A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations

Abstract Background Autopsies regularly aim to clarify the cause of death; however, relatives may directly benefit from autopsy results in the setting of heritable traits (“mortui vivos docent”). Case presentation A case of a sudden unexpected cardiac death of a 5.5-months-old child is presented. Autopsy and thorough postmortem cardiac examinations revealed a massively enlarged heart with endomyocardial fibroelastosis. Postmortem molecular testing (molecular autopsy) revealed an unusual combination of two biparental MYBPC3 gene mutations likely to underlie the cardiac abnormalities. Thus, the molecular autoptic findings also had consequences for the relatives of the deceased child and impact on further family planning. Conclusions The presented case highlights the need for clinical autopsies including cardiac examinations and postmortem molecular testing; it also paves the way for further cascade screening of family members for cardiac disease, if a distinct genetic disorder is suspected.

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Tyrosinase gene mutations in the Chinese Han population with OCA1

Genetics Research ◽

10.1017/s0016672314000160 ◽

2014 ◽

Vol 96 ◽

Cited By ~ 5

Author(s):

NING LIU ◽

XIANG DONG KONG ◽

HUI RONG SHI ◽

QING HUA WU ◽

MIAO JIANG

Keyword(s):

At Risk ◽

Genetic Disorder ◽

Severe Disease ◽

Genetic Diagnosis ◽

Gene Mutations ◽

Oculocutaneous Albinism ◽

Compound Heterozygous ◽

Chinese Han ◽

Essential Information ◽

Prenatal Genetic Diagnosis

SummaryOculocutaneous albinism (OCA) is a heterogeneous autosomal recessive genetic disorder that affects melanin synthesis. OCA results in reduced or absent pigmentation in the hair, skin and eyes. Type 1 OCA (OCA1) is the result of tyrosinase (TYR) gene mutations and is a severe disease type. This study investigated TYR mutations in a Chinese cohort with OCA1. This study included two parts: patient genetic study and prenatal genetic diagnosis. A total of 30 OCA1 patients were subjected to TYR gene mutation analysis. Ten pedigrees were included for prenatal genetic diagnosis. A total of 100 unrelated healthy Chinese individuals were genotyped for controls. The coding sequence and the intron/exon junctions of TYR were analysed by bidirectional DNA sequencing. In this study, 20 mutations were identified, four of which were novel. Of these 30 OCA1 patients, 25 patients were TYR compound heterozygous; two patients carried homozygous TYR mutations; and three were heterozygous. Among the ten prenatally genotyped fetuses, three fetuses carried compound heterozygous mutations and seven carried no mutation or only one mutant allele of TYR and appeared normal at birth. In conclusion, we identified four novel TYR mutations and showed that molecular-based prenatal screening to detect TYR mutations in a fetus at risk for OCA1 provided essential information for genetic counselling of couples at risk.

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Kleefstra syndrome and epilepsy

Russian Journal of Child Neurology ◽

10.17650/2073-8803-2019-14-4-32-37 ◽

2020 ◽

Vol 14 (4) ◽

pp. 32-37

Author(s):

R. G. Gamirova ◽

N. G. Lyukshina ◽

R. R. Gamirova ◽

M. E. Farnosova

Keyword(s):

Autosomal Dominant ◽

Genetic Disorder ◽

Underlying Disease ◽

Congenital Defects ◽

First Year ◽

Intellectual Deficiency ◽

Pharmacoresistant Epilepsy ◽

Epileptic Spasms ◽

Kleefstra Syndrome ◽

First Year Of Life

Kleefstra syndrome is a rare autosomal dominant genetic disorder caused by haploinsufficiency of the EHMT1 (Euchromatic Histone MethylTransferase 1). Patients with Kleefstra syndrome have following most common symptoms: moderate or severe intellectual deficiency, absence of speech, significant diffuse muscular hypotonia, micro-brachycephaly, congenital defects of heart, kidneys, genitourinary tract and recognizable dysmorphic features of face. The article presents 2 similar clinical cases of Kleefstra syndrome in combination with epilepsy. Both patients, along with a typical clinical picture of the underlying disease, have serial epileptic spasms with an onset after first year of life, modified hypsarrhythmia with tendency to synchronization on the electroencephalogram, pharmacoresistant epilepsy. This indicates that Kleefstra syndrome can include epilepsy as one of symptoms of the disease.

