alanine stretch results in OPMD. We report a 77-year-old man with the novel missense mutation c.34G > T (p.Gly12Trp) in PABPN1 gene whose clinicopathological findings were compatible with OPMD. He presented with slowly progressive bilateral ptosis, dysphagia, and symmetrical proximal dominant muscle weakness. Magnetic resonance imaging revealed selective fat replacement of the tongue, bilateral adductor magnus, and soleus muscles. Immunohistochemistry studies of the muscle biopsy sample revealed PABPN1-posibive aggregates in the myonuclei which have been reported to be specific to OPMD. This is the first OPMD case caused by neither the expansion nor the elongation of alanine stretch. The present case suggests that OPMD may be caused not only by triplet repeats but also by point mutations.

Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy.

Oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy (OPMD) are similar and even believed to be indistinguishable in terms of their myopathological features. To address the diagnostic gap, we evaluated the muscle biopsy samples for p62 expression by immunohistochemistry and compared the occurrence and the frequency of intranuclear inclusions among the individuals with OPDM (harboring CGG repeat expansion in LRP12 (n = 19), GIPC1 (n = 6), or NOTCH2NLC (n = 7)), OPMD (n = 15), and other rimmed vacuolar myopathies. We found that myonuclei with p62-positive intra-nuclear inclusions (myo-INIs) were significantly more frequent in OPMD (11.9 ± 1.1%, range 5.9-18.6%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (0.9-1.5% on average, range 0.0-2.8%, p < 0.0001). In contrast, INIs in non-muscle cells such as blood vessels, peripheral nerve bundles, and muscle spindles (non-muscle-INIs) were present in OPDM, but absent in OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark.

Frontal lobe-dominant cerebral blood flow reduction and atrophy can be progressive in Duchenne muscular dystrophy.

This study aimed to clarify the characteristics and progressive changes of brain image abnormalities in Duchenne muscular dystrophy (DMD). Brain images of 39 adult patients (median age, 24 years) were retrospectively reviewed, along with intellectual and/or neurodevelopmental test results. On magnetic resonance imaging (n = 13), atrophy of the frontal lobe, pars opercularis (without other frontal atrophy), and cerebellum was observed in 6, 1, and 1 patients, respectively. On computed tomography (n = 32), atrophy of the frontal lobe, pars opercularis, temporal lobe, and occipital lobe was observed in 20, 1, 1, and 1 patients, respectively. Re-imaging of 12 patients revealed progression of cerebral atrophy in 6. All 18 patients who underwent single photon emission computed tomography had reduced total and/or focal blood flow. Reduced total cerebral blood flow was observed significantly more frequently in patients with deleterious Dp140 mutations compared to those without. Re-examination 4 years later revealed worsening of reduced blood flow in the frontotemporal lobe in 1 patient. Abnormalities were detected by at least one imaging modality in 32 of 39 patients. No significant relationship was observed between imaging abnormalities and developmental disorders or intelligence quotient. In conclusion, DMD patients frequently exhibit frontal lobe-dominant cerebral blood flow reduction and atrophy, and may be at risk of progressive cerebral atrophy and reduced cerebral blood flow. MRI, CT, and/or brain single photon emission CT are useful for detecting brain abnormalities in adult DMD patients.

Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy.

AIMS: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy. METHODS: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2). RESULTS: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy. CONCLUSION: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. CASE PRESENTATION: A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. CONCLUSION: We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

A symptomatic male carrier of Duchenne muscular dystrophy with Klinefelter's syndrome mimicking Becker muscular dystrophy.

Duchenne and Becker muscular dystrophy (DMD/BMD) are commonly inherited muscle disorders. We report a 31-year-old male who had muscle symptoms with left-right differences and intellectual disability. He was diagnosed with BMD at age 15 primarily based on muscle biopsy findings. A few years later, DMD gene analysis revealed that he was a heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation. A karyotype analysis was compatible with XXY Klinefelter's syndrome. The analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample revealed a skewed XCI pattern. This is the first reported case of a symptomatic male carrier of DMD caused by skewed XCI in Klinefelter's syndrome with a genetically proven heterozygous mutation of the DMD gene. The skewed XCI pattern could also explain the left-right differences in skeletal muscle symptoms observed in this patient.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

Respiratory Dysfunction in Becker Muscular Dystrophy Patients: A Case Series and Autopsy Report.

