Diaphragmatic paralysis in a neonate with circumferential skin creases Kunze type.

BACKGROUND: A range of clinical features have been confirmed with heterozygous mutations in Beta Tubulin (TUBB), including skin creases, facial deformities, abnormal cerebral structures, and intellectual disability, and were defined as Circumferential Skin Creases Kunze type (CSC-KT). METHODS: Clinical information was obtained retrospectively on a neonate hospitalized in the Neonatal Intensive Care Unit, Wuhan Children's Hospital. Genomic DNA was extracted from circulating leukocytes of the proband according to standard procedures. RESULTS: The neonate presented dyspnea resulting from diaphragmatic paralysis, accompanied by other typical features of CSC-KT. Additionally, exome sequencing confirmed a new variant (NM_178,014. 4: c. 1114 A > G) in TUBB. We also summarized features described in previous cases, thus representing phenotype extension of CSC-KT. CONCLUSION: Our report is the youngest confirmed case, which could extend the current phenotype of CSC-KT as well as the clinical diagnostic approach.

An infant with congenital respiratory insufficiency and diaphragmatic paralysis: A novel BICD2 phenotype?

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Diaphragmatic dysfunction in SEPN1-related myopathy.

SEPN1-related myopathy (SEPN1-RM) is characterized by predominant axial muscle weakness, early scoliosis, rigid spine and severe respiratory insufficiency. The aim of the study was to characterize the mechanisms of respiratory dysfunction in SEPN1-RM patients. Breathing pattern and respiratory muscle strength were measured by means of esophageal (Pes) and gastric (Pgas) pressures. Seven patients aged 7-55 years (1 adult) at first respiratory muscle test were studied. Five patients were treated by nocturnal noninvasive ventilation (NIV) ≥ 4 months. Mean ΔPes was within normality during tidal breathing, but the ΔPgas/ΔPes index indicated an increased contribution of the rib cage and expiratory muscles, as compared to the diaphragm, in the pediatric patients and bilateral diaphragmatic paralysis in the adult patient. Forced vital capacity (FVC) was reduced in all patients (52 ± 19%pr) with mean FVC seated-supine drop of 24 ± 7%. Global inspiratory muscle and diaphragmatic strengths were moderately reduced in 2 patients, highly reduced in 4 patients and severely reduced in the adult patient. Expiratory muscle strength was moderately reduced in 6 patients and severely reduced in the adult patient. FVC and respiratory muscle strength remained stable in 2 patients treated by nocturnal NIV within a 3-year follow-up. This study confirms that diaphragmatic dysfunction is a characteristic feature of SEPN1-RM and NIV may stabilize the decline in respiratory muscle strength.

[VOLTAGE-GATED CALCIUM CHANNELS: CLASSIFICATION AND PHARMACOLOGICAL PROPERTIES (PART I).]

Calcium influx though voltage-gated calcium channels mediate a huge amount of physiological events and cellular responses. Numerous scientific reports indicate that calcium channels are involved in synaptic transmission, neurotransmitter release, regulation of gene expression, cellular membrane voltage oscillations, pacemaker activity, secretion of specific substances from nerve and secretory cells, morphological differentiation, activation of calcium-dependent enzymes, etc. This review represents the modern classification, molecular structure, physiological and pharmacological properties of voltage-gated calcium channels expressed in mammalian cells.

Evaluation of Respiratory Muscle Strength and Pulmonary Function in Patients with Charcot-Marie-Tooth Disease Type 2.