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Plasmapheresis-induced Clinical Improvement in a Patient with Steroid-Resistant Nephrotic Syndrome Due to Podocin (NPHS2) Gene Station

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2016.76 ◽

2010 ◽

Vol 53 (3) ◽

pp. 157-159 ◽

Cited By ~ 3

Author(s):

Sylva Skálová ◽

Miroslav Podhola ◽

Karel Vondrák ◽

Gil Chernin

Keyword(s):

Nephrotic Syndrome ◽

Clinical Improvement ◽

Combined Therapy ◽

Immunosuppressive Agents ◽

Gene Mutations ◽

First Year ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Heterozygous Form ◽

First Year Of Life

Podocin mutations (NPHS2 gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients with NPHS2 gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of two NPHS2 gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated.

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Molecular and genetic insights into progressive cardiac conduction disease

EP Europace ◽

10.1093/europace/euz109 ◽

2019 ◽

Vol 21 (8) ◽

pp. 1145-1158 ◽

Cited By ~ 3

Author(s):

Babken Asatryan ◽

Argelia Medeiros-Domingo

Keyword(s):

Molecular Mechanisms ◽

Metabolic Diseases ◽

Heart Diseases ◽

Genetic Disorder ◽

Genetic Diagnosis ◽

Gene Mutations ◽

Structural Heart Disease ◽

Cardiac Conduction ◽

Cascade Screening ◽

Disease Associated Genes

Abstract Progressive cardiac conduction disease (PCCD) is often a primarily genetic disorder, with clinical and genetic overlaps with other inherited cardiac and metabolic diseases. A number of genes have been implicated in PCCD pathogenesis with or without structural heart disease or systemic manifestations. Precise genetic diagnosis contributes to risk stratification, better selection of specific therapy and allows familiar cascade screening. Cardiologists should be aware of the different phenotypes emerging from different gene-mutations and the potential risk of sudden cardiac death. Genetic forms of PCCD often overlap or coexist with other inherited heart diseases or manifest in the context of multisystem syndromes. Despite the significant advances in the knowledge of the genetic architecture of PCCD and overlapping diseases, in a measurable fraction of PCCD cases, including in familial clustering of disease, investigations of known cardiac disease-associated genes fail to reveal the underlying substrate, suggesting that new causal genes are yet to be discovered. Here, we provide insight into genetics and molecular mechanisms of PCCD and related diseases. We also highlight the phenotypic overlaps of PCCD with other inherited cardiac and metabolic diseases, present unmet challenges in clinical practice, and summarize the available therapeutic options for affected patients.

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CYP21 Genotype, Adult Height, and Pubertal Development in 55 Patients Treated for 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030123 ◽

2003 ◽

Vol 88 (12) ◽

pp. 5680-5688 ◽

Cited By ~ 55

Author(s):

Antonio Balsamo ◽

Alessandro Cicognani ◽

Lilia Baldazzi ◽

Michela Barbaro ◽

Federico Baronio ◽

...

Keyword(s):

Early Diagnosis ◽

First Year ◽

Compound Heterozygous ◽

Target Height ◽

Hydroxylase Deficiency ◽

Genotypic Analysis ◽

Group A ◽

Group B ◽

21 Hydroxylase Deficiency ◽

First Year Of Life

Abstract In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), <1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, ∼2–3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 sd of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.

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A rare case report of unusual presentation of Edward’s syndrome (trisomy 18)

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20182589 ◽

2018 ◽

Vol 5 (4) ◽

pp. 1685

Author(s):

Meenakshi S. Kushwah ◽

Ajay Gaur

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Rare Case ◽

Genetic Disorder ◽

Failure To Thrive ◽

First Year ◽

Extra Copy ◽

Edwards Syndrome ◽

Rare Case Report ◽

First Year Of Life

Edwards syndrome, a rare genetic disorder is characterized by the extra copy of chromosome 18. About 50% babies with this syndrome do not survive one week of age and approx. 95% do not survive past the first year of life. The syndrome is usually characterized by dysmorphic facies, microcephaly, flexion finger deformity and rocker- bottom feet. There is involvement of cardiacvascular and renal system with intellectual disability. Authors report a case of Edwards syndrome presenting with failure to thrive and developmental delay in the absence of usual clinical features of Edwards syndrome.