BACKGROUND: Few studies have examined respiratory dysfunction in patients with Becker muscular dystrophy (BMD). OBJECTIVE: This study aimed to examine the characteristics of respiratory dysfunction in patients with BMD. METHODS: The present retrospective study assessed respiratory parameters of adult BMD patients using medical records and compared these parameters with various patient characteristics to identify correlations. BMD patients aged 17 years and older who had been diagnosed genetically and/or pathologically were included in the analysis. RESULTS: Of the source population of 133 patients, respiratory function was assessed in 85. Two of these patients had no symptoms, and eight had died. Mean % forced vital capacity (% FVC) was 94.2+/-21.7% (median, 96.1%; range, 5.1-134.1%). In 16 (19%) of the 85 patients, % FVC was <80%. Of these, seven were non-ambulant. Age, ambulation, and cardiac function did not significantly differ between patients with or without respiratory dysfunction, whereas age at onset was significantly lower in patients with respiratory dysfunction (7.7+/-4.7 years vs. 14.4+/-11.9 years; p = 0.001). One non-ambulant patient was a continuous NPPV user, and one patient had been recommended NPPV use but refused. Autopsy of one patient revealed that the diaphragm and intercostal muscles were less affected than proximal skeletal muscles. CONCLUSION: BMD patients are at risk of developing respiratory dysfunction due to dystrophic changes in respiratory muscles. Respiratory function should be carefully and periodically monitored in these patients.

Severe cardiac involvement with preserved truncated dystrophin expression in Becker muscular dystrophy by +1G>A DMD splice-site mutation: a case report.

Becker muscular dystrophy (BMD) is caused by specific mutations in the DMD gene that causes progressive muscle weakness and primarily affects skeletal and cardiac muscle. Although cardiac involvement is a significant cause of mortality in BMD, the genetic-phenotype correlation for skeletal and cardiac muscles has not been elucidated. Here, we described a 39-year-old man with BMD, who presented with subtle skeletal muscle weakness in the right leg in his 20s and underwent left ventricular restoration for severe dilated cardiomyopathy at the age of 29. He had difficulty climbing stairs after the age of 35. Neither duplication nor deletion of exons was detected by multiplex ligation-dependent probe amplification. A hemizygous c.264 + 1G>A mutation in intron 4 of the DMD was identified by next-generation sequencing. Furthermore, exon 4 skipping of the DMD was confirmed in both skeletal and cardiac muscles evaluated by reverse transcriptase PCR. Endomyocardial and skeletal muscle biopsies revealed dystrophic pathology characterized by muscle fiber atrophy and hypertrophy with a mild degree of interstitial fibrosis. Interestingly, dystrophin immunohistochemistry demonstrated patchy and faint staining of the skeletal muscle membranes but almost normal staining of the cardiac muscle membranes. Western blot analysis revealed a decreased amount of truncated dystrophin in skeletal muscle but surprisingly almost normal amount in cardiac muscle. This case indicates that BMD patients may have severe cardiac dysfunction despite preserved cardiac truncated dystrophin expression.

Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs). RESULTS: We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types. CONCLUSION: Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.

Severe Ocular Complications After Blepharoptosis Correction in the Oculopharyngeal Muscular Dystrophy Patient: Literature Review and Case Presentation.

BACKGROUND: Blepharoptosis correction in oculopharyngeal muscular dystrophy (OPMD) patients may result in severe ocular complications owing to lagophthalmos and ophthalmoplegia. Managing the acute episode to prevent further aggravation of the keratopathy or blindness is of paramount importance. METHODS: A review of the literature for severe chemosis, keratopathy, and corneal ulceration in the patient population was performed using the PubMed database, with key words including ptosis surgery, ptosis correction, ptosis repair, and oculopharyngeal muscular dystrophy. A retrospective review of all patients with blepharoptosis from a single surgeon from September 2009 and May 2017 was performed, selecting those with OPMD who underwent blepharoptosis correction. RESULTS: Our literature review revealed a total of 15 articles after excluding repeated articles and selecting those meeting our inclusion criteria. A total of 232 OPMD patients underwent blepharoptosis correction. Severe ocular complications were noted in 7 patients, with treatment unspecified. For 9 years, 2 OPMD patients at our institute underwent blepharoptosis correction, with one developing severe acute keratitis, chemosis, and corneal ulceration due to lagophthalmos and ophthalmoplegia. Use of the temporary drawstring tarsorrhaphy and topical eye drop treatment for 2 weeks led to resolution of corneal ulcerations without necessitating further intervention. CONCLUSIONS: Severe ocular complications may occur after blepharoptosis correction in OPMD patients, potentially owing to lagophthalmos and ophthalmoplegia. Temporary drawstring tarsorrhaphy is an effective option to treat these adverse outcomes.

Psychiatric and neurodevelopmental aspects of Becker muscular dystrophy.

Little is known about the relationship between Becker Muscular Dystrophy (BMD) and mental disorders. This study aimed to clarify whether BMD is a risk factor for psychiatric diseases. We asked genetically or immunohistochemically confirmed BMD patients to participate in the study interview. Participants who consented to psychiatric tests underwent further assessments of intellectual, psychological, and neurodevelopmental disorders. In total, 76 (73%) of 105 BMD patients (median age, 37 years) completed the interview. Of these, 6 had developmental disorders (mental retardation, pervasive developmental disorder), 33/76 (43%) experienced bullying in school, 11 exhibited problematic behaviors such as cutting class and violent incidents, and 16 had psychiatric disorders (schizophrenia spectrum, 5; depressive spectrum, 4; stress-related disorders, 3; obsessive-compulsive and related disorders, 2; somatic symptom and related disorders, 2; bipolar and related disorders, 1). Mean IQ was normal, whereas 13/40 (32.5%) of participants were in a depressive state. High trait anxiety was found in 20/40 (50%) of patients, while 15/40 (38.5%) were in an anxious state. Review of MRI data from 14 participants revealed brain atrophy caused solely by BMD and unrelated to any other complication. Our findings suggest that BMD patients are at risk of developing psychiatric disorders. Physical handicap or bullying may influence their mental state, as many of them have high trait anxiety. Parents, teachers, and supporters should be mindful of the daily environment of BMD patients and provide support to help them cope with stress.

