Diagnosis Of Congenital Muscular Dystrophy Research Articles

Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families

Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders.

Clinical and genetic characteristics of congenital muscular dystrophies (part 2)

Dystroglycanopathy is one of the groups of congenital muscular dystrophies, the occurrence of which is associated with a disorder of α-dystroglycan glycosylation. To date, 18 genes responsible for the development of this condition are known. The 2nd part of this review presents the classification, phenotypic forms, clinical features, pathogenesis and etiology of this type of congenital muscular dystrophies. In addition, the issues of molecular diagnosis of congenital muscular dystrophies are considered and information on modern developments in the treatment of this pathology is provided.

Clinical and genetic characteristics of congenital muscular dystrophies (Part 1)

Congenital muscular dystrophy is an extremely heterogeneous group of hereditary neuromuscular diseases that are clinically characterized by muscular hypotonia, progressive muscle weakness, and dystrophic changes in the muscles. Overlapping clinical symptoms and many genes that have to be analyzed to determine the specific form of the disease in the patient make diagnosis difficult. The molecular genetic stage of diagnosis includes many different methods depending on the clinical hypothesis and their application has not lost its relevance even in the era of massive parallel sequencing. In addition to DNA sequence analysis, the analysis of muscle protein expression can also play a significant role in the diagnosis of congenital muscular dystrophy. In the review, we will consider the most important etiological, pathophysiological, clinical and laboratory data of the main forms of congenital muscular dystrophy known today.

Genetic and Clinical Advances of Congenital Muscular Dystrophy.

Objective:The aim was to update the genetic and clinical advances of congenital muscular dystrophy (CMD), based on a systematic review of the literature from 1991 to 2017.Data Sources:Articles in English published in PubMed from 1991 to 2017 English were searched. The terms used in the literature searches were CMD.Study Selection:The task force initially identified citations for 98 published articles. Of the 98 articles, 52 studies were selected after further detailed review. Three articles, which were not written in English, were excluded from the study. This study referred to all the important and English literature in full.Results:CMD is a group of early-onset disorders encompassing great clinical and genetic heterogeneity. Patients present with muscle weakness typically from birth to early infancy, delay or arrest of gross motor development, and joint and/or spinal rigidity. The diagnosis of CMD relies on clinical findings, brain and muscle imaging, muscle biopsy histology, muscle and/or skin immunohistochemical staining, and molecular genetic testing.Conclusions:Advances in next-generation sequencing and histopathological techniques have enabled the recognition of distinct CMD subtypes supported by specific gene identification. Genetic counseling and multidisciplinary management of CMD play an important role in help patients and their family. Further elucidation of the significant clinical and genetic heterogeneity, therapeutic targets, and the clinical care for patients remains our challenge for the future.

Clinical manifestations and prenatal diagnosis of congenital muscular dystrophy

Objective To summarize the clinical features of 22 probands diagnosed with congenital muscular dystrophy (CMD), and to provide genetic counseling and prenatal diagnosis for 23 fetuses of these pedigrees. Methods Data of 22 CMD patients who were treated in the Pediatric Department of Peking University First Hospital during October 2006 to March 2016 were analyzed. Informed written consents for participation in this study were obtained from the parents or guardians. Prenatal diagnosis was performed using DNA samples extracted from fetal villus cells of 12 cases at 11-13 gestational weeks and amniotic fluid of 11 cases at 18-22 gestational weeks. Direct DNA sequencing by polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) were used to detect CMD-related gene mutations. Linkage analysis of short tandem repeats (STRs) was used to identify maternal blood contamination and biological parents. Results Thirteen out of the 22 probands with CMD were diagnosed with congenital muscular dystrophy type 1A (MDC1A), and all of them carried compound heterozygous mutations in LAMA2 gene. Prenatal diagnosis of 13 fetuses from these pedigrees found that four fetuses were wild-type, seven were heterozygotes and two carried the same mutations as their proband. Three probands with LMNA-related congenital muscular dystrophy (L-CMD) carried de novo mutations in LMNA gene. In these pedigrees, two fetuses were wild-type and one whose mother was mosaicism carried the same mutations as the proband. One proband with Ullrich congenital muscular dystrophy carried compound heterozygous mutations in COL6A2 gene and the fetus of the same pedigree was wild-type. Five probands were diagnosed with α-dystroglycanopathies. And among them, two cases of muscle-eye-brain disease (MEB) carried compound heterozygous mutations in POMGnT1 gene and the fetuses of the two peidgrees were heterozygotes; one case of congenital muscular dystrophy type 1C (MDC1C) had compound heterozygous mutations in FKRP gene and the fetus carried the same mutations; one patient diagnosed with POMGnT1-related congenital muscular dystrophy with mental retardation (CMD-MR) carried compound heterozygous mutations in POMGnT1 gene, and the fetus was positive for the same mutations; one proband with POMT1-related CMD-MR was positive for compound heterozygous mutations in POMT1 gene and the results of prenatal diagnosis for two fetuses of this pedigree showed that the first fetus had the same mutations as the proband, while the second was heterozygote. Conclusions No effective therapeutic method is available for CMD. Therefore, accurate genetic counseling and prenatal diagnosis are necessary to prevent CMD child from birth. Key words: Muscular dystrophies; Prenatal diagnosis; Genetic testing

Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions; some fatal in the first few years of life and with central nervous system involvement, whereas others present a milder course. We provide a comprehensive report of the relative frequency and clinical and genetic spectrum of CMD in the UK. Genetic analysis of CMD genes in the UK is centralised in London and Newcastle. Between 2001 and 2013, a genetically confirmed diagnosis of CMD was obtained for 249 unrelated individuals referred to these services. The most common CMD subtype was laminin-α2 related CMD (also known as MDC1A, 37.4%), followed by dystroglycanopathies (26.5%), Ullrich-CMD (15.7%), SEPN1 (11.65%) and LMNA (8.8%) gene related CMDs. The most common dystroglycanopathy phenotype was muscle–eye–brain-like disease. Fifteen patients carried mutations in the recently discovered ISPD, GMPPB and B3GALNT2 genes. Pathogenic allelic mutations in one of the CMD genes were also found in 169 unrelated patients with milder phenotypes, such as limb girdle muscular dystrophy and Bethlem myopathy. In all, we identified 362 mutations, 160 of which were novel. Our results provide one of the most comprehensive reports on genetics and clinical features of CMD subtypes and should help diagnosis and counselling of families with this group of conditions.

Electromyoneurographic findings in patient with congenital muscular dystrophy

Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of inherited muscle disorders defined by early onset of hypotonia and muscle weakness. They are the second most common myopathic cause of floppy infant syndrome, following the group of congenital myopathies. The main CMD are classified by involved protein function and gene in which causative mutations occur. Merosin-negative muscle dystrophy is the most common CMD, characterized by early onset hypotonia, delayed motor milestones, contractures, normal cognitive abilities and diffuse brain white matter changes. Some forms of CMD are characterized by mental retardation, eye involvement, epileptic seizures and structural brain abnormalities. The diagnosis of CMD is based on clinical findings, elevated muscle enzymes, brain imaging, muscle biopsy histology and immunohistochemical staining and molecular genetic testing. The vast majority of patients have myopathic findings on electromyography (EMG). Slowed motor and sensory nerve conduction velocities could be found in patients with merosin deficiency. Electromyography has a significant role in the primary assessment of patients with muscle weakness. Myopathic EMG findings ruled out other causes of floppy infant syndrome and led to a muscle biopsy and focused genetic tests. An associated demyelinating neuropathy could focus the investigation on primary or secondary merosin deficit.

Orthognathic Surgery in Patients With Congenital Myopathies and Congenital Muscular Dystrophies: Case Series and Review of the Literature

This case series examined preoperative findings and the surgical, anesthetic, and postoperative management of 6 patients with congenital myopathies (CMs) and congenital muscular dystrophies (CMDs) treated at a tertiary medical institution with orthognathic surgery over 15 years to describe pertinent considerations for performing orthognathic surgery in these complex patients. According to the institutional review board-approved protocol, chart records were reviewed for all orthognathic surgical patients with a clinical, genetic, or muscle biopsy-proved diagnosis of CM or CMD. Six patients (5 male, 1 female) qualified, and they were treated by 4 surgeons in the division of oral and maxillofacial surgery from 1992 through 2007. Average age was 19.5 years at the time of orthognathic surgery. Five patients had Class III malocclusions and 1 patient had Class II malocclusion. All 6 patients had apertognathia with lip incompetence. Nasoendotracheal intubation with a difficulty of 0/3 (0=easiest, 3=most difficult) was performed in all cases. Routine induction and maintenance anesthetics, including halogenated agents and nondepolarizing muscle relaxants, were administered without malignant hyperthermia. All 6 patients underwent Le Fort level osteotomies; 4 also had mandibular setback surgery with or without balancing mandibular inferior border osteotomies. Five patients required planned intensive care unit care postoperatively (average, 18.4 days; range, 4 to 65 days). Postoperative respiratory complications resulting in major blood oxygen desaturations occurred in 5 patients; 4 of these patients required reintubation during emergency code response. Five patients required extended postoperative intubation (average, 4.2 days; range, 3 to 6 days) and ventilatory support. Average hospital length of stay was 21.8 days (range, 6 to 75 days). Average postoperative follow-up interval was 29.8 weeks (range, 6 to 128 weeks). Patients with CMs or CMDs often have characteristic dentofacial malocclusions that contribute to functional problems with feeding and drooling and psychosocial problems. Orthognathic surgery, usually bimaxillary, can be judiciously considered in these patients; these procedures typically require multidisciplinary pre- and postoperative evaluation and care over lengthy hospital stays with a high risk of respiratory complications that bear consideration in treatment planning.

