[Clinical characteristics of Danon disease].

Objective: To review the clinical data of 7 patients with Danon disease and analyze their clinical characteristics. Methods: The medical records of 7 patients with Danon disease, who were hospitalized in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from April 2008 to July 2021, were reviewed and summarized, of which 6 cases were diagnosed as Danon disease by lysosomal-associated membrane protein-2 (LAMP-2) gene mutation detection and 1 case was diagnosed by clinicopathological features. Clinical manifestations, biochemical indexes, electrocardiogram, echocardiography, skeletal muscle and myocardial biopsy and gene detection results were analyzed, and patients received clinical follow-up after discharge. Results: Six patients were male and average age was (15.4±3.5) years and the average follow-up time was (27.7±17.0) months. The main clinical manifestations were myocardial hypertrophy (6/7), decreased myodynamia (2/7) and poor academic performance (3/7). Electrocardiogram features included pre-excitation syndrome (6/7) and left ventricular hypertrophy (7/7). Echocardiography examination evidenced myocardial hypertrophy (6/7), and left ventricular dilatation and systolic dysfunction during the disease course (1/7). The results of skeletal muscle biopsy in 6 patients were consistent with autophagy vacuolar myopathy. Subendocardial myocardial biopsy was performed in 3 patients, and a large amount of glycogen deposition with autophagosome formation was found in cardiomyocytes. LAMP-2 gene was detected in 6 patients, and missense mutations were found in all these patients. During the follow-up period, implantable cardioverter defibrillator implantation was performed in 1 patient because of high atrioventricular block 4 years after diagnosis, and there was no death or hospitalization for cardiovascular events in the other patients. Conclusion: The main clinical manifestations of Danon disease are cardiomyopathy, myopathy and mental retardation. Pre-excitation syndrome is a common electrocardiographic manifestation. Autophagy vacuoles can be seen in skeletal muscle and myocardial pathological biopsies. LAMP-2 gene mutation analysis is helpful in the diagnose of this disease.

Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.

Electro-vectorcardiographic demonstration of bifascicular block associated with ventricular preexcitation.

Down syndrome occurs more frequently in the offsprings of older pregnant women and may be associated with atrioventricular septal defect. This refers to a broad spectrum of malformations characterized by a deficiency of the atrioventricular septum and abnormalities of the atrioventricular valves caused by an abnormal fusion of the superior and inferior endocardial cushions with the midportion of the atrial septum and the muscular portion of the ventricular septum.

Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage.

RATIONALE: AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target. OBJECTIVE: We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. METHODS AND RESULTS: In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth. CONCLUSIONS: Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.

Perioperative management of patients with genetic multisystem diseases associated with pre­excitation.

Pre-excitation is associated with life-threatening arrhythmias. Apart from the well-known Wolff-Parkinson-White syndrome, a number of rare diseases are associated with pre-excitation due to the existence of accessory pathways. The present review aims to focus on anaesthesia and perioperative care of patients with rare genetic diseases associated with pre-excitation due to the existence of a bundle of Kent or other accessory pathways. The Danon disease, Fabry disease and Pompe disease, tuberous sclerosis, Leber hereditary optic neuropathy (LHON), and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome are genetic multisystem disorders which may involve pre-excitation, usually combined with cardiomyopathy. The anaesthetic management of the above syndromes may become quite challenging. We conducted a PubMed and manual literature search for all types of relevant publications; we identified 58 articles suitable to be included in the present review. According to the literature, a high index of suspicion for the possibility of pre-excitation is required, and anaesthetic drugs and adjuvants should be chosen carefully, in order to prevent or at least not facilitate arrhythmias associated with accessory pathways. The perioperative management should be further tailored to the specific abnormalities of each condition. Multidisciplinary consultation and care, according to the affected organs, are mandatory for a safe outcome. The anaesthetic plan should be focused on preoperative clinical optimization and on case-specific management, tailored to the various systems involved.

Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson-White syndrome.

OBJECTIVES: We sought to characterize an animal model of the Wolff-Parkinson-White (WPW) syndrome to help elucidate the mechanisms of accessory pathway formation. BACKGROUND: Patients with mutations in PRKAG2 manifest cardiac hypertrophy and ventricular pre-excitation; however, the mechanisms underlying the development and conduction of accessory pathways remain unknown. METHODS: We created transgenic mice overexpressing either the Asn488Ile mutant (TG(N488I)) or wild-type (TG(WT)) human PRKAG2 complementary deoxyribonucleic acid under a cardiac-specific promoter. Both groups of transgenic mice underwent intracardiac electrophysiologic, electrocardiographic (ECG), and histologic analyses. RESULTS: On the ECG, approximately 50% of TG(N488I) mice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TG(WT) mice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TG(N488I) mice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TG(WT) mice but not TG(N488I) mice with pre-excitation. Serial ECGs in 16 mice pups revealed no differences at birth. After one week, two of eight TG(N488I) pups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TG(N488I) mouse with WPW syndrome lost this phenotype, whereas TG(WT) pups never developed pre-excitation. Histologic investigation revealed postnatal development of myocardial connections through the annulus fibrosum of the AV valves in young TG(N488I) but not TG(WT) mice. CONCLUSIONS: Transgenic mice overexpressing the Asn488Ile PRKAG2 mutation recapitulate an electrophysiologic phenotype similar to humans with this mutation. This includes procainamide-sensitive, adenosine-resistant accessory pathways induced in postnatal life that may rarely disappear later in life.

