Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting the function of motile cilia in several organ systems. In PCD, male infertility is caused by defective sperm flagella composition or deficient motile cilia function in the efferent ducts of the male reproductive system. Different PCD-associated genes encoding axonemal components involved in the regulation of ciliary and flagellar beating are also reported to cause infertility due to multiple morphological abnormalities of the sperm flagella (MMAF). Here, we performed genetic testing by next generation sequencing techniques, PCD diagnostics including immunofluorescence-, transmission electron-, and high-speed video microscopy on sperm flagella and andrological work up including semen analyses. We identified ten infertile male individuals with pathogenic variants in CCDC39 (one) and CCDC40 (two) encoding ruler proteins, RSPH1 (two) and RSPH9 (one) encoding radial spoke head proteins, and HYDIN (two) and SPEF2 (two) encoding CP-associated proteins, respectively. We demonstrate for the first time that pathogenic variants in RSPH1 and RSPH9 cause male infertility due to sperm cell dysmotility and abnormal flagellar RSPH1 and RSPH9 composition. We also provide novel evidence for MMAF in HYDIN- and RSPH1-mutant individuals. We show absence or severe reduction of CCDC39 and SPEF2 in sperm flagella of CCDC39- and CCDC40-mutant individuals and HYDIN- and SPEF2-mutant individuals, respectively. Thereby, we reveal interactions between CCDC39 and CCDC40 as well as HYDIN and SPEF2 in sperm flagella. Our findings demonstrate that immunofluorescence microscopy in sperm cells is a valuable tool to identify flagellar defects related to the axonemal ruler, radial spoke head and the central pair apparatus, thus aiding the diagnosis of male infertility. This is of particular importance to classify the pathogenicity of genetic defects, especially in cases of missense variants of unknown significance, or to interpret HYDIN variants that are confounded by the presence of the almost identical pseudogene HYDIN2.

PD-1 AND TIM-3 BLOCKING CANNOT ENHANCE APOPTOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA CELLS INDUCED BY PERIPHERAL BLOOD CD8+ T CELLS.

AIM: Given the invaluable success of immune checkpoint inhibitors for tumor immunotherapy, in this study, the effect of programmed cell death 1 (PD-1) and T cell immunoglobulin-3 (TIM-3) blocking was investigated to induce apoptosis of leukemic cells by exhausted CD8+ T cells in patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: Peripheral blood CD8+ T cells were positively isolated from 16 CLL patients using magnetic beads separation method. Isolated CD8+ T cells were treated with either blocking anti-PD-1, anti-TIM-3 and isotype-matched control antibodies and then co-cultured with CLL leukemic cells as target. The percentage of apoptotic leukemic cells and the expression of apoptosis-related genes were evaluated by flow cytometry and real-time polymerase chain reaction methods, respectively. Interferon gamma and tumor necrosis factor alpha concentration was also measured by ELISA. RESULTS: Flow cytometric analysis of apoptotic leukemic cells indicated that the blockade of PD-1 and TIM-3 did not significantly enhance the apoptosis of CLL cells by CD8+ T cells, which then were confirmed by analysis of BAX, BCL2 and CASP3 gene expression, which was similar in blocked and control groups. No significant difference was found between blocked and control groups in terms of interferon gamma and tumor necrosis factor alpha production by CD8+ T cells. CONCLUSION: We concluded that the blockade of PD-1 and TIM-3 is not an effective strategy to restore the function of CD8+ T cells in CLL patients at the early clinical stages of the disease. Further in vitro and in vivo studies are needed to more address the application of immune checkpoint blockade in CLL patients.

[Management of Primary Ciliary Dyskinesia]. / Management der Primären Ciliären Dyskinesie.

Primary Ciliary Dyskinesia (PCD, MIM 242650) is a rare, hereditary multiorgan disease characterized by malfunction of motile cilia. Hallmark symptom is a chronic airway infection due to mucostasis leading to irreversible lung damage that may progress to respiratory failure. There is no cure for this genetic disease and evidence-based treatment is limited. Until recently, there were no randomized controlled trials performed in PCD, but this year, data of the first placebo-controlled trial on pharmacotherapy in PCD were published. This cornerstone in the management of PCD was decisive for reviewing currently used treatment strategies. This article is a consensus of patient representatives and clinicians, which are highly experienced in care of PCD-patients and provides an overview of the management of PCD. Treatments are mainly based on expert opinions, personal experiences, or are deduced from other lung diseases, notably cystic fibrosis (CF), COPD or bronchiectasis. Most strategies focus on routine airway clearance and treatment of recurrent respiratory tract infections. Non-respiratory symptoms are treated organ specific. To generate further evidence-based knowledge, other projects are under way, e. g. the International PCD-Registry. Participating in patient registries facilitates access to clinical and research studies and strengthens networks between centers. In addition, knowledge of genotype-specific course of the disease will offer the opportunity to further improve and individualize patient care.

