Neonatal Hypertrophic Cardiomyopathy Research Articles

Neonatal hypertrophic cardiomyopathy with dyspnoea as the first symptom: a case report

Neonatal hypertrophic cardiomyopathy (HCM) is an idiopathic disease characterised by myocardial hypertrophy with normal or small ventricular chambers, a systolic hyperdynamic state and diastolic dysfunction. The etiology, pathogenesis and clinical manifestations of HCM are diverse, and it is likely to progress to sudden cardiac death. The highly heterogeneous nature of this disease determines the difficulty of its diagnosis, and it is especially rare to report that can be diagnosed conclusively in the neonatal period. However, when it does occur, the younger the age of onset is, the higher the mortality rate and the worse the prognosis. The genetic variants and diagnostic timing can affect the life course of the patient. This case report describes a neonate with a family history of HCM who was diagnosed with hypertrophic non-obstructive cardiomyopathy by echocardiography shortly after birth. At 4 years of age, the patient presented with slow weight gain, feeding difficulties, tachypnoea and diaphoresis, and cardiac ultrasound findings suggesting progression to severe hypertrophic obstructive cardiomyopathy, with a high likelihood of arrhythmias, heart failure, pulmonary hypertension, syncope and even sudden death. Neonatal congenital hypertrophic cardiomyopathy is extremely rare and difficult to diagnose before the onset of symptoms. Echocardiography has a definite diagnostic value in hypertrophic cardiomyopathy and helps in early detection and treatment. At the time of clinical diagnosis, children with hypertrophic cardiomyopathy should be asked about their family history and, if necessary, a survey of family members should be conducted for the early detection of mildly ill patients and gene carriers to enable timely intervention and treatment, which remains the focus of our research and efforts.

Use of vasopressin in neonatal hypertrophic obstructive cardiomyopathy: case series

To determine the effect of vasopressin on arterial blood pressure in infants with neonatal hypertrophic obstructive cardiomyopathy (HOCM). Retrospective case study in Neonatal ICU involving six infants; five born to mothers with diabetes mellitus (mean gestational age 37.5 ± 0.9 weeks). Vasopressin infusion was started at a mean dose of 0.3 ± 0.2 mU/kg/min. Initiation of vasopressin was followed by improved mean (p = 0.004), systolic (p = 0.028), and diastolic (p = 0.009) arterial pressure within 2 h. Heart rate (p = 0.025) and oxygen requirement (p = 0.021) also declined after initiation. Serum sodium declined initially and recovered by 72 h (p = 0.017). Although there is limited experience with vasopressin use in neonatal HOCM, our case series suggests it may be beneficial for improving systemic hypotension and stabilization of hemodynamics. The potential for hyponatremia is high, necessitating careful fluid/electrolyte management. A prospective randomized trial is necessary to confirm safety and efficacy of vasopressin treatment in neonatal HOCM.

Neonatal Autopsies with Heart Disease: A Challenge for Pathologist

Congenital Heart Diseases (CHD) carry significant morbidity and mortality in paediatric patients. Transposition of Great Arteries (TGA) is a common cyanotic CHD. However, onset of Pulmonary Arterial Hypertension (PAH) is potentially severe and rare complication reported in 1-3% of newborns. Hypertrophic Cardiomyopathy (HOCM) is a primary disease of cardiac muscle usually recognised in adulthood. Neonatal HOCM without other congenital anomalies, no family history of HOCM, no history of exposure to corticosteroids or any inborn errors of metabolism is rarely recognised. Authors hereby report two cases of neonatal autopsy showing TGA with PAH (Grade 2) and another with HOCM without any primary cause received in our hospital. With this case report authors wish to stress on the importance of cardiac examination (heart and the associated vessels) in autopsy specimen which in turn requires training of pathologists in cardiac pathology along with routine fetal anomaly scanning in arriving successively at the final diagnosis and detecting the cause of death which helps in management of future pregnancies by the clinicians.

Fatal neonatal hypertrophic cardiomyopathy caused by compound heterozygous truncating MYBPC3mutation.

Fatal neonatal hypertrophic cardiomyopathy caused by compound heterozygous truncating MYBPC3mutation.

