Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome.

One form of congenital muscular dystrophy, rigid spine syndrome (MIM 602771), is a rare neuromuscular disorder characterized by early rigidity of the spine and respiratory insufficiency. A locus on 1p35-36 (RSMD1) was recently found to segregate with rigid spine muscular dystrophy 1 (ref. 1). Here we refine the locus and find evidence of linkage disequilibrium associated with SEPN1, which encodes the recently described selenoprotein N (ref. 2). Our identification and analysis of mutations in SEPN1 is the first description of a selenoprotein implicated in a human disease.

Recommendations for the diagnosis and management of typical childhood spinal muscular atrophy.

Typical childhood spinal muscular atrophy is a disease that affects the anterior horn of the spinal cord related to SMN1 gene defects. Since no etiological treatment is currently available, its management is necessarily symptomatic and involves multidisciplinary care. The national plan on rare diseases for 2005-2008 developed by the French Ministry of Health resulted in the creation of 12 reference centres for neuromuscular diseases, mainly to improve their diagnosis and management. During the first one-day clinical research meeting on neuromuscular disorders, organized by the French Association to fight myopathies (AFM) in May 2007, clinicians from the 12 national reference centers led workshops for each of the main neuromuscular diseases. Concerning spinal muscular atrophy, discussions involving specialists from medical and allied professions were led by clinicians in charge of the workshop sessions. This paper reports the final version of their recommendation regarding the diagnosis, monitoring and management of typical infantile spinal muscular atrophy, which is necessarily multidisciplinary, including orthopedic, pulmonary, gastroenterology and nutrition care.

Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome.

Rigid spine syndrome is a neuromuscular disorder characterised by early rigidity of the spine due to axial muscle contractures, generally associated with muscle weakness, limb-joint contractures, and often respiratory failure. This phenotype may be associated with several muscular diseases. In cases of merosin-positive congenital muscular dystrophies (CMD) with rigid spine syndrome, we have recently identified a new locus (RSMD1) on chromosome 1p35-36. In the present study, we report the clinical, morphological and genetic analysis of other patients affected by a CMD with rigid spine syndrome from nine consanguineous families. Homozygosity mapping showed that the disease was linked to RSMD1 in one of the nine families. The other families were excluded from RSMD1, and the patients presented highly variable phenotypes suggesting the involvement of more than one gene defect in rigid spine syndrome. Nevertheless, a subgroup of patients who never walked, and had very early rigidity of the spine and scoliosis, may be considered for further genetic analysis.

Long-term noninvasive mechanical ventilation for children at home: a national survey.

Experience with domiciliary noninvasive mechanical ventilation (NIMV) in children is limited. The aim of this study was to determine the number of patients and categorize the use of domiciliary NIMV in children in France. An anonymous cross-sectional national study was performed, using a postal questionnaire sent to all specialist centers utilizing domiciliary NIMV for chronic respiratory failure. Patients aged <18 years and receiving home NIMV were included in the study. Detailed information was obtained from 102 patients from 15 centers: 4/15 centers cared for 84% of patients; 7% of patients were under 3 years old; 35% were between 4-11 years old; and 58% were older than 12 years. Underlying diagnoses included neuromuscular disease (34%), obstructive sleep apnea (OSA) and/or cranio-facial abnormalities (30%), cystic fibrosis (17%), congenital hypoventilation (9%), scoliosis (8%), and other disorders (2%). NIMV was started because of nocturnal hypoventilation (67%), acute exacerbation (28%), and/or failure to thrive (21%). Volume-targeted ventilation was preferred in restrictive disorders (56%) and central hypoventilation (56%), while pressure support ventilation (PSV) was preferred in cystic fibrosis (71%). Patients with OSA and/or cranio-facial abnormalities were ventilated with continuous positive airway pressure (45%) or bilevel PSV (52%). In conclusion, NIMV is currently used in France for the domiciliary management of children with a variety of conditions causing chronic respiratory failure. However, NIMV in children is still performed on a small scale, and combined with the heterogeneity of the patient population, its application would best be served by centers specializing in the initiation and long-term follow-up of these patients.