G.P.207: Clinical and genetic spectrum in a large cohort of patients with a genetic diagnosis of congenital muscular dystrophies: Analysis of the UK diagnostic service 2001–2013

Congenital muscular dystrophies (CMD) are a highly heterogeneous group of conditions clinically characterized by muscle weakness from birth, or shortly after, and variable involvement of eyes, heart and central nervous system. Some of these disorders are fatal in the first year of life, whereas others have a milder course and are compatible with survival into adulthood. The Dubowitz Neuromuscular Centre (DNC) is the National Specialist Commissioning Team (NSCT) referral centre for CMD in the UK. A few years ago we reported the relative frequency of CMD subtypes referred for clinical assessment to the DNC, with collagen VI related disorders being the most common diagnosis. This study reports the relative frequency and clinical and genetic spectrum of CMD in the entire cohort of UK patients in whom the genetic analysis for the CMD genes was requested between 2001 and 2013, including recently identified dystroglycanopathy genes. A total of 700 DNA samples were referred during this time interval and genetic diagnosis was reached in 366 of them. Detailed clinical information was available for 340 patients; 234 fulfilled a clinical diagnosis of CMD while the others had milder forms, such as LGMD. The most common type of genetically confirmed CMD was laminin α2 related dystrophy (MDC1A) accounting for about 44 % of cases, followed by dystroglycanopathies (26 %), Ullrich CMD (16 %) and Rigid Spine muscular dystrophy associated with SEPN1 gene mutations (14 %). Fifteen patients carried pathogenic mutations in the newly discovered ISPD, GMPPB and B3GALNT2 genes responsible for glycosylation defects in alpha-dystroglycan and here we also describe the associated phenotypes. Our results indicate MDC1A as the most common subtype of CMD in the UK and further expand the clinical and genetic spectrum of CMDs.

Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject’s HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major “retractile” phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.

English Cross-Cultural Translation and Validation of the Neuromuscular Score: A System for Motor Function Classification in Patients With Neuromuscular Diseases

ObjectiveTo develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function. DesignValidation survey. SettingPatients seen at a medical research center between June and September 2013. ParticipantsConsecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy. InterventionsNot applicable. Main Outcome MeasuresAn English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa. ResultsSignificant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=−.944, P<.0001), ACTIVLIM (ρ=−.895, P<.0001), and hip abduction strength by myometry (ρ=−.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701–.914) but moderate for D2 (κ=.592; 95% CI, .412–.773) and D3 (κ=.485; 95% CI, .290–.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores. ConclusionsPatients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases.

Genotype/phenotype analysis in Chinese laminin‐α2 deficient congenital muscular dystrophy patients

Laminin-α2 deficient congenital muscular dystrophy (CMD) is an autosomal recessive disorder characterized by severe muscular dystrophy, which is typically associated with abnormal white matter. In this study, we assessed 43 CMD patients with typical white matter abnormality and laminin-α2 deficiency (complete or partial) diagnosed by immunohistochemistry to determine the clinical and molecular genetic characteristics of laminin-α2 deficient CMD. LAMA2 gene mutation analysis was performed by direct sequencing of genomic DNAs. Exonic deletion or duplication was identified by multiplex ligation-dependent probe amplification (MLPA) and verified by high-density oligonucleotide-based CGH microarrays. Gene mutation analysis revealed 86 LAMA2 mutations (100%); 15 known and 37 novel. Among these mutations, 73.9% were nonsense, splice-site or frameshift and 18.8% were deletions of one or more exons. Genetic characterization of affected families will be valuable in prenatal diagnosis of CMD in the Chinese population.