A Nationwide Survey on Danon Disease in Japan.

Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf⁻Parkinson⁻White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease.

Social involvement issues in patients with Becker muscular dystrophy: A questionnaire survey of subjects from a patient registry.

BACKGROUND: Little is known about the relationship between Becker Muscular Dystrophy (BMD) and developmental problems, school life, employment, and mental problems. We aimed to clarify whether BMD is a risk factor for developmental disorders, problematic behavior, psychiatric diseases, and other social difficulties in school life and employment. METHODS: Adults with genetically or immunohistochemically confirmed BMD from the Registry of Muscular Dystrophy in Japan (REMUDY) were asked to complete a questionnaire regarding patient history, school life, employment, and mental problems. RESULTS: In total, 125 (68.3%) of 183 participants with BMD (median age, 37.2 years) completed the questionnaire. Of these, ten had developmental disorders (mental retardation, autism, and speech disturbance). Fifty-eight (44%) experienced bullying in school, and 39 felt the reason for bullying was physical handicap. Sixteen participants experienced problematic behavior such as cutting class, domestic violence, violent incidents, suicide attempts, or self-mutilation. Employment histories were noted by 92 (73%), of whom 15 could not continue to work due to physical handicaps. Fifteen participants had psychiatric disorders, with 5, 3 and 1 having neurosis, depression, and bipolar disorder, respectively. The other 6 participants with psychiatric disorders did not specify their diagnoses. Patients carrying a Dp140 expression change had significantly more incidences of developmental disorders, but not bullying, problematic behavior, workplace difficulties, or psychiatric disorders. CONCLUSIONS: Patients with BMD risk bullying and workplace difficulties, as well as developing psychiatric disorders. Parents, teachers, and supporters should be mindful of the daily environment of BMD patients and provide support to help them cope with stress.

Corrigendum: Genetic diagnosis of Duchenne/Becker muscular dystrophy using next-generation sequencing: validation analysis of DMD mutations.

This corrects the article DOI: 10.1038/jhg.2016.7.

Induction of Pluripotent Stem Cells from a Manifesting Carrier of Duchenne Muscular Dystrophy and Characterization of Their X-Inactivation Status.

Three to eight percent of female carriers of Duchenne muscular dystrophy (DMD) develop dystrophic symptoms ranging from mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy due to skewed inactivation of X chromosomes during early development. Here, we generated human induced pluripotent stem cells (hiPSCs) from a manifesting female carrier using retroviral or Sendai viral (SeV) vectors and determined their X-inactivation status. Although manifesting carrier-derived iPS cells showed normal expression of human embryonic stem cell markers and formed well-differentiated teratomas in vivo, many hiPS clones showed bi-allelic expression of the androgen receptor (AR) gene and loss of X-inactivation-specific transcript and trimethyl-histone H3 (Lys27) signals on X chromosomes, suggesting that both X chromosomes of the hiPS cells are in an active state. Importantly, normal dystrophin was expressed in multinucleated myotubes differentiated from a manifesting carrier of DMD-hiPS cells with XaXa pattern. AR transcripts were also equally transcribed from both alleles in induced myotubes. Our results indicated that the inactivated X chromosome in the patient's fibroblasts was activated during reprogramming, and XCI occurred randomly during differentiation.

Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.

Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD.

Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A.

INTRODUCTION: Little is known about the frequency of cardiopulmonary failure in limb-girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. METHODS: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. RESULTS: Nine of the 43 patients had forced vital capacity (FVC) < 80%, and 3 used noninvasive positive pressure ventilation. Mean FVC was significantly lower in patients who were nonambulant and had normal creatine kinase levels. Only 1 patient had a prolonged QRS complex duration. Echocardiography revealed that 1 patient had very mild left ventricular dysfunction. CONCLUSIONS: These findings suggest that patients with calpainopathy may develop severe respiratory failure, but cardiac dysfunction is infrequent. Muscle Nerve 55: 465-469, 2017.

Novel TK2 mutations as a cause of delayed muscle maturation in mtDNA depletion syndrome.

Recessive mutations in TK2 cause a severe mitochondrial DNA depletion syndrome (MDS),(1) characterized by severe myopathy from early infancy. Recent reports have suggested a wider clinical spectrum including encephalomyopathic form.(1,2) We report a patient with infantile-onset fatal encephalomyopathy presenting with extreme muscle fiber immaturity.