ABSTRACT
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
Subject(s)
DNA Demethylation , Developmental Disabilities/genetics , Developmental Disabilities/pathology , Dioxygenases/deficiency , Adult , Amino Acid Sequence , Autistic Disorder/genetics , Autistic Disorder/pathology , Child , Child, Preschool , Dioxygenases/chemistry , Dioxygenases/genetics , Embryonic Development , Female , Gene Expression Regulation, Developmental , Growth Disorders/genetics , Growth Disorders/pathology , Humans , Infant , Male , Middle Aged , Movement Disorders/genetics , Movement Disorders/pathology , Pedigree , Protein Conformation , Sequence Homology , Young AdultABSTRACT
HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.
Subject(s)
Codon, Nonsense , Intellectual Disability , Prolyl Hydroxylases/metabolism , Amino Acids , Catalytic Domain , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Muscle Hypotonia/genetics , Phenotype , SyndromeABSTRACT
Inverted duplication deletion 8p [invdupdel(8p)] is a complex and rare chromosomal rearrangement that combines a distal deletion and an inverted interstitial duplication of the short arm of chromosome 8. Carrier patients usually have developmental delay and intellectual disability (ID), associated with various cerebral and extra-cerebral malformations. Invdupdel(8p) is the most common recurrent chromosomal rearrangement in ID patients with anomalies of the corpus callosum (AnCC). Only a minority of invdupdel(8p) cases reported in the literature to date had both brain cerebral imaging and chromosomal microarray (CMA) with precise breakpoints of the rearrangements, making genotype-phenotype correlation studies for AnCC difficult. In this study, we report the clinical, radiological, and molecular data from 36 new invdupdel(8p) cases including three fetuses and five individuals from the same family, with breakpoints characterized by CMA. Among those, 97% (n = 32/33) of patients presented with mild to severe developmental delay/ID and 34% had seizures with mean age of onset of 3.9 years (2 months-9 years). Moreover, out of the 24 patients with brain MRI and 3 fetuses with neuropathology analysis, 63% (n = 17/27) had AnCC. We review additional data from 99 previously published patients with invdupdel(8p) and compare data of 17 patients from the literature with both CMA analysis and brain imaging to refine genotype-phenotype correlations for AnCC. This led us to refine a region of 5.1 Mb common to duplications of patients with AnCC and discuss potential candidate genes within this region.
Subject(s)
Intellectual Disability , Leukoencephalopathies , Chromosome Deletion , Chromosome Inversion , Chromosomes, Human, Pair 8 , Corpus Callosum/diagnostic imaging , Genetic Association Studies , Humans , Intellectual Disability/diagnostic imaging , Intellectual Disability/genetics , Leukoencephalopathies/genetics , Phenotype , TrisomyABSTRACT
Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in â¼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.