Pregnancy planning in women with diabetes mellitus type 2

The aim of the study: to evaluate the role of pregnancy planning in patients with diabetes mellitus type 2 in improvement of pregnancy and birth outcomes.
 Material and methods. 80 women with type 2 diabetes mellitus who were referred to the centre “Diabetes mellitus and pregnancy” in Ott’s Research Institute of Obstetrics and Gynecology were examined.
 Results. In the group of women who underwent pre-pregnancy counseling, the course and outcome of pregnancy were significantly better. Since the frequency of gestosis was lower (60%) than in the group without pregnancy planning (86.7%), there was no gestosis of severe degree in the group of women who underwent pre-pregnancy counseling (in the group without pregnancy planning the rate of gestosis of moderate and severe degree was 25%). Frequency of preterm delivery was lower (15%) in the group of women who underwent pre-pregnancy counseling than in the group without pregnancy planning (38.3%). Also in the group of women who underwent pre-pregnancy counseling there were no fetal congenital malformations, neonatal hypoglycemic events and hypertrophic cardiomyopathy (in the group without pregnancy planning these indicators were respectively - 3.4; 28.8; 3.4%. Also in the group of women who underwent pre-pregnancy counseling there were no perinatal mortality (in the group without pregnancy planning this indicator was 3.4%.
 Conclusion: pregnancy planning in patients with diabetes mellitus significantly improves the course and outcome of pregnancy.

Cardiac Findings in Infants of Diabetic Mothers

Hypertrophic cardiomyopathy (HCM) associated with diabetes during pregnancy has been relatively recently described. The echocardiographic findings are similar to those found in the classic sarcomeric familial HCM. In addition, the hemodynamics and clinical presentation may be significant and can include impaired cardiac output and pulmonary hypertension as a result of diastolic dysfunction, left ventricular outflow tract obstruction, and systolic dysfunction. Unlike sarcomeric HCM, neonatal HCM associated with diabetes during pregnancy is self-limited and in fact tends to resolve in weeks to months. On the other hand, in the impaired neonate, a rational management plan needs to be instituted. This article describes the history, potential causes, and pathophysiology of HCM and details a rational management plan for the treatment of these patients.

Neonatal hypertrophic cardiomyopathy caused by double mutation in RAS pathway genes

Neonatal hypertrophic cardiomyopathy caused by double mutation in RAS pathway genes

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice.

Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.

COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.

Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency

Mitochondrial respiratory chain biogenesis is orchestrated by hundreds of assembly factors, many of which are yet to be discovered. Using an integrative approach based on clues from evolutionary history, protein localization and human genetics, we have identified a conserved mitochondrial protein, C1orf31/COA6, and shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells. A recent next-generation sequencing study reported potential pathogenic mutations within the evolutionarily conserved Cx₉CxnCx₁₀C motif of COA6, implicating it in mitochondrial disease biology. Using yeast coa6Δ cells, we show that conserved residues in the motif, including the residue mutated in a patient with mitochondrial disease, are essential for COA6 function, thus confirming the pathogenicity of the patient mutation. Furthermore, we show that zebrafish embryos with zfcoa6 knockdown display reduced heart rate and cardiac developmental defects, recapitulating the observed pathology in the human mitochondrial disease patient who died of neonatal hypertrophic cardiomyopathy. The specific requirement of Coa6 for respiratory complex IV biogenesis, its intramitochondrial localization and the presence of the Cx₉CxnCx₁₀C motif suggested a role in mitochondrial copper metabolism. In support of this, we show that exogenous copper supplementation completely rescues respiratory and complex IV assembly defects in yeast coa6Δ cells. Taken together, our results establish an evolutionarily conserved role of Coa6 in complex IV assembly and support a causal role of the COA6 mutation in the human mitochondrial disease patient.