Prognostic value of evoked potentials and sleep recordings in the prolonged comatose state of children. Preliminary data.

OBJECTIVES: Sleep recordings and evoked potentials (EPs) were used in five comatose children to evaluate their predictive value for outcome following a severe comatose state. METHODS AND SUBJECTS: The protocol included EEG, Brainstem Evoked Responses (BERs), Somatosensory Evoked Potentials (SEPs) and polysomnography. From 10 to 15 days post-coma (D10 to D15), EEG and clinical examinations were carried out every second day, then one day in four from 15 to 30 days post-coma (D15 to D30), and one day in seven from D30 to six months (M6). Evoked potentials and Polysomnography were recorded on D10-D15 or D30 in the second month (M2) and in M6. Of the five children, three were in anoxic coma and two in traumatic coma. All had extensive lesions and a Glasgow Coma Scale (GCS) score of less than five. The results of the EEG, polysomnographic and EP recordings were compared to the clinical outcome. RESULTS AND CONCLUSION: In the three anoxic comas we observed BER abnormalities and the absence of SEP N20 associated with wide cortical lesions with brainstem extension. Sleep recordings showed major alterations of the wake-sleep cycle without any improvement in M6. Abnormalities included loss of the normal REM-sleep pattern associated with alteration of NREM sleep and periods of increase in motor activity without EEG arousal. This sleep pattern appeared to be associated with involvement of the brainstem. In the two traumatic comas, alterations of the early cortical SEP responses were less severe and the BERs were normal. Some sleep spindles were observed as well as the persistence of sleep cycles in the first weeks post-coma. The combined use of EEG, EPs and polysomnography improved the outcome prediction in comparison with the use of just one modality. EPs and sleep recordings were far superior to clinical evaluation and to GCS in the appreciation of the functional status of comatose children. The reappearance of sleep patterns is considered to be of favorable prognosis for outcome of the coma state, as is the presence of sleep spindles in post-trauma coma. This study showed that EPs and sleep recordings help to further distinguish between patients with good or bad outcomes.

[Myasthenia and pernicious anemia or Biermer's (author's transl)]. / Myasthénie et anémie pernicieuse dite de Biermer.

The association of myasthenia and Biermer's anemia is very rarely reported. In a series of 138 cases of myasthenia, this association was found in only one patient, in whom the anemia developed 19 years after the discovery of a calcified thymoma and 13 years after the appearance of the first signs of myasthenia. This led the authors to conduct a prospective study for the presence of intrinsic antifactor antibodies. A total of 81 patients (20 men and 61 women) with myasthenia were studied. The myasthenia had appeared after 35 years of age in 40 patients and 19 had a thymoma. The results of the study for the antibodies was positive in 3 women, as was the test of inhibition of leucocyte migration, but none of them had anemia, vitamin B12 malabsorption, achlorhydria, or gastric atrophy. The discovery of these immunological disorders raises the problem of their significance ; two hypotheses can be discussed : pre-Biermer state or immunological disturbance without pathogenetic significance. The problem can probably only be resolved by studying these antibody levels in a very much larger number of patients with myasthenia.

[Infantile spinal muscular atrophy]. / Amyotrophie spinale infantile.