Molecular diagnosis of congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan using next-generation sequencing technology

Targeted resequencing using next-generation sequencing technology is being rapidly applied to the molecular diagnosis of human genetic diseases. The group of muscular dystrophies may be an appropriate candidate for this approach because these diseases exhibit genotype-phenotype heterogeneity. To perform a proof-of-concept study, we selected four patients with congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan. A custom-solution-based target enrichment kit was designed to capture whole-genic regions of the 26 muscular-dystrophy-related genes, including six genes implicated in alpha-dystroglycanopathies. Although approximately 95% of both coding and noncoding regions were covered with at least 15-read depth, parts of the coding exons of FKRP and POMT2 were insufficiently covered. Homozygous and compound heterozygous POMGnT1 mutations were found in two patients. Two novel noncoding variants of FKTN were identified in one patient who had a retrotransposon insertion mutation of FKTN in only one allele. The current targeted resequencing strategy yielded promising results for the extension of this method to other muscular dystrophies. As suboptimal coverage in a small subset of coding regions may affect the sensitivity of the method, complementary Sanger sequencing may be required.

Elevated Serum Creatine Kinase and Small Cerebellum Prompt Diagnosis of Congenital Muscular Dystrophy due to FKRP Mutations

Fukutin-related protein (FKRP) is a putative glycosyltransferase that mediate O-linked glycosylation of the α-dystroglycan. Mutations in the FKRP gene cause a spectrum of diseases ranging from a limb girdle muscular dystrophy 2I (LGMD2I), to severe Walker-Warburg or muscle-eye-brain forms and a congenital muscular dystrophy (with or without mental retardation) termed MDC1C. This article reports on a Moroccan infant who presented at birth with moderate floppiness, high serum creatine kinase (CK) levels, and brain ultrasonograph suggestive of widening of the posterior fossa. Muscle biopsy displayed moderate dystrophic pattern with complete absence of α-distroglycan and genetic studies identified a homozygous missense variant in FKRP. Mutations in FKRP should be looked for in forms of neonatal-onset hyperCKaemia with floppiness and small cerebellum.

G.P.24 Congenital muscular dystrophy with epidermolysis bullosa: A case report

Congenital muscular dystrophy (CMD) associated with familial junctional epidermolysis bullosa is a rare autosomal recessive disorder caused by mutation in the plectin gene located on chromosome 8q24.3. The first clinical symptoms manifest themselves at about 15days of life, when first blisters and erosions (very often haemorrhagic) develop on patient’s extremities, their back and face. Skin manifestations usually do not progress over time and skin fragility seems to be mild. The first symptoms of muscle weakness tend to manifest at the end of the first decade; gradual progression leads to patient’s disability and being bound to a wheelchair; around the age of 30, patients die because of weak respiratory muscles. Diagnosing of this disease is based on clinical features, findings in skin and muscle biopsies, and results of genetic testing for mutations in the plectin gene. Case report: boy (aged 14) has been monitored from birth at the Department of Paediatric Dermatology at University Hospital Brno for haemorrhagic blisters manifesting especially on his legs. His original diagnosis was epidermolysis bullosa simplex. From the age of 10, he has had difficulties with walking, from the age of 12 he has been using an electric wheelchair. The patient was hospitalized in December 2010 (aged 13) at the Department of Paediatric Neurology, where he underwent detailed examination including brain magnetic resonance, skin and muscle biopsies. The muscle biopsy revealed a severe myogenic lesion, consistent with muscular dystrophy with inflammatory features; the results of morphological testing as well as the analysis of proteins expression in muscle tissue were compatible with the diagnosis of CMD with EB. Subsequently, this diagnosis was also confirmed on a molecular genetic level. Direct sequencing of the plectin gene revealed c.5902_5903delAA and c.9109del17 mutations, disrupting translational reading frame. Both of these pathogenic mutations have not been reported yet.

G.P.40 LGMD2G with clinical presentation of congenital muscular dystrophy: A rare phenotype