Subject(s)
Epilepsy/genetics , Nerve Tissue Proteins/genetics , Potassium Channels, Sodium-Activated/genetics , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Genotype , Humans , Infant , Male , Mutation , Phenotype , Young AdultABSTRACT
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Subject(s)
Gain of Function Mutation , Genetic Association Studies , Genotype , Interferon-Induced Helicase, IFIH1/genetics , Phenotype , Alleles , Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/genetics , DNA Mutational Analysis , Female , Genetic Association Studies/methods , High-Throughput Nucleotide Sequencing , Humans , Interferon-Induced Helicase, IFIH1/chemistry , Male , Models, Molecular , Nervous System Malformations/diagnosis , Nervous System Malformations/genetics , Protein Conformation , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
Subject(s)
Genetic Variation/genetics , Hernia, Diaphragmatic/diagnostic imaging , Hernia, Diaphragmatic/genetics , Limb Deformities, Congenital/diagnostic imaging , Limb Deformities, Congenital/genetics , Membrane Proteins/genetics , Adult , Amino Acid Sequence , Child , Cohort Studies , Electroencephalography/methods , Facies , Hernia, Diaphragmatic/physiopathology , Humans , Infant, Newborn , Limb Deformities, Congenital/physiopathology , Magnetic Resonance Imaging/methods , MaleABSTRACT
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Alternative Splicing , Cell Cycle , Cell Line , DNA Mutational Analysis , Genetic Association Studies/methods , Genotype , Humans , Mutation , PhenotypeABSTRACT
The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
Subject(s)
Apnea/genetics , Mutation/genetics , Myasthenia Gravis/genetics , Presynaptic Terminals/metabolism , Symporters/genetics , Symporters/metabolism , Adolescent , Apnea/complications , Apnea/metabolism , Apnea/pathology , Arthrogryposis/complications , Arthrogryposis/genetics , Butyrylcholinesterase/metabolism , Child , Child, Preschool , Cholinergic Neurons/metabolism , Cholinergic Neurons/pathology , DNA Mutational Analysis , Exome/genetics , Female , Genes, Recessive/genetics , HEK293 Cells , Heterozygote , Homozygote , Humans , Infant , Infant, Newborn , Male , Muscle Hypotonia/genetics , Muscle Weakness/complications , Muscle Weakness/genetics , Muscle Weakness/pathology , Mutation, Missense/genetics , Myasthenia Gravis/complications , Myasthenia Gravis/metabolism , Myasthenia Gravis/pathology , Neuromuscular Junction/enzymology , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Presynaptic Terminals/pathology , Symporters/deficiency , Synaptic TransmissionABSTRACT
The article has been corrected to account for one patient being investigated through genome sequencing rather than exome sequencing as originally published; thus amendments to the Abstract and Methods have been made as well as addition of the relevant authors and acknowledgment.
ABSTRACT
PURPOSE: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. METHODS: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing. RESULTS: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. CONCLUSION: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.
Subject(s)
Epileptic Syndromes/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/physiology , WW Domain-Containing Oxidoreductase/genetics , WW Domain-Containing Oxidoreductase/physiology , Adolescent , Child , Child, Preschool , DNA Copy Number Variations/genetics , Epilepsy/genetics , Female , Genetic Association Studies/methods , Humans , Infant , Male , Mutation/genetics , Mutation, Missense/genetics , Syndrome , Tumor Suppressor Proteins/metabolism , WW Domain-Containing Oxidoreductase/metabolismSubject(s)
Autoimmune Diseases of the Nervous System/drug therapy , Interferons/metabolism , Nervous System Malformations/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Autoimmune Diseases of the Nervous System/metabolism , Cerebrovascular Circulation/drug effects , Dideoxynucleosides/therapeutic use , Drug Combinations , France , Gene Expression/drug effects , Humans , Interferons/genetics , Lamivudine/therapeutic use , Nervous System Malformations/metabolism , Pilot Projects , Zidovudine/therapeutic useABSTRACT
BACKGROUND: Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling. METHODS: By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX. RESULTS: We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate. CONCLUSIONS: Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.
Subject(s)
Oxidoreductases/genetics , Phenotype , Spasms, Infantile/genetics , Spinocerebellar Ataxias/genetics , Tumor Suppressor Proteins/genetics , Codon, Nonsense/genetics , Comparative Genomic Hybridization , High-Throughput Nucleotide Sequencing , Humans , Mutation, Missense/genetics , Spasms, Infantile/pathology , Spinocerebellar Ataxias/pathology , WW Domain-Containing OxidoreductaseABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number. RESULTS: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies. CONCLUSION: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies.