The authors report 100 cases with prolonged spinal muscular atrophy (SMA) and survival beyond 4 years old. There were 46 boys and 54 girls. 23 of them had histories with an autosomal recessive form of inheritance. One case had a dominant form. The unity of cases described as Werdnig Hoffman disease [SMA I, SMA II (Childhood), ans SMA III (Kugelberg Welander)] is supported and our cases fell in three groups according to their ambulatory capabilities: never acquired, lost, or retained. 71 cases have never walked: the onset of symptoms was noted at an average age of 6.4 months +/- 3; the average age at the last examination was 16 years (4-39). Death occurred in 6 cases. Loss of walking occurred in 24 cases: the onset of symptoms was noted at an average age of 17.4 months +/- 14.2. 5 cases were still ambulatory: the onset of symptoms was noted at an average age of 2.4 years +/- 2.8. For these last 29 cases the average age at the last examination was 20 years (4-38); death occurred in two cases. The weakness was symmetrical and proximal. The period of worsening varied but, frequently, patients with a later onset of symptoms had a longer period of deterioration. Tongue fasciculations were present in all cases who never walked. Facial and masseter weakness occurred in 3 cases. Oesophagus dyskinesia and distension of the stomach due to brain stem lesions occurred in many cases. This brain stem damage was responsible of 2 sudden deaths (8-30 years). Premature puberty occurred in 14 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Familial mitochondrial encephalopathy. A clinicopathologic study]. / Encéphalopathie mitochondriale familiale. Etude clinicopathologique.

We report the cases of 2 siblings with progressive encephalopathy. The first symptoms were noted when they were 6 years old. The full clinical picture included myoclonus, seizures, cerebellar ataxia, blindness due to optic atrophy and retinal degeneration, deafness, swallowing difficulties with relatively spared intellectual functions. The course was progressive and led to death within 8 years. The pathological findings included bilateral and almost symmetrical lesions involving the thalami, the colliculi, and the pontine and medullar tegmentum, similar to the changes described in Leigh disease. Neuronal loss and gliosis were noted in the dentate nucleus and in the inferior olive, as in MERRF syndrome. Laminar necrosis of the cerebral cortex could have been due to episodes of severe hypotension before death. Cytochrome c oxidase deficiency was found in case 2. The enzyme deficiency was present in muscle and in fibroblasts in culture.

[Congenital myasthenic syndromes due to mutations in the rapsyn gene]. / Syndromes myasthéniques congénitaux dus à des mutations du gène de la rapsyne.

Congenital myasthenic syndromes (CMS) are genetic diseases characterized by dysfunctional neuromuscular transmission and usually start during the neonatal period. Most are due to postsynaptic abnormalities, specifically to mutations in the acetylcholine receptor (AChR) genes. In 2002, the group of A Engel reported the first cases of CMS with mutations in the gene coding rapsyn, a postsynaptic molecule which stabilizes AChR aggregates at the neuromuscular junction. Since this first publication, more than 30 other cases, including six in France, have been reported. Study of these published cases allows us to distinguish three classes of phenotypes: 1) severe neonatal cases; 2) more benign cases, starting during infancy; 3) cases with facial malformations, involving Jewish patients originating from the Near-East. Comparison of the observations of other groups with our own has led us to the following conclusions: the N88K mutation is frequent (homozygous in 50% of cases); besides the N88K mutation, the second mutation varies considerably; heterozygous allelic cases (N88K + another mutation) are severe; there is probably a founder effect in the European population. There is phenotypic variability in the homozygous N88K cases, with benign cases and severe cases of early expression. A Engel and colleagues report that the seven cases of benign CMS with facial malformation, previously described in the Jewish population of Iraq and Iran, were caused by mutation in the promoter region of the rapsyn gene.

[Congenital muscular dystrophy with merosin deficiency: clinical, histopathological, immunocytochemical and genetic analysis]. / Dystrophie musculaire congénitale avec déficience en mérosine: analyse clinique, histopathologique, immunocytochimique et génétique.