Early effective treatment may protect from cognitive decline in paediatric multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is a critical feature for patients with childhood or juvenile multiple sclerosis (MS). OBJECTIVE: To promote the understanding of CI and to address the impact of different pharmacological treatment strategies on cognitive performance in this patient group. METHODS: A cohort of 19 patients with therapy-naïve or ß-Interferon-treated juvenile MS completed a comprehensive neuropsychological assessment at initial presentation (baseline) and on average 2.5 years later (follow-up). The assessments were complemented with a neuropaediatric examination and conventional cerebral magnetic resonance imaging (MRI). RESULTS: 9 patients (47%) were impaired in at least one test at baseline (z-score <-1.645 compared with age-adjusted normative data), with the highest impairment frequency in the domains processing speed and attention & executive functions. At follow-up a higher impairment frequency was prominent in those patients whose therapy had not been escalated (N = 13, 69% impaired in at least one test), while cognition was preserved or ameliorated in patients whose treatment had been escalated to highly effective drugs (N = 6, 0% impaired) during the observational period. These group differences at follow-up were not attributable to differences regarding demographics, MRI metrics or cognitive performance at baseline. CONCLUSION: Our findings confirm that paediatric MS is associated with considerable CI already in early disease stages. Early administration of highly effective treatment may protect from cognitive decline or alleviate CI in juvenile MS, but larger controlled trials are warranted to confirm these preliminary results.

[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia

Single-Readout High-Density Memristor Crossbar.

High-density memristor-crossbar architecture is a very promising technology for future computing systems. The simplicity of the gateless-crossbar structure is both its principal advantage and the source of undesired sneak-paths of current. This parasitic current could consume an enormous amount of energy and ruin the readout process. We introduce new adaptive-threshold readout techniques that utilize the locality and hierarchy properties of the computer-memory system to address the sneak-paths problem. The proposed methods require a single memory access per pixel for an array readout. Besides, the memristive crossbar consumes an order of magnitude less power than state-of-the-art readout techniques.

Factors influencing age at diagnosis of primary ciliary dyskinesia in European children.

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children.

Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage. This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.

Bridging of chronic oral anticoagulation with enoxaparin in patients with atrial fibrillation: results from the prospective BRAVE registry.

Current American College of Chest Physicians (ACCP) guidelines on the perioperative management of oral anticoagulation (OAC) suggest bridging therapy with therapeutic doses of low-molecular-weight heparin (LMWH) in patients with atrial fibrillation (AF) if at high or moderate thromboembolic (TE) risk, and with reduced doses in patients with low TE risk. Our objective was to assess the efficacy and safety of bridging OAC with enoxaparin in AF patients. These are the results of an open, prospective monocenter register. Hospitalized and ambulatory patients with AF requiring bridging therapy at high or moderate TE risk and normal renal function were treated with therapeutic LMWH doses; all other patients received reduced doses. A total of 703 patients were enrolled, of whom 358 (50.9%) were at moderate-to-high and 345 (49.1%) at low TE risk. Renal impairment was detected in 308 patients (43.8%). One hundred ninety patients (27.1%) were treated with therapeutic LMWH doses and 513 (72.9%) with reduced doses. No TE events were observed during the follow-up period (0%; 95% confidence interval [CI] 0.0-0.52). Three major bleeds (0.4%; 0.1-1.2) and 60 minor bleeds were noted (8.9%; 6.6-10.9). Age and total LMWH doses were risk factors for bleeding in the multivariate analysis. The study, under conditions of everyday clinical care, supports a predefined bridging regimen based on the individual patient's TE risk and renal function. Patients with low TE risk or with impaired renal function can be bridged effectively and safely with reduced LMWH doses.

Refining the phenotype of alpha-1a Tubulin (TUBA1A) mutation in patients with classical lissencephaly.

Mutations in the alpha-1a Tubulin (TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper.

L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.

Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma.

Astrocytomas are the most common brain tumors of childhood. However, knowledge of the molecular etiology of astrocytomas WHO grade I and II is limited. Germline mutations in the Ras-guanosine triphosphatase-activating protein, neurofibromin, in individuals with neurofibromatosis type I predispose to pilocytic astrocytomas. This association suggests that constitutive activation of the Ras signaling pathway plays a fundamental role in astrocytoma development. We screened 25 WHO I and II astrocytomas for mutations of PTPN11, NRAS, KRAS, and HRAS genes and identified the somatic G12A KRAS mutation in one pilocytic astrocytoma. These data suggest that Ras is rarely mutated in these tumors. Analyzed astrocytomas without mutations in Ras or neurofibromin may harbor mutations in other proteins of this pathway leading to hyperactive Ras signaling.

Atrial fibrillation - patients at high risk for cerebral embolism.

