X-Linked Myotubular Myopathy: A Novel Mutation Expanding the Genotypic Spectrum of a Phenotypically Heterogeneous Myopathy

AbstractX-linked myotubular myopathy (XLMTM), a centronuclear congenital myopathy secondary to pathogenic variants in the MTM1 gene encoding myotubularin, is typically recognized for its classic and severe phenotype which includes neonatal hypotonia, severe muscle weakness, long-term ventilator dependence, markedly delayed gross motor milestones with inability to independently ambulate, and a high neonatal and childhood mortality. However, milder congenital forms of the condition and other phenotypes are recognized. We describe a 6-year-old boy with a mild XLMTM phenotype with independent gait and no respiratory insufficiency even in the neonatal period. The child has a hemizygous novel splice site variant in the MTM1 gene (c.232–25A > T) whose pathogenicity was confirmed by cDNA studies (exon 5 skipping) and muscle biopsy findings. We also compared the phenotype of our patient with the few reported cases that presented a mild XLMTM phenotype and no respiratory distress at birth, and discussed the potential mechanisms underlying this phenotype such as the presence of residual expression of the normal myotubularin transcript.

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Exome sequencing in the assessment of congenital malformations in the fetus and neonate

Archives of Disease in Childhood - Fetal and Neonatal Edition ◽

10.1136/archdischild-2018-316352 ◽

2019 ◽

pp. fetalneonatal-2018-316352 ◽

Cited By ~ 1

Author(s):

Fionnuala Mone ◽

Elizabeth Quinlan-Jones ◽

Andrew K Ewer ◽

Mark D Kilby

Keyword(s):

Next Generation Sequencing ◽

Exome Sequencing ◽

Congenital Malformations ◽

Neonatal Period ◽

Diagnostic Yield ◽

Prolonged Hospitalisation ◽

Pathogenic Variants ◽

Fetus And Neonate ◽

Generation Sequencing

Major congenital anomalies are often associated with perinatal mortality, long-term morbidity and prolonged hospitalisation. Prenatal ultrasound remains the principle diagnostic test for many anomalies, but despite this up to one-third are only identified in the neonatal period. The primary step in determining underlying aetiology is to define accurately the phenotype by recognition of dysmorphology (both prenatally and postnatally). The potential introduction of next-generation sequencing, primarily through exome sequencing, into perinatal practice may improve the pathological diagnostic yield. However, clinicians must understand both the benefit and potential harms of this technology in facilitating the discovery of relevant pathogenic variants in the diagnosis and management of congenital malformations.

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Detection of Ace-1 gene with insecticides resistance in Aedes aegypti populations from DHF-endemic areas in Padang, Indonesia

Biodiversitas Journal of Biological Diversity ◽

10.13057/biodiv/d190105 ◽

2018 ◽

Vol 19 (1) ◽

pp. 31-36 ◽

Cited By ~ 2

Author(s):

HASMIWATI HASMIWATI ◽

SELFI RENITA RUSJDI ◽

EKA NOFITA

Keyword(s):