A selective deficiency of a specific laminin isovariant, merosin made of M, B1 and B2 chains, was found in a series of 17 patients affected with congenital muscular dystrophy (CMD). The merosin deficiency was complete in 15 cases, and almost complete in two cases. An overexpression of the laminin A chain was seen in these biopsies, while B1 and B2 chains were normally expressed. Comparison of the clinical data with a series of 18 "merosin-non deficient" cases showed that the "merosin-deficient" cases were forming a more homogenous group than the "non-deficient" one. Hypotonia, contractures, motor development delay were generally more severe in the "merosin-deficient" series of cases. Moreover, white matter alterations were seen in most cases explored by MRI or scan imaging. A genetic linkage with a 6q2 locus, corresponding to the M chain gene localization, was found in a panel of informative families from French and Turkish origin with "merosin deficient" CMD. "Merosin non-deficient" families did not map on this locus. So, the "merosin-deficient" CMD can be considered as a peculiar entity within the group of Congenital Muscular Dystrophies.

[Ventricular staphylococcal infections. Treatment with vancomycin by continuous venous infusion]. / Infections ventriculaires à staphylocoque. Traitement par la vancomycine en perfusion veineuse continue.

Thirteen cases of meningeal and/or ventricular infection and 1 case of septicaemia, all caused by staphylococci, were treated with continuous intravenous infusions of vancomycin. Repeated measurements of vancomycin plasma and CSF levels by microbiological assay or by high performance liquid chromatography showed that the antibiotic entered the CSF after 48 hours of treatment and that its concentrations in CSF remained stable at 1 to 4 micrograms/ml (mean: 2 micrograms/ml) throughout the 3 weeks' treatment period. After treatment was discontinued, vancomycin became undetectable in CSF within less than 24 hours. All the children were cured.

[Thoracic scoliosis: exothoracic and endothoracic deformations and the spinal penetration index]. / Scolioses thoraciques: les gibbosités exo et endo thoraciques et l'index de pénétration rachidienne.

PURPOSE OF THE STUDY: We reviewed retrospectively our patients with thoracic lordoscoliosis and conducted a conceptual analysis of the patients with airway compression and atelectasia due to anterior protrusion of the vertebral bodies in order to describe the pathological conditions involved and the management methods used. Our goal was to develop a new concept for quantifying thoracic deformation. The individual cases discussed here have been reported earlier, but this is the first series analysis to date. MATERIAL AND METHODS: Eighteen patients, aged 7.3 to 18 years, with thoracic lordoscoliosis due to a variety of causes, mostly neuromuscular disorders (12 cases), are described. Most patients were treated by anterior subtotal periosteal resection of the vertebral body followed by posterior instrumentation and arthrodesis. RESULTS: Atelectasia disappeared with a normalization of blood gases but the effect was variable on vital capacity. The analysis of the CT studies led to the concept of spinal deformity as an endothoracic deformation resulting from protrusion of the vertebral body into the thorax, the endothoracic vertebral hump. This concept was developed and quantified leading to the definition of a new index: the spinal penetration index. The spinal penetration index was obtained by tracing a line tangent to the posterior curve of the concave and convex ribs on each CT slice to determine a relationship between the real thoracic surface and theoretical thoracic surface measured with this tangent and the circumference of the thoracic cage. The index was expressed as a percent of the endothoracic surface occupied by the protruding veterbral body and the associated ribs. Calculated for each successive CT slice for the entire height of the thorax yielded a spinal penetration index quantifying the thoracic volume occupied by the spine. For the control population, we used CT series of the thorax obtained to search for pulmonary metastases in patients with malignant tumors. This gave a theoretical volume of 8 to 10% occupied by the spine in normal subjects. In our patients with lordoscoliotic deformations we obtained real volumes of 15, 20 and even 50%. DISCUSSION: The spinal penetration index is an important morphological index of thoracic anatomy that measures the real volume of the functional thoracic cavities and which must be differentiated from vital capacity which measures both volume and function. This index can be used for pre- post-operative comparisons and constitutes a first step in 3-D assessment of thoracic spine deformations. It can also be used to classify spinal deformations and to make general recommendations concerning the management of both endothoracic humps and exothoracic rib humps.

