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Movement Disorders Clinical Practice Jan 2020
PubMed: 31970219
DOI: 10.1002/mdc3.12860 -
The American Journal of Case Reports Jan 2020BACKGROUND Congenital myotonic dystrophy is a subtype of type 1 myotonic dystrophy presenting in the neonatal period. Cardiac involvement is commonly seen in patients...
BACKGROUND Congenital myotonic dystrophy is a subtype of type 1 myotonic dystrophy presenting in the neonatal period. Cardiac involvement is commonly seen in patients with type 1 myotonic dystrophy beyond the neonatal period. Brugada syndrome is a conduction abnormality associated with a mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and has been described in adult patients with type 1 myotonic dystrophy. Two cases are presented of type 1 myotonic dystrophy in neonates, one who had family members with a confirmed diagnosis of Brugada syndrome. CASE REPORT Case 1: A female infant at 40 weeks gestational age, birth weight of 3,395 grams was born to a 40-year-old gravida 4, para 3 (G4P3) mother. The mother had previously been diagnosed with Brugada syndrome. Multiple family members were identified and diagnosed with type 1 myotonic dystrophy and Brugada syndrome. The infant is being monitored closely with a plan to perform genetic testing for Brugada syndrome if she develops cardiac conduction abnormalities. Case 2: A male infant at 37 weeks gestational age, with a birth weight of 2,900 grams, was born to a 24-year-old gravida 2, para 1 (G2P1) mother. He was admitted to the neonatal intensive care unit (NICU) secondary to poor respiratory effort and generalized hypotonia. Severe polyhydramnios was diagnosed during pregnancy. The mother had previously been diagnosed with type 1 myotonic dystrophy. CONCLUSIONS Infants with congenital myotonic dystrophy should be carefully monitored for both structural and conduction abnormalities of the heart, supported by genetic testing.
Topics: Adult; Brugada Syndrome; Female; Genetic Testing; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Mutation; Myotonia Congenita; Myotonic Dystrophy; Myotonin-Protein Kinase; NAV1.5 Voltage-Gated Sodium Channel; Pregnancy
PubMed: 31915326
DOI: 10.12659/AJCR.919867 -
World Journal of Clinical Cases Jan 2024Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on...
BACKGROUND
Paramyotonia congenita (PMC) stands as a rare sodium channelopaty of skeletal muscle, initially identified by Eulenburg. The identification of PMC often relies on electromyography (EMG), a diagnostic technique. The child's needle EMG unveiled trains of myotonic discharges with notably giant amplitudes, alongside irregular wave trains of myotonic discharges. This distinctive observation had not surfaced in earlier studies.
CASE SUMMARY
We report the case of a 3-year-old female child with PMC, who exhibited laryngeal stridor, muffled speech, myotonia from birth. Cold, exposure to cool water, crying, and physical activity exacerbated the myotonia, which was relieved in warmth, yet never normalized. Percussion myotonia was observable in bilateral biceps. Myotonia symptoms remained unchanged after potassium-rich food consumption like bananas. Hyperkalemic periodic paralysis was excluded. Cranial magnetic resonance imaging yielded normal results. Blood potassium remained within normal range, while creatine kinase showed slight elevation. Exome-wide genetic testing pinpointed a heterozygous mutation on chromosome SCN4A: c.3917G>A (p.G1306E). After a six-month mexiletine regimen, symptoms alleviated.
CONCLUSION
In this case revealed the two types of myotonic discharges, and had not been documented in other studies. We underscore two distinctive features: Giant-amplitude potentials and irregular waves.
PubMed: 38322461
DOI: 10.12998/wjcc.v12.i3.587 -
Heliyon Jan 2024mutations have been shown to be associated with myotonia, paramyotonia congenita, and periodic paralyses. More recently, loss-of-function variants in the gene were...
mutations have been shown to be associated with myotonia, paramyotonia congenita, and periodic paralyses. More recently, loss-of-function variants in the gene were also noted to be associated with rarer, autosomal recessive forms of congenital myasthenic syndrome and congenital myopathy. Diagnosis is challenging as the initial clinical presentation and histological features on muscle biopsies are non-specific. We report a Han Chinese patient presented with congenital myopathy with two missense variants. The patient had an antenatal history of reduced fetal movements, polyhydramnios and a very preterm birth. At birth, she was noted to have low Apgar score, respiratory distress syndrome and hypotonia. Delayed motor development was noted in early childhood. Dysmorphic features such as an elongated face, dolichocephaly and high arched palate were present. At 16 years of age, the patient developed progressive muscle weakness and was wheelchair-bound by age 20. Muscle biopsy revealed non-specific changes only. Targeted hereditary myopathy panel testing by next generation sequencing revealed two previously unreported missense variants c.1841A > T p.(Asn614Ile) and c.4420G > A p.(Ala1474Thr) in the gene. The clinical features of -related congenital myopathy and myasthenic syndrome were reviewed. This case exemplifies the utility of next generation sequencing in the diagnosis of undifferentiated muscle disease.
PubMed: 38187266
DOI: 10.1016/j.heliyon.2023.e23663 -
Molecular Genetics & Genomic Medicine Aug 2020αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that...
BACKGROUND
αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance.
METHODS
The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques.
RESULTS
CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization.
CONCLUSIONS
The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.