The aim of this study was to evaluate the pulmonary condition in a large family with Charcot-Marie-Tooth disease type 2 (CMT2). Eighteen participants diagnosed with CMT2 and 20 healthy individuals were evaluated by spirometry and maximal expiratory and maximal inspiratory pressures (MEP and MIP, respectively). Clinical disability was measured with CMT neuropathy score (CMTNS; range 0-36). One control group (CG) comprising 20 individuals, matched for age, sex and body mass index, were used for comparison. Eight patients were female (44.5%) and 10 patients were male (55.5%); mean age was 31.8 years (range 11-79) and CMTNS range was 6-26. Differences between CMT2 and CG in the spirometry and respiratory muscle strength were statistically significant for all dimensions. There were significant correlations between CMTNS and MIP (Pearson = -0.581) and MEP (Pearson = -0.5090). The results of this study show that patients with CMT, in spite of not showing clinical signs of advanced respiratory impairment, may present subclinical respiratory changes. The respiratory comprise in the CMT disease can be silent and insidious without presenting characteristic clinical signals.

Patient with spinal muscular atrophy with respiratory distress type 1 presenting initially with hypertonia.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene and characterized by life-threatening respiratory distress due to irreversible diaphragmatic paralysis between 6weeks and 6months of age. In this study, we describe a two-month-old boy who presented with hypertonia at first and developed to hypotonia progressively, which was in contrast to the manifestations reported previously. Bone tissue compromise was also observed as one of the unique symptoms. Muscle biopsy indicated mild myogenic changes. He was misdiagnosed until genetic screening to be confirmed as SMARD1. SMARD1 is a clinical heterogeneous disease and this case broadens our perception of its phenotypes.

Fulminant respiratory muscle paralysis, an expanding clinical spectrum of mitochondrial A3243G tRNALeu mutation.

Mitochondrial disease is a group of rare disorders, caused by mitochondrial dysfunction. They are usually the result of mutations of either mitochondrial DNA or nuclear DNA. A3243G transition in the tRNALeu is one the most frequent mutations of the mitochondrial DNA. Phenotypic expression of this mutation varies. The most well-recognized phenotype is Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Isolated myopathy with respiratory muscle weakness in this mutation has been rarely documented. The authors reported a 20-year-old Asian female presenting with a fulminant hypoventilatory respiratory failure with mild weakness of the limbs. Electrophysiologic study showed evidences of myopathy. Restrictive physiology of the lungs was demonstrated by pulmonary function test. Subsarcolemmal accumulation of mitochondria was demonstrated by Gomori trichrome and succinate dehydrogenase stains. Genetic study revealed the A3243G mutation in mitochondrial DNA in peripheral blood Isolated mitochondrial myopathy severely affecting respiratory muscles may be considered as an uncommon clinical spectrum of A3243G mitochondrial disease.

Genotype-phenotype correlations in alternating hemiplegia of childhood.

OBJECTIVE: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. METHODS: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. RESULTS: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. CONCLUSIONS: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.

Diaphragmatic weakness with progressive sensory and motor polyneuropathy: case report of a neonatal IGHMBP2-related neuropathy.

The authors present a child affected with diaphragmatic paralysis in the early neonatal period. Although no electroneuromyographic abnormalities were reported, the patient developed dramatic motor and respiratory impairment with impossibility to wean from mechanical ventilation. Repeated electroneuromyographic study at age 4 months revealed severe neurogenic changes and sensory nerve abnormalities with more preserved nerve conduction velocities. Genetic studies identified 2 mutations in the gene IGHMBP2. These results support the consideration of this entity as a form of sensory-motor rapidly progressive polyneuropathy rather than a primary anterior horn disease (IGHMBP2-related neuropathy). A review of the series of mutated patients in the French National Database gives new insights of the incidence of this disease in France.

[A rare cause of respiratory failure in infants: distal spinal-muscular atrophy 1 (DSMA1 or SMARD1)]. / Une cause rare d'insuffisance respiratoire aiguë chez le nourrisson : l'amyotrophie spinale distale de type 1 (DSMA1 ou SMARD1).