Leber's hereditary optic neuroretinopathy, a maternally inherited disease. A genealogic study in four pedigrees.

Previous genealogic studies of Leber's disease have focused on affected individuals with optic atrophy. Despite its diagnostic importance, peripapillary microangiopathy has not been widely recognized. In our study, the genealogic evaluation includes asymptomatic subjects with microangiopathy. Another new aspect is a genealogic analysis of the cardiovascular abnormalities found in members of families with Leber's disease. Our results suggest that every daughter and son of a female carrier inherits the trait, thus satisfying the criteria for a maternally inherited disease. Microangiopathy, without optic nerve dysfunction, probably represents the mildest stage of the disease. The high frequency of electrocardiographic abnormalities in the off-spring of the female carriers suggests an important link with Leber's disease.

The preexcitation syndrome: epidemiological and genetic study.

A sample of 4210 subjects of both sexes aged 35-54 years was examined, chosen at random from six regions of Croatia. An electrocardiogram at rest was performed in all subjects and changes analyzed by the Minnesota code. A short P-R interval together with a widening QRS complex and a delta wave was found in 0.05%, while 42 (1.0%) of the examinees had a short P-R interval, but only 0.21% were symptomatic. Three years after the first examination 0.06% of the subjects had preexcitation with a delta wave, and in one subject it appeared after three years. 0.35% of the subjects had a short P-R interval after three years but only 0.18% were symptomatic and in 22 (0.65%) it had disappeared in three years. After 13 years these subjects did not appear for an examination, and the short P-R interval did not appear in any of other subjects during this period. There were more short P-R intervals: 3.22% in females and 1.96% in males, but 0.33% only were symptomatic. Antigens of the human leukocyte group A (HLA) system were analyzed in 46 patients: the Wolff-Parkinson-White syndrome was found in 35, while 11 had the Lown-Ganong-Levine syndrome. Antigens of the HLA-A, HLA-B and HLA-DR locuses were determined by the microlymphocytotoxicity method. The results of the frequency of HLA system antigens were compared to the results of the control group of a Croatian population consisting of 175 people. There was an increased frequency of HLA-A9 and HLA-B5 (P = 0.026 and 0.0092) in the investigated population as a whole. The participation of HLA-A3 antigen was significantly less among patients (P = 0.03), while HLA-B14 antigen was not found in patients with preexcitation. Within 10 HLA-DR locuses, HLA-DR7 antigen was rather more frequently present, although this was not statistically significant (P = 0.173).

[Association between pre-excitation syndrome and 7q3 D7S505 pseudonym gene].

OBJECTIVE: Pre-excitation syndrome is considered to be autosomal dominant hereditary disease. The objective of this study was to search the genetic foundation of the pre-excitation syndrome. METHODS: Genomic DNA was isolated from peripheral lymphocytes obtained from 44 cases of patients with pre-excitation syndrome and 53 normal persons. Polymorphic short tandem repeats(STR) were amplified using polymerase chain reaction (PCR) and analyzed by polyacrylamide gel electrophoresis. The genotype of each individual was determined by polymorphic STR including D7S505,D7S688,D7S483. Association analysis between the pre-excitation syndrome and the 3 STR (D7S505,D7S483 and D7S688) was tested by genotyping. RESULTS: The relative risk(RR) of alleles A2 A3 A4 and A6 of D7S505 were 1.051 6, 3.432,1.563 1 and 1.714 3 respectively all of which were more than 1, but only the RR of A3 had statistic significant difference, P < 0.05 after tested by kappa(2). It supposed that the distribution of allele A3(266 bp) of D7S505 in patients with pre-excitation syndrome was much higher than that in normal controls, which suggested that pre-excitation syndrome is associated with D7S505. Whereas, there were no significant difference in every allele of D7S483 between the pre-excitation syndrome and normal persons, which suggested that pre-excitation syndrome is not associated with D7S483. CONCLUSION: The pre-excitation syndrome is associated with D7S505,the result is the foundation of the molecular genetics of the disease.

