Asparagine Synthetase Deficiency (ASNSD) is a disease caused by mutations in asparagine synthetase (ASNS). Newborns exhibit microcephaly, intractable epileptic-like seizures, progressive brain ...atrophy, and axial hypotonia. ASNSD results in global developmental delays and premature death. The present report describes a 9-year-old child who is a compound heterozygote with ASNS mutations c.1439C > T and c.239A > G leading to variants p.S480F and p.N80S, respectively. When grown in a complete culture medium, primary fibroblasts from the child contained ASNS mRNA and protein levels similar to an unrelated wild-type fibroblast cell line. When the child’s fibroblasts were cultured for up to 72 h in a medium lacking asparagine, proliferation was reduced by about 50%. Purification of ASNS proteins harboring either the S480F or the N80S substitution had reduced enzymatic activity by 80% and 50%, respectively. Ectopic expression of either variant in ASNS-null Jensen rat sarcoma (JRS) cells did not support proliferation in the absence of medium-supplied asparagine, whereas expression of wild-type enzyme completely restored growth. These studies add to the list of pathogenic ASNS variants and use enzyme activity and protein expression in ASNS-null cells to expand our knowledge of the biological impact of mutations in the ASNS gene.
Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying ...molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.
Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these ...short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months 0.6-10.4. Seventy-seven patients died at a median 6 months of age1-27: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).
Pathophysiology of cerebral palsy Marret, Stéphane; Vanhulle, Catherine; Laquerriere, Annie
Handbook of Clinical Neurology,
2013, 20130000, 2013-00-00, Volume:
111
Book Chapter, Reference, Journal Article
Peer reviewed
Cerebral palsy (CP), defined as a group of nonprogressive disorders of movement and posture, is the most common cause of severe neurodisability in children. Understanding its physiopathology is ...crucial to developing some protective strategies. Interruption of oxygen supply to the fetus or brain asphyxia was classically considered to be the main causal factor explaining later CP. However several ante-, peri-, and postnatal factors could be involved in the origins of CP syndromes. Congenital malformations are rarely identified. CP is most often the result of environmental factors, which might interact with genetic vulnerabilities, and could be severe enough to cause the destructive injuries visible with standard imaging (i.e., ultrasonographic study or MRI), predominantly in the white matter in preterm infants and in the gray matter and the brainstem nuclei in full-term newborns. Moreover they act on an immature brain and could alter the remarkable series of developmental events. Biochemical key factors originating in cell death or cell process loss, observed in hypoxic−ischemic as well as inflammatory conditions, are excessive production of proinflammatory cytokines, oxidative stress, maternal growth factor deprivation, extracellular matrix modifications, and excessive release of glutamate, triggering the excitotoxic cascade. Only two strategies have succeeded in decreasing CP in 2-year-old children: hypothermia in full-term newborns with moderate neonatal encephalopathy and administration of magnesium sulfate to mothers in preterm labor.
Abstract
Background
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been ...covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination–Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age.
Results
Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2.
Survival motor Neuron 2
(
SMN2)
copy numbers were available for all but 6 patients.
Patients under 2 years of age (
n
= 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking.
Conclusion
Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.
Sulfated proteoglycans are essential in skeletal and brain development. Recently, pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis have been identified in a ...range of chondrodysplasia associated with intellectual disability. Nevertheless, several patients remain with unidentified molecular basis. This study aimed to contribute to the deciphering of new molecular bases in patients with chondrodysplasia and neuro-developmental disease. Exome sequencing was performed to identify pathogenic variants in patients presenting with chondrodysplasia and intellectual disability. The pathogenic effects of the potentially causative variants were analyzed by functional studies. We identified homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2 in two patients with pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. By functional analyses, we showed that the variants affect SLC35B2 mRNA expression and protein subcellular localization leading to a functional impairment of the protein. Consistent with those results, we detected proteoglycan sulfation impairment in SLC35B2 patient fibroblasts and serum. Our data support that SLC35B2 functional impairment causes a novel syndromic chondrodysplasia with hypomyelinating leukodystrophy, most likely through a proteoglycan sulfation defect. This is the first time that SLC35B2 variants are associated with bone and brain development in human.
To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management.
Among the 2,697 ...patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed.
We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce.
The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.
•Fingerprint bodies are now recognized as non-specific.•They may be observed alone or with other lesions.•Association with rods has never been reported so far.•They may be present in case of ...mutations in the LMOD3 gene.•And be associated with a milder phenotype than previously reported.
Fingerprint bodies are observed in a variety of clinical situations with no definite genetic cause identified so far. We report for the first time the association of fingerprint bodies with rods in a patient who developed a slowly progressive myopathy affecting the face and limb extremities. Ultrastructural examination first disclosed fingerprint bodies and on a second biopsy, associated cytoplasmic bodies and rods. Next Generation Sequencing panel of congenital nemaline myopathy genes allowed the identification of two novel variants, a deleterious missense variant (c.1628G>T, p.Arg543Leu) located in the WASP-homology 2 domain, and a deletion (c.366delG, p.Lys122AsnFs*6) in the LMOD3 gene, generally causing severe nemaline myopathy with antenatal onset and early death. Recently, a less severe phenotype similar to our case has been reported. Our study confirms the existence of milder phenotypes linked to LMOD3 mutations and underlines that fingerprint bodies, though not specific, may be an early ultrastructural marker that could be linked, among others, to nemaline myopathy.
This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type ...B, MPSIVB).
Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.
The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the
gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.
This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.
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