LGMD2G is a relatively rare and mild autosomal recessive form of progressive neuromuscular disorder with a wide spectrum of inter and intrafamilial clinical variability. The age at onset ranges from 9 to 15 years old and loss of ambulation is uncommon, or in the third or fourth decade of life. LGMD2G is caused by mutations in the TCAP gene, causing the deficiency of the sarcomeric protein telethonin in muscle of affected patients. Up to now, only a few families have been described, mainly in Brazil. In a recent screening for mutation in the TCAP gene, including 200 additional LGMD adult patients, we identified six new cases, confirming the rarity of the disease also in Brasil. All these patients carried the same c.157C>T (Q53X) homozygous missense mutation, identified in the first families, suggesting a common origin of this mutation. In addition,we studied a five years-old patient with clinical diagnosis of congenital muscular dystrophy. Immunohistochemical analysis for muscle protein excluded the deficiency of dystrophin, the four sarcoglycans, α2-laminin, dysferlin and calpain3 proteins. Surprisingly, telethonin analysis showed a total deficiency, both through immune fluorescence and western blot analyses. Sequencing of the TCAP gene identified the common c.157C>T mutation in a homozygous state in the patient and in heterozygosity in both non-consanguineous parents. This called our attention to the fact that the rarity of the disease could be due to the screening of the improper patients. Telethonin deficiency could be, in fact, the cause of more severe forms of muscular dystrophies. To test this hypothesis, we analyzed telethonin deficiency in the muscle of 118 patients with clinical diagnosis of congenital MD, from which we selected sixteen patients for gene sequencing. However, no alteration was found in any of them. Therefore, mutation in the TCAP gene is not a common cause of severe forms of MD. FAPESP-CEPID, CNPq-INCT, FINEP, ABDIM.

Relative frequency of congenital muscular dystrophy subtypes: Analysis of the UK diagnostic service 2001–2008

The Dubowitz Neuromuscular Centre is the UK National Commissioning Group referral centre for congenital muscular dystrophy (CMD). This retrospective review reports the diagnostic outcome of 214 UK patients referred to the centre for assessment of ‘possible CMD’ between 2001 and 2008 with a view to commenting on the variety of disorders seen and the relative frequency of CMD subtypes in this patient population. A genetic diagnosis was reached in 53 of 116 patients fulfilling a strict criteria for the diagnosis of CMD. Within this group the most common diagnoses were collagen VI related disorders (19%), dystroglycanopathy (12%) and merosin deficient congenital muscular dystrophy (10%). Among the patients referred as ‘possible CMD’ that did not meet our inclusion criteria, congenital myopathies and congenital myasthenic syndromes were the most common diagnoses. In this large study on CMD the diagnostic outcomes compared favourably with other CMD population studies, indicating the importance of an integrated clinical and pathological assessment of this group of patients.

Congenital Muscular Dystrophies: A Brief Review

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments.

Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin

Mutations in the PLEC1 gene encoding plectin have been reported in neonatal epidermolysis bullosa simplex with muscular dystrophy of later-onset (EBS-MD). A neuromuscular transmission defect has been reported in one previous patient. We report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms. Repetitive nerve stimulation showed significant decrement, and strength improved with pyridostigmine. Subtle blistering noticed only retrospectively prompted further genetic testing, revealing recessive PLEC1 mutations. We conclude that PLEC1 should be considered in the differential diagnosis of congenital muscular dystrophies and myasthenic syndromes, even in the absence of prominent skin involvement.

Index Of Suspicion In The Nursery

A male infant who has trisomy 21 is born large for gestational age at 36 weeks' gestation to a 40-year-old G4P2 mother. The mother experienced gestational diabetes and hypertension during the pregnancy. The hospital course in the neonatal intensive care unit (NICU) is uneventful. The infant consumes human milk supplemented with formula every 3 hours. Due to decreased intake, nutritional supplementation by nasogastric tube is initiated. He requires 25 to 30 minutes to feed by mouth with chin support and pacing. There is minimal emesis with feedings until 9 days after birth, when he begins vomiting with each feeding. The amount of emesis varies, consists of undigested milk, and is otherwise nonbilious and nonbloody. The infant can tolerate only small amounts of his feedings by either mouth or nasogastric tube before vomiting, but he continues to have two to three bowel movements per day and good urine output. On physical examination, the baby has physical features consistent with trisomy 21, including epicanthal folds, a flat nasal bridge, macroglossia, Brushfield spots, widened space between the first and second toes, single palmar creases, and generalized hypotonia. There is no notable abdominal distention or palpable abdominal masses. The remainder of the examination yields normal results. A radiologic study helps to reveal the diagnosis. A term male infant is admitted to the NICU after difficulty feeding and respiratory distress at 5 hours of age. The baby was born to a 35-year-old G3T2P0A0L2 woman. All maternal laboratory results were negative during prenatal screening, although prenatal ultrasonography during the third trimester showed oligohydramnios and intrauterine growth restriction. The initial evaluation after delivery revealed an asymmetric, small-for-gestational age infant whose birthweight was 2,215 g and Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. On physical examination, the infant exhibited generalized hypotonia, poor suck …