A new score combining compound muscle action potential (CMAP) amplitudes and motor score is predictive of motor outcome after AVXS-101 (Onasemnogene Abeparvovec) SMA therapy.

Spinal muscular atrophy 1 (SMA1) is a severe early genetic disease with degeneration of motor neurons. Motor development is still suboptimal after gene replacement therapy in symptomatic patients. In this study, compound muscle action potential (CMAP) amplitudes were explored as predictors of motor recovery after gene therapy. Thirteen symptomatic SMA1 patients were prospectively included at the Necker Enfants Malades Hospital, Paris, France (Cohort 1) and 12 at the other pediatric neuromuscular reference centers of the French Filnemus network (Cohort 2). In Cohort 1, median CMAP amplitudes showed the best improvement between baseline and the 12 months visit compared to the other tested nerves (ulnar, fibular and tibial). High median CMAP amplitudes at baseline was associated with unaided sitting achievement at M6 (AUC 90%). None of the patients with CHOPINTEND at M0 < 30/64 and median CMAP < 0.5 mV achieved unaided sitting at M6 and this result was confirmed on Cohort 2 used as an independent validation data. Thus, median CMAP amplitude is a valid biomarker for routine practice to predict sitting at M6. A median CMAP amplitude over 0.5 mV at baseline may predict better motor recovery.

Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.

Clinical features of spinal muscular atrophy (SMA) type 3 (Kugelberg-Welander disease).

Spinal muscular atrophy type 3 (SMA3), also called Kugelberg-Welander SMA, typically presents with muscle fatigue, slowly progressive weakness and atrophy of lower limbs once they have already acquired independent ambulation. Visceral involvement frequent in type 1 and 2 subtypes is rare in SMA3. Hypotonia, hyperlaxity and absent osteo-tendinous reflexes are typical features. By definition, standing or walking without support is achieved but the vast majority of SMA3 patients lose ambulation with time. Lifespan is normal. In some classifications, an additional subtype is included in the mild end of the spectrum, namely spinal muscular atrophy type 4 (SMA4). In this rare subtype, symptoms begin in adulthood; patients remain ambulatory at least until the fifth decade and have a normal respiratory function. Molecular genetic testing is the gold standard tool for diagnosis of SMA. However, diagnosis in a child affected with SMA3 is often challenging because clinical presentation mimics a muscular dystrophy. Electrodiagnostic studies and muscle biopsy are useful tools for demonstrating the presence of denervation but sometimes may not show meaningful differences to help distinguish between SMA and myopathy. Recent specific therapies show promising results before severe neuronal degeneration and motor dysfunction is installed. Therefore, high suspicion should be maintained and genetic analysis performed early in the diagnostic process when facing patients with symmetric and prominent proximal weakness, especially if they present progressive motor impairment. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[The place of neuropathy in the early diagnosis of Cockayne syndrome: Report on two siblings]. / Place de la neuropathie dans le diagnostic précoce du syndrome de Cockayne : à propos de deux cas dans une fratrie.

Two siblings affected with Cockayne syndrome (CS) are described: this diagnosis was suggested by the finding of a demyelinating neuropathy on electromyography in both children and consistent clinical features. CS is a rare genetic disorder with severe prognosis and a highly varied phenotype, making early diagnosis difficult. Taking into account these two cases and the literature, the current diagnosis criteria are insufficiently specific and appear late: the diagnosis may be delayed because multi-organ involvement and sensorial impairment suggests more frequent neurometabolic disorders. Neuroradiologic abnormalities are suggestive but may occur later. The finding of a demyelinating peripheral neuropathy seems to be a more useful marker to suspect this disorder in the presence of other clinical features. Further studies are required to better define the chronology of the symptoms, not only for adequate genetic counseling and eventual prenatal diagnosis, but also to assess the efficacy of future therapies.

A penicillin- and metronidazole-resistant Clostridium botulinum strain responsible for an infant botulism case.

The clinical course of a case of infant botulism was characterized by several relapses despite therapy with amoxicillin and metronidazole. Botulism was confirmed by identification of botulinum toxin and Clostridium botulinum in stools. A C. botulinum A2 strain resistant to penicillins and with heterogeneous resistance to metronidazole was isolated from stool samples up to 110 days after onset. Antibiotic susceptibility was tested by disc agar diffusion and MICs were determined by Etest. Whole genome sequencing allowed detection of a gene cluster composed of blaCBP for a novel penicillinase, blaI for a regulator, and blaR1 for a membrane-bound penicillin receptor in the chromosome of the C. botulinum isolate. The purified recombinant penicillinase was assayed. Resistance to ß-lactams was in agreement with the kinetic parameters of the enzyme. In addition, the ß-lactamase gene cluster was found in three C. botulinum genomes in databanks and in two of 62 genomes of our collection, all the strains belonging to group I C. botulinum. This is the first report of a C. botulinum isolate resistant to penicillins. This stresses the importance of antibiotic susceptibility testing for adequate therapy of botulism.