Subject(s)
DNA Copy Number Variations , Muscular Atrophy, Spinal , Child, Preschool , Humans , Mutation , Oligonucleotides/therapeutic use , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease in children causing sleep and respiratory disorders that are poorly described in the literature compared to adult forms. This retrospective observational study was performed at the Armand Trousseau University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France. We retrospectively collected data from lung function tests, nocturnal gas exchange recordings, and polysomnography of 24 children with DM1. 39% of the children with DM1 reported respiratory symptoms indicative of sleep disordered breathing. Three patients (12%) presented with a restrictive respiratory pattern, 10 (42%) with a sleep apnoea syndrome, mainly of obstructive origin (2/10 with severe obstructive sleep apnea syndrome), and 11 (45%) with nocturnal alveolar hypoventilation. Non-invasive ventilation (NIV) was indicated in 9 (37.5%) children, although tolerance was poor. No significant deterioration in respiratory function or nocturnal gas exchange was observed during the NIV-free period. This study provides new and useful insights into DM1 disease evolution in children to better adapt for respiratory follow-up and management. This highlights the need for future research to better understand the origin of respiratory and sleep disorders in patients with DM1.
Subject(s)
Myotonic Dystrophy , Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Adult , Humans , Child , Retrospective Studies , Sleep , Sleep Apnea Syndromes/diagnosisABSTRACT
Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the ß1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated ß1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases.
Subject(s)
Myasthenic Syndromes, Congenital , Humans , Myasthenic Syndromes, Congenital/genetics , Agrin/genetics , Mutation , Foot , LDL-Receptor Related Proteins/geneticsABSTRACT
Background: SMA type 1 is a severe neurodegenerative disorder that, in the absence of curative treatment, leads to death before 1 year of age without ventilatory support. Three innovative therapies are available to increase life expectancy. Purpose: (i) To increase knowledge about parents' experiences with their decision to have opted for an innovative therapy; (ii) to assess the middle-term psychological consequences in the parents' lives. Methods: We used an in-depth interview; a self-administrated questionnaire and self-report scales (BDI-II, STAI-Y, PSI-SF, SOC-13, PBA, DAS 16 and FICD). We compared parents hesitant before the decision to parents who were not-hesitant and the group of parents whose child was treated with gene therapy (GT) to parents whose child received another innovative therapy. Main results: We included n = 18 parents of 13 children. Parent's mean age was 34.7 (±5.2), child's average age was 44.3 months (±38.0). Retrospectively, most parents felt involved by doctors in decision-making on treatment, they felt their point of view was considered and were satisfied with the effects of the treatment. The group of parents "non-hesitant" was more depressed (p < 0.001), more anxious (p = 0.022) and had higher parental stress (p = 0.026) than the group of "hesitant" parents; the group of "GT-treated" parents was more depressed (p = 0.036) than the group of parents with "other therapy". Qualitative data highlights revealed: the need to save the child's life at all costs; the fear of coping with end of life and palliative care, the high value of perceived physician confidence in the treatment, the hope that the child will acquire autonomy or be cured. At the time of the decision, no parents felt they fully understood all of the issues regarding therapy and the disease. Conclusion: Hesitating before making a decision did not predispose parents to depression and anxiety. The narratives suggest that the parents faced a dilemma regarding their child's health in an urgent context. The decision was not final, and parents will continue to think about it throughout the care process.
ABSTRACT
The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Subject(s)
Disease Progression , Muscle Hypotonia/diagnosis , Muscle Hypotonia/genetics , Ryanodine Receptor Calcium Release Channel/genetics , Adolescent , Adult , Age of Onset , Aged , Child, Preschool , Female , Humans , Male , Middle Aged , Pedigree , Young AdultABSTRACT
TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3's direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
ABSTRACT
OBJECTIVE: To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 (SYT2) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs). METHODS: Next-generation sequencing identified new homozygous intronic and frameshift mutations in the SYT2 gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ). RESULTS: The 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328_331dup in patient 2, located respectively in the 5' splice donor site of SYT2 intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects. CONCLUSIONS: This study identifies new homozygous recessive SYT2 mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive SYT2-related CMS associated with defects in neurotransmitter release.
ABSTRACT
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 age[1-27]: 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).