Aedes Aegypti ◽

Novel Mutation ◽

Hemorrhagic Fever ◽

Gene Encoding ◽

Development Of Resistance ◽

West Sumatra ◽

Primary Vector ◽

Endemic Areas ◽

Larval Susceptibility

Hasmiwati, Rusjdi SR, Nofita E. 2018. Detection of Ace-1 gene with insecticides resistance in Aedes aegypti populations from DHF-endemic areas in Padang, Indonesia. Biodiversitas 19: 31-36. Aedes aegypti is distributed widely in West Sumatra as a primary vector of Dengue hemorrhagic fever, especially in Padang City. Synthetic insecticide control is one currently used method to prevent mosquito-borne diseases. The extensive, long-term application of Temephos along with inappropriate dosages, have resulted in the development of resistance in Ae. aegypti populations. Mutation of the Ace-1 gene, encoding an acetyl cholinesterase, is one of the mechanisms that confer resistance to organophosphate (OP). The Temephos resistance status of Ae. aegypti in Padang city has not yet been studied. This study aimed to investigate the resistance status of Ae. aegypti and identify any possible mutation (s) of the Ace-1 gene in Padang city. Ae. aegypti samples were collected in five population in Padang city (Jati (JT), Gunung Pangilun (GP), Lubuk Minturun (LM), Korong Gadang (KG), and Bandar Buat (BB)). The larval susceptibility to Temephos was tested by larval bioassays with Temephos pestanal at 0.02 mg/L dosages. Larval susceptibility was determined by mortality percentage values. The relationship between Ace-1 genotypes and the resistant phenotype was analyzed by percentage of genotype frequency. Out of five populations, assessed by larval bioassays, JT and GP were resistant to Temephos; LM, KG, and BB were tolerant. A total of 50 individuals from larval bioassays were genotyped for Ace-1 gene. Our findings showed that Ace-1 was 495 bp in length. Mutation was not found in the G119S location but in the T506T location. Three alleles in T506T location were detected, including a wild type allele, TT (65.21%), and two mutant alleles, TA (26.08%), AA (8.69%). The use of Temephos showed that some Ae. aegypti populations were resistant, others were tolerant, but no population was vulnerable to Temephos. A novel mutation was detected as substitution in T506T location (ACT>ACA).

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Clinical Spectrum Of CACNA1C Variants, Revisited

10.21203/rs.3.rs-28919/v1 ◽

2020 ◽

Author(s):

Anwar Baban ◽

Bernadette Corica ◽

Maria Gnazzo ◽

Federica Calì ◽

Nicoletta Cantarutti ◽

...

Keyword(s):

Independent Risk Factor ◽

Heart Defects ◽

Disease Recurrence ◽

Long Term Results ◽

Phenotype Correlation ◽

Phenotypic Analysis ◽

Gene Encoding ◽

Pathogenic Variants ◽

Qt Syndrome

Abstract Background CACNA1C is a gene encoding the CaV1.2 calcium channel and several cardiac conditions are potentially associated with pathogenic variants in this gene. The aim of this study is to explore genotype-phenotype correlations related to CACNA1C ever described variants and vast phenotypic spectrum.MethodsWe analyzed 102 patients with CACNA1C variants (CACNA1Cv) (9 our cohort and 93 from literature). We studied the association between CACNA1Cv and clinical parameters: arrhythmias, structural heart defects, cardiomyopathy and survival. We followed the American College Medical Genetics (ACMG) scoring system to grade variants’ pathogenicity and their domains.Results CACNA1Cvwith high ACMG scores were associated with higher mortality than variants with lower scores (p < 0.001). CACNA1Cv in Cytoplasmic and Transmembrane domains were associated with higher mortality than other domains (p = 0.005). Multivariate analysis for higher ACMG scores, indicates cardiomyopathy and a lesser extent domain, as independent risk factor for mortality (p = 0.031 and p = 0.04). Cytoplasmic domain variants were frequently associated with long-QT syndrome; C-terminal variants were often linked to Brugada syndrome. Parental mosaicism was relatively high (4–5%) and must not be overlooked in parents’ phenotypic analysis and in calculation of disease recurrence riskConclusionTo the best of our knowledge, this is the first study trying to create genotype-phenotype correlation and better risk stratification in CACNA1Cv in relation to survival and long-term results.

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A novel mutation in protein C gene (PROC) causing severe phenotype in neonatal period

Pediatric Blood & Cancer ◽

10.1002/pbc.24782 ◽

2013 ◽

Vol 61 (4) ◽

pp. 763-764 ◽

Cited By ~ 4

Author(s):

Sule Unal ◽

Fatma Gumruk ◽

Sule Yigit ◽

Murat Tuncer ◽

Betul Tavil ◽

...

Keyword(s):

Protein C ◽

Neonatal Period ◽

Novel Mutation ◽

Severe Phenotype

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Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

Neurology Genetics ◽

10.1212/nxg.0000000000000589 ◽

2021 ◽

Vol 7 (3) ◽

pp. e589

Author(s):

Daniel G. Calame ◽

Jawid Fatih ◽

Isabella Herman ◽

Zeynep Coban Akdemir ◽

Haowei Du ◽

...