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.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients.

Upper limb assessment in non-ambulant patients remains a challenge. We have designed new tools to precisely assess pinch (MyoPinch), grip (MyoGrip), wrist flexion and extension (MyoWrist) strength. We have also designed a new tool to assess the ability of patients to produce repetitive flexion/extension movements of wrist and fingers (MoviPlate). We have assessed the feasibility and reliability of these new tools in 30 non-ambulant patients with Duchenne muscular dystrophy and in 30 age-matched male controls. Existing measures, such as Motor Function Measure, Tapping, and the Brooke Upper Extremity Functional Rating Scale were also performed. Results demonstrated that assessments were feasible in nearly all upper limbs tested for MyoGrip, MyoPinch and MoviPlate. The reliability of all tests, including MyoWrist which was not feasible in the patients presenting with contractures, was excellent in patients as in controls. Motor capacities decrease with the number of months spent in the wheelchair. The scores in the tests were partially correlated with each other, and with clinical measures such as vital capacity, Motor Function Measure, functional hand scale and Brooke score. This study validates a panel of upper limb muscle strength and function measures for Duchenne Muscular Dystrophy which can be applied from controls to extremely weak patients.

Expanding CEP290 mutational spectrum in ciliopathies.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype.

Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker-Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.

Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue.

Mutations in COL6A1, COL6A2 and COL6A3, the genes which encode the extra-cellular matrix component collagen VI, lead to Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). Although the Col6a1(-/-) null mouse has an extremely mild neuromuscular phenotype, a mitochondrial defect has been demonstrated, linked to dysregulation of the mitochondrial permeability transition pore (PTP) opening. This finding has been replicated in UCMD muscle cells in culture, providing justification for a clinical trial using cyclosporine A, an inhibitor of PTP opening. We investigated whether PTP dysregulation could be detected in UCMD fibroblasts (the predominant source of muscle collagen VI), in myoblast cells from patients with other diseases and its response to rescue agents other than collagen VI. Although we confirm the presence of PTP dysregulation in muscle-derived cultures from two UCMD patients, fibroblasts from the same patients and the majority of fibroblasts from other well-characterized UCMD patients behave normally. PTP dysregulation is found in limb girdle muscular dystrophy (LGMD) type 2B myoblasts but not in myoblasts from patients with Bethlem myopathy, merosin-deficient congenital muscular dystrophy, LGMD2A, Duchenne muscular dystrophy and Leigh syndrome. In addition to rescue by cyclosporine A and collagen VI, this cellular phenotype was also rescued by other extra-cellular matrix constituents (laminin and collagen I). As the muscle derived cultures demonstrating PTP dysregulation shared poor growth in culture and lack of desmin labelling, we believe that PTP dysregulation may be a particular characteristic of the state of these cells in culture and is not specific to the collagen VI defect, and can in any case be rescued by a range of extra-cellular matrix components. Further work is needed on the relationship of PTP dysregulation with UCMD pathology.

New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.

OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2. METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis. RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys). CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation.

BACKGROUND: Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. METHODS: We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. RESULTS: We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. CONCLUSIONS: Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.

[Campylobacter jejuni and cytomegalovirus (CMV) infections in patients with the Guillain-Barre syndrome]. / Infections à Campylobacter jejuni et à cytomégalovirus (CMV) associées au syndrome de Guillain-Barré (SGB).

Guillain-Barre syndrome (GBS) is a rare disease triggered by postinfectious mechanisms. The disease concerns all ages, and is widely distributed around the world. The principal risks are respiratory failure, especially during the initial phase of the disease, and persisting deficit at long term. Among the infectious known agents, Campylobacter jejuni and CMV represent more than 40% of GBS causes. The clinical presentation, and the long-term prognosis of GBS related to these two etiologies are different. The physiopathological mechanisms of the nervous attack are probably also different. There is no proof, at this time, that anti-infectious treatment can improve the prognosis. The treatment is based on the early use of immunomodulatory treatments like intravenous immunoglobulins or plasma exchanges.

[Cerebellar ataxia of Norman-Jaeken. Presentation of seven Spanish patients]. / Ataxia cerebelosa de Norman-Jaeken. Presentación de siete pacientes españoles.