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ATP8A2 and AKAP10 Gene Mutations in a Patient with Prader-Willi Syndrome: A Case Report and Literature Review

Iranian Journal of Pediatrics ◽

10.5812/ijp.104043 ◽

2020 ◽

Vol 30 (4) ◽

Author(s):

Kemi Wu ◽

Yanfei Tang ◽

Qiong Zhou ◽

Chaochun Zou

Keyword(s):

Developmental Delay ◽

Genetic Disorder ◽

Gene Mutations ◽

Poor Response ◽

Hereditary Diseases ◽

Cardiac Conduction ◽

Facial Features ◽

Compound Heterozygous ◽

Prader Willi Syndrome ◽

Exon 2

Introduction: Prader-Willi syndrome (PWS) is an epigenetic disease. Cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4 (CAMRQ4) is a genetic disorder caused by ATP8A2 gene mutation. AKAP10 gene is related to autosomal dominant cardiac conduction defect and cardiac susceptibility. Here, we report a PWS infant with ATP8A2 and AKAP10 mutations, who presented multiple dysmorphic features and review correlative literature. Case Presentation: A 3-month-old boy presented to our unit because of developmental delay after birth. He had a poor response, feeble cry, hypotonia of extremities, empty scrotum, and characteristic facial features. The whole-exome sequencing showed c.187C>G (p.P63A) in exon 2 originated from his father and c.2138T>C (p.I713T) in exon 23 originated from his mother, which were compound heterozygous variants of the ATP8A2 gene. A c.43delC heterozygous variant in exon 1 of the AKAP10 gene was also detected. Genetic analysis revealed normal copy numbers but abnormal methylation in the 15q11-13 region, which implied nondeletion type PWS. Conclusions: In patients with dysmorphic facial features, hypotonia and developmental delay, PWS should be considered in the differential diagnosis. Moreover, other complicated hereditary diseases should be considered in patients with PWS.

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Infant with infantile spasms: early intervention improves neurodevelopmental outcome

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20213327 ◽

2021 ◽

Vol 8 (9) ◽

pp. 1605

Author(s):

Rajeshwari Narayanan ◽

Aparna Gilbert ◽

Savitha Arunachalam

Keyword(s):

Autistic Spectrum Disorder ◽

Early Recognition ◽

Genetic Disorder ◽

Neurodevelopmental Outcome ◽

Skin Lesions ◽

Infantile Spasms ◽

Spectrum Disorder ◽

First Year ◽

Autistic Spectrum ◽

First Year Of Life

Tuberous sclerosis complex is a multisystem genetic disorder with characteristic skin lesions and variable neurological manifestations like seizures, cognitive impairment and autistic spectrum disorder. Epilepsy and infantile spasms during first year of life are risk factors for mental impairment and Autistic spectrum disorder (ASD). In asymptomatic TSC infants, hypsarrhythmia pattern in EEG suggests early treatment with vigabatrin to improve neurodevelopmental outcome. Early recognition of skin lesions by pediatrician is crucial for timely intervention.

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Variants in the ATP1A3 Gene Mutations within Severe Apnea Starting in Early Infancy: An Observational Study of Two Cases with a Possible Relation to Epileptic Activity

Neuropediatrics ◽

10.1055/s-0038-1653978 ◽

2018 ◽

Vol 49 (05) ◽

pp. 342-346 ◽

Cited By ~ 1

Author(s):

Niklas Holze ◽

Andreas Baalen ◽

Ulrich Stephani ◽

Ingo Helbig ◽

Hiltrud Muhle

Keyword(s):

Neurological Disorders ◽

Gene Mutations ◽

Epileptic Seizures ◽

Rapid Onset ◽

Epileptic Activity ◽

First Year ◽

Pathogenic Variants ◽

Alternating Hemiplegia Of Childhood ◽

First Year Of Life ◽

Atp1a3 Gene

AbstractMutations in the ATP1A3 gene are known to cause alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). Both conditions are childhood-onset neurological disorders with distinct symptoms and different times of onset. ATP1A3 has also been associated with CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss). Within the various ATP1A3-related neurological syndromes, a specific genotype–phenotype correlation is starting to emerge. Several mutations such as the relatively common p.E815K pathogenic variant have been shown to strongly correlate with AHC, while others may cause both AHC and RDP. A significant subset of patients with AHC and RDP are reported to have epileptic seizures. Even though detailed clinical descriptions of seizures in childhood are rare, seizures involving apneic events seem to be frequent in ATP1A3-related neurological disorders. Here, we describe two children with unexplained severe apnea beginning around the first year of life and pathogenic variants in ATP1A3. We hypothesize that the symptoms are early-onset autonomic seizures related to the underlying pathogenic ATP1A3 variants.

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Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous CACNA2D2 Variants

Case Reports in Genetics ◽

10.1155/2018/6308283 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Kameryn M. Butler ◽

Philip J. Holt ◽

Sarah S. Milla ◽

Cristina da Silva ◽

John J. Alexander ◽

...

Keyword(s):

Cerebellar Atrophy ◽

Epileptic Encephalopathy ◽

First Year ◽

Compound Heterozygous ◽

Whole Exome ◽

Novel Variants ◽

Voltage Dependent ◽

Clinical Description ◽

Compound Heterozygous Variants ◽

First Year Of Life

CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.

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