Resolution of Neonatal Hypertrophic Cardiomyopathy Presumed Secondary to Acquired Maternal Ribonucleoprotein and Smith Autoantibodies

Severe asymmetrical hypertrophic cardiomyopathy without heart block accompanied by neuromuscular hypotonia and feeding difficulties was evident shortly after birth in the second child of a mother with systemic lupus erythematosus who had no indication of gestational diabetes. High-level anti-ribonucleoprotein (RNP) and Smoth (Sm) antibodies arising from transplacental transfer of maternal antibodies were detected in the child's serum. The cardiac abnormalities improved with a commensurate decline in antibody titers. Previously reported cases of neonatal cardiomyopathy with endocardial fibroelastosis have been ascribed to the transplacental transfer of maternal Sjogrens Syndrome (SS) A (Ro) and Sjogrens Syndrome (SS) B (La) antibodies and have been more severe and persistent compared with our patient. We advocate close monitoring of all babies of mothers with systemic autoimmunity for changes in heart rate during pregnancy and signs of heart failure and neuromuscular weakness after delivery.

PF.76 Pregnancy Outcome and Management of Fetal Hypertrophic Cardiomyopathy: A Case Report and Literature Review

We report an interesting case of a diabetic pregnancy with fetal hypertrophic cardiomyopathy. The diagnosis was made following an emergency caesarean delivery at 37 weeks for fetal distress and was...

Hypertrophic cardiomyopathy in the Amish community — What we may learn from it

Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330 + 2 T > G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330 + 2 T > G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study.

Diagnostic problems of cytomegalovirus infections in premature newborns

Abstract Introduction Cytomegaly is an infectious, widespread viral disease. It is caused by Cytomegalovirus (CMV), which belongs to the DNA viruses group from the Herpesviridae family. The virus is human specific. Once infected, a person remains seropositive to the end of life and the virus remains latent particularly in leukocytes, which are its main reservoir. Many different disease manifestations, which depend partially on a patient's age, but mostly on an immunological state, may be caused by CMV. Aim The aim of this work was the assessment and histoclinical analysis of CMV infection in a male newborn with a congenital anomaly syndrome. Case study and examination results A male newborn, born in the 30th week of gestation, diagnosed with congenital anomaly syndrome, Apgar score was 2. In the neonatal period hypertrophic cardiomyopathy involving the right ventricle, esophageal atresion, esophagotracheal fistula, hepatosplenomegaly, respiratory insufficiency and hyperechogenic periventricular structures in the brain were diagnosed. During the entire hospitalization period a progression of inflammatory changes in the lungs was observed. The results of serological tests to detect anti-CMV and toxoplasmosis specific antibodies were: CMV–IgG 21.00 IU/mL; CMV–IgM negative; Toxo–IgG 4.0 IU/mL; Toxo–IgM negative. Restoration of esophageal continuity and repair of the fistula were performed surgically. Follow-up serological test was positive for anti- CMV antibodies in the IgG and IgM classes. The patient died on the 79th day following hospital admission. Autopsy and histopathological tests confirmed generalized cytomegalovirus infection. Discussion Most advanced histopathological changes were observed in lungs, liver, spleen and brain. Characteristically changed cells, confirming generalized cytomegalovirus infection were found in all the aforementioned organs. Conclusions . CMV infections, particularly congenital infections in premature newborns are challenging diagnostic and therapeutic problems. Routine diagnostic procedures to detect CMV infections seem to be necessary in risk groups, particularly for premature infants. Negative anti-CMV antibodies result in patients with an insufficient immune system, does not exclude the presence of this infection. Early diagnosis and treatment of congenital cytomegaly may positively affect a patient's clinical condition and prolonged prognosis.

PTPN11 Gene Mutation and Severe Neonatal Hypertrophic Cardiomyopathy: What Is the Link?

Noonan syndrome (NS) is an autosomal dominant disorder characterized by multiple dysmorphic features and a broad spectrum of congenital heart defects. Specific mutations of the PTPN11 gene are associated with 50% of the NS cases and 90% of the multiple lentigines/LEOPARD syndrome (ML/LS) cases. These two allelic conditions have several overlapping clinical features. This study describes the association between the Gln510Glu mutation of the PTPN11 gene and lethal progressive hypertrophic cardiomyopathy (HCM) in a newborn with the NS phenotype. The findings confirm the intriguing relationship between site-specific mutations of the PTPN11 gene and rapidly progressive HCM.