[Oxygen therapy and assisted ventilation in children at home]. / Oxygénothérapie et ventilation assistée à domicile chez l'enfant.

Home oxygen therapy is indicated in children with chronic obstructive lung disease when the oxygen content of arterial blood is decreased (oxygen partial pressure less than or equal to 50 mmHg). Three systems are available: compressed gas, bulk liquid, and oxygen concentrator. Oxygen may be administered via nasal cannulae, masks, hoods or endotracheal tubes 15 hours per day. FIO2 and SaO2 are periodically measured. Since 1972, when the experience of mechanical ventilation at home began with poliomyelitis teenagers, many children with neuromuscular diseases have been discharged from hospital with a ventilator. More recently, younger children with chronic lung diseases have also managed at home using intermittent positive pressure ventilation. Oral mechanical ventilation using pressure preset ventilators has been used in neuromuscular diseases; early and daily ventilation of children with paralytic respiratory muscles provides better development of the thoracic cage and of the lungs. Artificial ventilation can be performed by external means; we consider this type of ventilation as contraindicated as it causes thoracic deformities in young children.

Diaphragmatic dysfunction in Collagen VI myopathies.

Collagen VI-related myopathies are hereditary disorders causing progressive restrictive respiratory insufficiency. Specific diaphragm involvement has been suggested by a drop in supine volumes. This pilot study aimed at characterizing the respiratory muscle phenotype in patients with COL6A1-3 genes mutations. Lung function, blood gases, muscle strength and respiratory mechanics were measured in 7 patients between 2002 and 2012. Patients were classified as Early-Severe (n = 3), Moderate-Progressive (n = 2) and Mild (n = 2) according to clinical disease presentation. Seven patients (aged 6-28) were evaluated. Forced vital capacity distinguished the Mild group (>60% predicted) from the two other groups (<50% predicted). This distinction was also possible using the motor function measure scale. Diaphragmatic dysfunction at rest was observed in all the Early-Severe and Moderate-Progressive patients. During a voluntary sniff maneuver diaphragmatic dysfunction was observed in all patients, as assessed by a negative gastric pressure. All patients had diaphragmatic fatigue assessed by a tension-time index over the threshold of 0.15. Diaphragmatic dysfunction during a maximal voluntary maneuver and diaphragmatic fatigue are constant features in Collagen VI myopathies. These observations can assist the diagnosis and should be taken in account for the clinical management, with the early detection of sleep-disordered breathing.

[Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. / Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d'accompagnement palliatif sur deux périodes successives de 10ans.

AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers.

Respiratory care in neuromuscular disorders.

In neuromuscular disorders beginning in childhood, the involvement of respiratory muscles is common. Deterioration of respiratory function occurs insidiously, contributes to significant morbidity, and is often responsible for mortality. Since symptoms of respiratory involvement are not obvious, especially in the presence of maintained ambulation, respiratory failure must be systematically searched for in order to allow early care. The key to care of respiratory problems in neuromuscular disorders is a preventive approach. Careful monitoring of symptoms, regular assessment of pulmonary function, appropriate presurgical management, and aggressive treatment of respiratory infections must be considered a standard of care.

[A neonatal case of immunoallergic acute interstitial nephritis]. / Néphropathie interstitielle aiguë immunoallergique néonatale : à propos d'un cas.

Acute interstitial nephritis accounts for about 10 % of the cases of acute renal failure. An adverse drug reaction caused by an immunoallergic mechanism is suggested when fever, skin rash, eosinophilia, and eosinophiluria are associated. The outcome is favorable after withdrawal of drug therapy in most cases. We report a case of acute interstitial nephritis induced by immunoallergic drug mechanisms, in a 3-week-old infant who presented with acute renal failure associated with eosinophilia and hepatitis and who had received cefotaxime and gentamicin. The patient's progression was favorable with normalization of renal and liver function 1 week after suspension of antibiotic drugs.