Distal spinal-muscular atrophy 1 (DSMA1) or spinal-muscular atrophy with respiratory distress type 1 (SMARD1) is a rare neuromuscular disorder resulting from IGHMBP2 mutations. It is an autosomal recessive disease. We present the case of a 1-year-old girl admitted for respiratory failure associated with pneumonia. Right hemidiaphragmic elevation on the chest radiograph and distal retractions suggested the diagnosis of DSMA1. It was confirmed by muscle biopsy and molecular analysis. This unrecognized diagnosis should be considered when respiratory failure develops in the first year of life and is associated with diaphragmatic paralysis and distal muscle atrophy. Electromyography with measurement of nerve conduction velocity and muscle biopsy suggest the diagnosis, which must be confirmed by genetic analysis. After identifying the mutations, it is possible to perform prenatal diagnosis.

Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): an atypical phenotype and review of the literature.

Spinal muscular atrophy with respiratory distress (SMARD 1) is a very rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, symmetrical distal muscular weakness, muscle atrophy, peripheral sensory neuropathy and autonomic nerve dysfunction. SMARD 1 is inherited as an autosomal recessive trait and the mutations have been identified in the gene encoding immunoglobulin µ-binding protein 2 (IGHMBP2), located on chromosome 11q13. It is considered a fatal form of infantile motoneuron disease and most of the patients dies within the first 13 months of life. We present a female child with genetically confirmed SMARD 1 displaying a mild phenotype and no severe signs of respiratory involvement, typically found in this form, up to 38 months despite a diaphragmatic palsy diagnosed at 6 months of age. Therefore, our clinical observation suggests that respiratory failure is not secondary, in any case, to the diaphragmatic palsy but other pathogenetic mechanisms might be involved.

Noisy breathing and hemidiaphragm paralysis progressing to respiratory failure in an infant.

Spinal muscular atrophy with respiratory distress (SMARD1) is a rare autosomal recessive disease that is caused by mutations in the gene encoding for immunoglobulin µ-binding protein 2. Unlike the relatively more common spinal muscular atrophy, patients with SMARD1 have respiratory distress prior to manifestation of distal muscle weakness making the diagnosis a challenge. Because respiratory distress is a hallmark feature of this disease, pediatric pulmonologists should recognize its features, and consider it as a diagnostic entity.

Adult-onset acid maltase deficiency with isolated axial muscle involvement.

INTRODUCTION: We report a patient with acid maltase deficiency who presented with subacute respiratory failure as the first symptom without significant extremity weakness. METHODS AND RESULTS: Electromyography of extremities was normal but showed myopathic changes and myotonic discharges limited to axial muscles only. Muscle biopsy confirmed the diagnosis. CONCLUSION: It is essential to examine axial muscles during electromyography if a patient presents with respiratory failure of unclear etiology even if the clinical examination does not show significant weakness in the extremities and electromyographic findings in the extremities are unremarkable.

Cardiac and pulmonary function variability in Duchenne/Becker muscular dystrophy: an initial report.

The Duchenne and Becker forms of muscular dystrophy are associated with dilated cardiomyopathy and are diseases in which pulmonary function peaks and then progressively declines. In this report, the authors quantify cardiopulmonary function variability among brothers. Brothers in 3 of 7 eligible sibships had discordant pulmonary function, with significant differences between the brothers' peak forced vital capacities and their vital capacities at last comparable age. There was no relationship between pulmonary and cardiac function among the siblings. The authors concluded that despite identical genetic mutations, cardiac and pulmonary function variability was common among brothers in their clinic with Duchenne or Becker muscular dystrophy. If confirmed by larger studies, these results have negative implications for the use of genetic testing to predict cardiopulmonary course and response to therapies in Duchenne or Becker muscular dystrophy.

Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1.

Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far. We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5 years of age. Muscle biopsy at 5 weeks of age was uninformative. Repeat biopsy at 4.5 years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met49Val [corrected] mutation. In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness.

Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here new SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor defects and developmental breathing disorders reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of neuromuscular junction defects in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating new therapeutics.

Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget's disease of bone and frontotemporal dementia.

We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget's disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget's disease or cognitive impairment.