Topics: Cataract; Child, Preschool; Genes, Dominant; Humans; Male; Muscle, Skeletal; Mutation; Myotonia Congenita; Phenotype; Syndrome; Twins; alpha-Crystallin B Chain
PubMed: 32420686
DOI: 10.1002/mgg3.1290 -
Medicine Jul 2020we report on the first case of a woman affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and recessive myotonia congenita (MC), treated with...
Chronic inflammatory demyelinating polyradiculoneuropathy relapse after mexiletine withdrawal in a patient with concomitant myotonia congenita: A case report on a potential treatment option.
INTRODUCTION
we report on the first case of a woman affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and recessive myotonia congenita (MC), treated with mexiletine. We aimed at describing the possible role of mexiletine in CIDP management.
PATIENT CONCERNS
A 44-year-old female affected by CIDP and MC, gained beneficial effects for CIDP symptoms (muscle weakness, cramps, and fatigue) and relapses, after mexiletine intake (200 mg twice a day). The patient presented with detrimental effects after mexiletine drop out, with a worsening of CIDP symptoms.
INTERVENTIONS
The patient reported a nearly complete remission of muscle stiffness and weakness up to 3 years since mexiletine intake. Then, she developed an allergic reaction with glottis edema, maybe related to mexiletine intake, as per emergency room doctors' evaluation, who suggested withdrawing the drug.
OUTCOMES
The patient significantly worsened after the medication drop out concerning both CIDP and MC symptoms.
CONCLUSION
This is the first report on the association of CIDP and MC in the same patient. Such diseases may share some clinical symptoms related to a persistent sodium currents increase, which maybe due either to the over-expression of sodium channels following axonal damage due to demyelination or to the chloride channel genes mutations. This is the possible reason why mexiletine maybe promising to treat CIDP symptoms.
Topics: Adult; Chronic Disease; Female; Follow-Up Studies; Humans; Mexiletine; Myotonia Congenita; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Recurrence; Voltage-Gated Sodium Channel Blockers; Withholding Treatment
PubMed: 32664137
DOI: 10.1097/MD.0000000000021117 -
Molecular Genetics & Genomic Medicine Aug 2020GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture...
BACKGROUND
GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture syndrome 1 (LCCS1, OMIM#253310) and congenital arthrogryposis with anterior horn cell disease (CAAHD, OMIM#611890). The clinical spectrum of GLE1-related disorders has been expanding these past years, including with adult-onset amyotrophic lateral sclerosis (ALS) GLE1-related forms, especially through the new molecular diagnosis strategies associated with the emergence of next-generation sequencing (NGS) technologies. However, despite this phenotypic variability, reported congenital or ALS adult-onset forms remain severe, leading to premature death.
METHODS
Through multidisciplinary interactions between our Neuropediatric and Medical Genetics departments, we were able to diagnose two siblings presenting with congenital disorder, using an NGS approach accordingly to the novel French national recommendations.
RESULTS
Two siblings with very similar clinical features, meaning neuromuscular disorder of neonatal onset with progressive improvement, were examined in our Neuropediatrics department. The clinical presentation evoked initially congenital myopathy with autosomal recessive inheritance. However, additional symptoms such as mild dysmorphic features including high anterior hairline, downslanted palpebral fissures, anteverted nares, smooth philtrum with thin upper-lip, narrow mouth and microretrognathia or delayed expressive language and postnatal growth retardation were suggestive of a more complex clinical presentation and molecular diagnosis. Our NGS approach revealed an unexpected molecular diagnosis for these two siblings, meaning the presence of the homozygous c.1808G>T GLE1 variant.
CONCLUSIONS
We here report the mildest phenotype ever described, in two siblings carrying the homozygous c.1808G>T GLE1 variant, further widening the clinical spectrum of GLE1-related diseases. Moreover, by reflecting current medical practice, this case report confirms the importance of establishing regular multidisciplinary meetings, essential for discussing such difficult clinical presentations to finally enable molecular diagnosis, especially when NGS technologies are used.
Topics: Child; Child, Preschool; Diagnosis, Differential; Female; Homozygote; Humans; Male; Myotonia Congenita; Nucleocytoplasmic Transport Proteins; Pedigree; Phenotype; Point Mutation
PubMed: 32537934
DOI: 10.1002/mgg3.1277 -
Molecular Genetics & Genomic Medicine Oct 2021Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies.
Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d-transposition of the great arteries.
BACKGROUND
Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies.
METHODS
Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole-exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole-genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis.
RESULTS
WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1-RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries.
CONCLUSION
While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1-RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.
Topics: Biopsy; Echocardiography; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Heterozygote; Humans; Infant, Newborn; Intracranial Hemorrhages; Introns; Magnetic Resonance Imaging; Male; Mutation; Myotonia Congenita; Respiratory Insufficiency; Ryanodine Receptor Calcium Release Channel; Transposition of Great Vessels; Whole Genome Sequencing
PubMed: 34528764
DOI: 10.1002/mgg3.1804 -
Journal of Neuromuscular Diseases 2024Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological...
Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.
Topics: Humans; Genetic Association Studies; Mosaicism; Myotonia Congenita; Phenotype; Ryanodine Receptor Calcium Release Channel; Male; Child, Preschool
PubMed: 38489196
DOI: 10.3233/JND-230216 -
Neurology India Jan 2024
Topics: Humans; Glycosylation; Myasthenic Syndromes, Congenital; Muscular Diseases; Myotonia Congenita; Mutation
PubMed: 38443029
DOI: 10.4103/neurol-india.Neurol-India-D-23-00582