[The inheritance of disorders of heart rhythm in 3 generations (a family history)]. / Nasledovanie narushenii serdechnogo ritma v trekh pokoleniiakh (opisanie sem'i).

The paper is concerned with the description of a family where father suffered from right bundle-branch block, his daughter--from Wolff-Parkinson-White syndrome (type B) with attacks of supraventricular paroxysmal tachycardia, one granddaughter--from Clerc-Lévy-Cristesco syndrome with attacks of sinus tachycardia, the two other granddaughters had a short P-R interval. Medicogenetic investigation revealed not only the inheritance of myocardial conduction changes of autosomal dominant type but also of syndromes characterizing primary dysplasia of connective tissue in 3 generations.

[Phenotypic characteristics of patients with the premature ventricular excitation syndrome]. / Fenotipicheskie osobennosti bol'nykh s sindromom prezhdevremennogo vozbuzhdeniia zheludochkov.

Wolff-Parkinson-White syndrome (WPWS) was combined in a majority of patients with various syndromes of primary dysplasia of connective tissue determining phenotypic characteristics of patients. They are also of considerable diagnostic importance. During examination of 200 WPWS patients, asthenic constitution, dolichocephalism and arachnodactyly were revealed in most of them. The most frequent stigmata of dysembryogenesis were the high palate (76%) the 3rd type of the ear lobe (36.6%), and epicanthus (20.5%). The funnel chest and thoracic kyphosis in the sagittal plane were noted in 30% of WPWS patients. The syndrome of articular hypermobility was diagnosed in 51.6% of the patients with WPWS, of them 37% had extraarticular manifestations in the form of varicosis of the crural veins.

[The inheritance of the ventricular pre-excitation syndrome]. / Nasledovanie sindroma prezhdevremennogo vozbuzhdeniia zheludochkov.

Medico-genetic studies including preparation of the family pedigree, interviews, examinations, electro- and echocardiography were carried out in the families of 75 patients with pre-excitation syndrome (PES). Of these, 35 patients presented with Wolff-Parkinson-White (WPW) syndrome and 40 with Clerc-Lévy-Cristesco (CLC) syndrome. The studies made in possible to define the autosomal-dominant type of the syndrome or PES inheritance and to diagnose for the first time WPW syndrome in 3, PES in 1, CLC syndrome in 32 and CLC phenomenon in 89 persons out of 233 relatives of the first and second degree kinship.

Familial conduction system disease associated with hypertrophic cardiomyopathy.

A large family with a new phenotype of conduction system disease including heart blocks and preexcitation associated with hypertrophic cardiomyopathy and transmitted in an autosomal dominant pattern is described.

Is Wolff-Parkinson-White syndrome a genetic disease?

Family studies, and more recent molecular genetic investigations, indicate that the Wolff-Parkinson-White (WPW) syndrome and associated preexcitation disorders can have a substantial genetic component. Because preexcitation disorders are sometimes inherited as single gene disorders, key mechanistic insights can be gained that are expected to be relevant also to the more common multifactorial forms of these traits. Potentially, such insights will inform the future management of these conditions. Where WPW is inherited as a familial trait, with or without associated cardiac defects or a systemic syndrome, there are clinical genetic ramifications that are already of practical importance.

Familial Mahaim syndrome.

We describe the occurrence of Mahaim syndrome in a mother and her son. The occurrence of such a rare disorder in two members of a family is noteworthy, has not been reported before, and suggests the possibility of genetic transmission. A genetic transmission of supraventricular tachycardia has been described only in rare cases for the Wolff-Parkinson-White syndrome. No such data is available for the Mahaim syndrome.

Familial occurrence of accessory atrioventricular pathways (preexcitation syndrome).

Accessory atrioventricular pathways, the anatomical structures responsible for the preexcitation syndromes, may result from a developmental failure to eradicate the remnants of the atrioventricular connections present during cardiogenesis. To study whether preexcitation syndromes could also be transmitted genetically, we determined the prevalence of preexcitation in the first-degree relatives of 383 of 456 consecutive patients (84 percent) with electrophysiologically proved accessory pathways. We compared the observed prevalence of preexcitation among the 2343 first-degree relatives with the frequency reported in the general population (0.15 percent). For 13 of the 383 index patients (3.4 percent), accessory pathways were documented in one or more first-degree relatives. At least 13 of the 2343 relatives identified (0.55 percent) had preexcitation; this prevalence was significantly higher than that in the general population (P less than 0.0001). Identification of affected relatives may have been incomplete because clinical information was obtained only about symptomatic relatives. Patients with familial preexcitation have a higher incidence of multiple accessory pathways and possibly an increased risk of sudden cardiac death. Our data suggest a hereditary contribution to the development of accessory pathways in humans. The pattern of inheritance appears to be autosomal dominant.