AIM: To show that the cerebellar ataxias described by Norman and by Jaeken (CDG1a) are the same disease. PATIENTS AND METHODS: Seven patients, five females and two males (there were two siblings pairs), who presented a severe cerebellar disease slowly progressive associated with generalized cerebellar atrophy. The sister of one of the patients of the series had been studied because of psychomotor retardation but she died at two years of age due to respiratory problems. An autopsy was carried out that showed severe cerebellar atrophy, and the histological study revealed loss of granular cells and diverse abnormalities of Purkinje's cells, especially focal swellings of 'asteroid bodies' or 'cactus like' type. This suggested to us that Norman's ataxia and CDG1a could be the same pathological entity. RESULTS: All seven patients had severe cerebellar hypoplasia-atrophy and a small brainstem. Most patients showed peripheral neuropathy with decreased motor nerve conduction velocity, but very little decreased sensory nerve conduction velocity. All seven patients had highly raised serum concentrations of asialotransferrin, and heterozygous molecular PMM2 deficit (CDG1a). One of these seven cases was the patient whose sister had histological cerebellar changes corresponding to Norman's ataxia. CONCLUSION: The findings observed in our series suggest that the diseases described by Norman and Jaeken are the same pathological entity and CDG1a can be the biological basis of the histological changes of the cerebellum in Norman's ataxia. We suggest the name of Norman-Jaeken ataxia or disease for this entity.

Ataxia cerebelosa de Norman-Jaeken. Presentación de siete pacientes españoles / Cerebellar ataxia of norman-jaeken. Presentation of seven spanish patients

Objetivo. Mostrar que las ataxias cerebelosas descritas por Norman y por Jaeken (CDG1a) son el mismo trastorno. Pacientes y métodos. Siete pacientes, cinco mujeres y dos varones (había dos pares de hermanos), que presentaban una ataxia aguda lentamente progresiva asociada con atrofia cerebelosa generalizada. La hermana de uno de los pacientes de esta serie había sido objeto de estudio por un retraso psicomotor, pero murió a los dos años de edad debido a problemas respiratorios. La autopsia mostraba atrofia cerebelosa aguda, y el estudio histológico revelaba pérdida de la capa de los granos y diversas anormalidades de las células de Purkinje, especialmente inflamación focal de tipo ‘cuerpos asteroides' o cactus-like. Esto nos hizo pensar que la ataxia de Norman y laCDG1a podrían ser la misma entidad patológica. Resultados. Los siete pacientes tenían hipoplasia-atrofia aguda y disminución del grosor del tronco cerebral. La mayoría de los pacientes mostraba una neuropatía periférica con reducción de la velocidad de conducción motora, pero con muy poca disminución de la conducción sensitiva. Los siete pacientes tenían aumentados los niveles séricos deasia lotransferrina, y presentaban una deficiencia molecular heterocigótica PMM2 (CDG1a). Uno de estos siete casos era el paciente cuya hermana tenía cambios histológicos cerebelosos correspondientes a la ataxia de Norman. Conclusiones. Los hechos clínicos y de imagen de los pacientes de nuestra serie, a los que se les había diagnosticado la enfermedad de Norman, son similares a los descritos en los pacientes con síndrome de Jaeken. Ello nos hace pensar que ambas enfermedades son una misma entidad patológica. Los hallazgos obtenidos en nuestra serie indican que la CDG1a es la base bioquímica de los cambios histológicos en el cerebelo en los casos de ataxia de Norman (AU)

Aim. To show that the cerebellar ataxias described by Norman and by Jaeken (CDG1a) are the same disease. Patients and methods. Seven patients, five females and two males (there were two siblings pairs), who presented a severe cerebellar disease slowly progressive associated with generalized cerebellar atrophy. The sister of one of the patients of the series had been studied because of psychomotor retardation but she died at two years of age due to respiratory problems. An autopsy was carried out that showed severe cerebellar atrophy, and the histological study revealed loss of granular cells and diverse abnormalities of Purkinje’s cells, especially focal swellings of ‘asteroid bodies’ or ‘cactus like’ type. This suggested tous that Norman’s ataxia and CDG1a could be the same pathological entity. Results. All seven patients had severe cerebellar hypoplasia-atrophy and a small brainstem. Most patients showed peripheral neuropathy with decreased motor nerve conduction velocity, but very little decreased sensory nerve conduction velocity. All seven patients had highly raised serum concentrations of asial o transferrin, and heterozygous molecular PMM2 deficit (CDG1a). One of these seven cases was the patient whose sister had histological cerebellar changes corresponding to Norman’s ataxia. Conclusion. The findings observed in our series suggest that the diseases described by Norman and Jaeken are the same pathological entity and CDG1a can be the biological basis of the histological changes of the cerebellum in Norman’s ataxia. We suggest the name of Norman-Jaeken ataxia or disease for this entity (AU)