Mutations in sarcomeric protein genes not only lead to cardiomyopathy but also to congenital cardiovascular malformations

Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta-myosin heavy chain gene Budde et al. (2007) PLoS ONE 2: e1362 Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy Xin et al. (2007) Am J Med Genet 143: 2662-2667 Alpha-cardiac actin mutations produce atrial septal defects Matsson et al. (2008) Hum Mol Genet 17: 256-265.

Molecular mechanisms of pediatric cardiomyopathies and new targeted therapies

Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330 + 2 T > G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330 + 2 T > G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study.

Homozygosity for a novel splice site mutation in the cardiac myosin‐binding protein C gene causes severe neonatal hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern and has a variable age of onset and prognosis. Mutations in the myosin-binding protein C (MYBPC3) gene are one of the most frequent genetic causes of the disease. Patients with MYBPC3 mutations generally have a late onset and a relatively good prognosis. We report here more than 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene. The affected children typically presented with signs and symptoms of congestive heart failure during the first 3 weeks of life. Echocardiography revealed hypertrophic non-obstructive cardiomyopathy. These children had a life span averaging 3-4 months. All patients died from heart failure before 1 year of age unless they received a heart transplant. A genome-wide mapping study was performed in three patients. The disease related gene was localized to a 4.6 Mb region on chromosome 11p11.2-p11.12. This homozygous block contained MYBPC3, a previously identified cardiomyopathy related gene. We identified a novel homozygous mutation, c.3330 + 2T > G, in the splice-donor site of MYBPC3 intron 30. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). We have found a substantial incidence of this phenotype in Old Order Amish communities. It is also concerning that many unidentified heterozygous individuals who are at risk for development of hypertrophic cardiomyopathy do not receive proper medical attention in the communities.

Neonatal Screening by Tandem Mass Spectrometry

After completing this article, readers should be able to: 1. List the major categories of diseases detectable by expanded newborn screening. 2. Give examples of the benefits and limitations of screening by tandem mass spectrometry. 3. Describe the appropriate follow-up for an abnormal screening result. The screening of newborns for inherited metabolic disorders is a well-established public health activity, first implemented in the early 1960s for the presymptomatic identification of patients who have phenylketonuria (PKU). Since then, significant technological advances, most importantly the development of tandem mass spectrometry (MS/MS), have enabled the detection of an increasing number of metabolic disorders in newborn blood. This article reviews the basic technology of MS/MS and its application to newborn screening, with the aim of highlighting the benefits and pointing out some limitations of this powerful technology. Early screening for PKU used the bacterial inhibition assay of Guthrie, in which inhibition of bacterial growth on an agar medium, introduced by the addition of a phenylalanine analog, was overcome by the presence of dried blood discs containing high levels of phenylalanine (such as from a PKU patient). This approach later was adapted for the detection of leucine in patients who have maple syrup urine disease (MSUD), methionine in patients who have classic homocystinuria, and tyrosine in patients who have tyrosinemia. Over the years, other techniques have been implemented to screen for additional disorders, including congenital hypothyroidism, biotinidase deficiency, galactosemia, hemoglobinopathies, and congenital adrenal hyperplasia. The classic criteria used to determine whether a disorder is suitable for screening include: 1) the disorder is clinically and biochemically well defined, 2) it is associated with significant morbidity or mortality, 3) an effective treatment is available, and 4) there is a simple and safe screening test. (1) By the early 1990s, all states offered screening for at least PKU and congenital hypothyroidism, …

Cushing's syndrome in pregnancy and neonatal hypertrophic obstructive cardiomyopathy

Cushing's syndrome is rare in pregnancy but can cause spontaneous abortion, stillbirth or premature birth. We report a case of transient hypertrophic obstructive cardiomyopathy in a newborn whose mother had hypercortisolism due to a primary adrenal lesion. There was no family history of hypertrophic obstructive cardiomyopathy. Follow‐up revealed complete resolution of the cardiac abnormalities in the infant. Cushing's syndrome in the mother resolved after delivery. Although maternal hypercortisolism seldom results in symptomatic hypercortisolism in the newborn, hypertrophic obstructive cardiomyopathy can occur.