Keyword(s):

Troponin T ◽

Nemaline Myopathy ◽

Congenital Myopathy ◽

Sequencing Data ◽

Gene Encoding ◽

Distal Arthrogryposis ◽

Pathogenic Variants ◽

Patient Reported ◽

History Of ◽

Nemaline Rods

ObjectivePathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants.MethodsClinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy.ResultsA homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here.ConclusionsThis report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

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Spondylometaepiphyseal Dysplasia Short Limb-Abnormal Calcification Type in Turkish Patients Reveals a Novel Mutation and New Features

Molecular Syndromology ◽

10.1159/000517848 ◽

2021 ◽

pp. 1-15

Author(s):

Elif Yilmaz Gulec ◽

Bassam R. Ali ◽

Anne John ◽

Beyhan Tuysuz

Keyword(s):

Novel Mutation ◽

Middle Eastern ◽

Autosomal Recessive Disorder ◽

Gene Encoding ◽

Short Limb ◽

Pathogenic Variants ◽

Tyrosine Kinase 2 ◽

Fatal Course ◽

Turkish Case ◽

Turkish Patients

Spondylometaepiphyseal dysplasia short limb-abnormal calcification type (SMED-SL/AC) is a rare autosomal recessive disorder. It is a severe dwarfism syndrome with a characteristic feature of progressive calcification of epiphyseal and other cartilaginous tissues. It is caused by pathogenic variants in the <i>DDR2</i> gene encoding the discoidin domain receptor tyrosine kinase 2. Thus far, 37 cases and 8 pathogenic variants have been reported. Most of the reported cases are of Middle Eastern and Puerto Rican origins. Only one Turkish case has been reported previously with a novel truncating variant p.(R489*). Here, we report 2 new cases, 1 with a novel variant p.(S311G) and 1 with a splice site variant c.2283+1G>A. In addition, we reviewed a previously reported case, and sequencing of stored DNA revealed the recently reported nonsense variant p.(R489*) as the underlying cause. Therefore, our data increase the number of SMED-SL/AC Turkish patients with molecular results to 4. Furthermore, we compared the features of Turkish patients with other reported cases and expanded the characteristics of the disorder with new features such as triventricular hydrocephalus, intracranial hemorrhage, hypopigmentation of hair, dry and scaly skin, arthralgia, and hypocalcemia. We also compared the pathogenic variants of Turkish patients with other variants, aiming to explain the mechanism leading to a more severe and early fatal course in Turkish patients.

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Faculty Opinions recommendation of Myotonic dystrophy type I in childhood Long-term evolution in patients surviving the neonatal period.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1119933.576047 ◽

2008 ◽

Author(s):

Nigel Clarke

Keyword(s):

Myotonic Dystrophy ◽

Neonatal Period ◽

Long Term Evolution ◽

Type I ◽

Myotonic Dystrophy Type ◽

Term Evolution

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Severe tricuspid regurgitation 14 years after diagnosis of “transient neonatal tricuspid regurgitation”

Heart ◽

10.1136/hrt.86.1.88 ◽

2001 ◽

Vol 86 (1) ◽

pp. 88-90

Author(s):

D Boshoff ◽

L Mertens ◽

M Gewillig

Keyword(s):

Tricuspid Regurgitation ◽

Neonatal Period ◽

Clinical Course ◽

Subsequent Evolution ◽

Severe Tricuspid Regurgitation ◽

Echocardiographic Examination ◽

Long Term Follow Up ◽

Transient Tricuspid Regurgitation

A 14 year old girl presented with severe tricuspid regurgitation after she was diagnosed with “transient tricuspid regurgitation of the newborn”. In the neonatal period she had presented with severe tricuspid regurgitation without an obvious underlying anatomical cause. This spontaneously regressed during the first months of life. She was dismissed from follow up at the age of 5 years after complete normalisation of the clinical and echocardiographic examination. The subsequent evolution and management of the patient, as well as the possible pathogenesis responsible for the unusual clinical course, is discussed. This case stresses the importance of long term follow up of patients with transient tricuspid regurgitation.

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Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms22084202 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4202

Author(s):

Carlotta Spagnoli ◽

Carlo Fusco ◽

Antonio Percesepe ◽

Vincenzo Leuzzi ◽

Francesco Pisani

Keyword(s):

Movement Disorders ◽

Time Course ◽

Neonatal Period ◽

Age Of Onset ◽

Brain Mri ◽

Neonatal Seizure ◽

Mri Findings ◽

Epileptic Encephalopathies ◽

Pathogenic Variants ◽

Neonatal Onset

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

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