OBJECTIVE: Patients with atrial fibrillation (AF) have a risk of cerebral embolism. Echocardiographic parameters elevate this risk significantly. However, there is little knowledge about the long-term fate and the rate of clinically silent cerebral embolism under continued oral anticoagulation. The aims of our study were to assess prognosis of patients with AF and determine a high risk group with an increased risk of cerebral embolism under oral anticoagulation. METHODS: Consecutive patients with persistent or permanent AF and left atrial (LA) thrombi, dense spontaneous echo contrast (SEC) and/or reduced LA appendage peak emptying velocities (LAAv) were included in the study (N = 128). Patients with AF and without echocardiographic risk factors (N = 114) served as controls. All patients were examined with transesophageal echocardiography, cranial magnetic resonance imaging and clinically during a period of three years. RESULTS: During the three-year follow-up period 6 (5%) of the high risk patients had cerebral embolism with neurological deficits. 4 (3%) patients died due to embolic events and 17 (13%) patients had silent embolism as documented on MRI. In the control group 8 (7%) patients had embolic events (n = 1 clinically apparent and n = 7 silent embolism) documented on MRI, one was clinically apparent. Study patients with an event had more commonly previous thromboembolism (p < 0.0001). CONCLUSIONS: Patients with peristent or permanent AF and LA thrombi, dense SEC or reduced LAAv have an explicitly increased risk of cerebral embolism (21%) despite oral anticoagulation. Previous thromboembolic event is another important predictor for an event.

[Long-term fate of left atrial thrombi and incidence of cerebral embolism under continuous anticoagulation therapy]. / MR-tomographische Evaluation der Inzidenz zerebraler Embolien bei Patienten mit Vorhofflimmern und linksatrialen Thromben.

PURPOSE: Patients (pts.) with atrial fibrillation (AF) and atrial thrombi are known to have an increased risk for cerebral embolism. However, little is known about the clinical course of atrial thrombi and the incidence of cerebral embolism in those patients during anticoagulation therapy. The high sensitivity of MR imaging (MRI) including diffusion-weighted imaging (DWI) suggests that this technique could provide an improved estimate of cerebral embolism associated with the presence of left atrial thrombi. The aims of this prospective study were to evaluate 1) the prevalence of clinically silent and apparent cerebral embolism in pts. with newly diagnosed AF and atrial thrombi using MRI/DWI, 2) the long-term fate of atrial thrombi under continues anticoagulation therapy and 3) the incidence of cerebral embolism during a follow-up period of 12 months with continuous anticoagulation therapy. MATERIALS AND METHODS: The study group consisted of 32 pts. with 1) newly diagnosed AF and evidence of left atrial (LA) thrombi detected by TEE and 2) a new start of anticoagulation therapy [International Normalized Ratio (INR) 2.0 - 3.0]. 19 pts. with 1) newly diagnosed AF and no evidence of atrial thrombi and 2) an equivalent anticoagulation regimen served as the control group. In both groups a) MRI/DWI studies of the brain (weeks 0, 4, 8, 12, 20, 28, 36, 44, and 52), b) transesophageal echocardiographic studies (TEE) for assessment of LA-Thrombi (weeks 0 and 52) and c) clinical neurological assessments (weeks 0, 20 and 52) were performed. RESULTS: In the study group (AF and LA-Thrombi) 11 out of 32 pts. (34 %) displayed signs of acute (n = 8) or chronic (n = 3) cerebral embolism in the initial MRI studies. In 4 out of 32 pts. (13 %), MRI/DWI depicted new or additional cerebral emboli (n = 12) during the follow-up period despite continuous anticoagulation therapy. 2 (n = 2/4; 50 %) of these patients had clinically apparent neurological deficits. In the control group 1 out of 19 pts. (5 %) showed evidence of chronic cerebral embolism as assessed by MRI/DWI at the beginning of the study (week 0). No embolic cerebral lesions were detected during the 12-month follow-up. Within 12 months only 63 % (n = 20/32) of LA thrombi in the study group resolved completely under anticoagulation. CONCLUSION: 1. The incidence of clinically inapparent cerebral emboli in pts. with newly diagnosed AF and atrial thrombi is much higher than the incidence of clinically apparent emboli and has been underestimated in the past. 2. New cerebral embolism may occur even with continued effective anticoagulation therapy in 13 % of pts. 3. Only 63 % of atrial thrombi resolve completely within 12 months under anticoagulation therapy.

Congenital myopathy with arrest of myogenesis prior to formation of myotubes.

We report a novel type of congenital myopathy, which is characterized by an early arrest of muscle formation prior to formation of myotubes. A female infant born prematurely at 32 weeks of gestational age died after six weeks of continuous ventilatory support. Various muscle specimens including quadriceps, deltoid, pectoral, neck, psoas, tongue, and diaphragm musculature were studied. Light and electron microscopy revealed well-demarcated fascicular structures interspersed with undifferentiated, mononuclear myogenic cells. Multinucleated myotubes and muscle fibres were not detectable, pointing towards a defect prior to the generation of myotubes during myogenesis. Immunohistochemistry identified the absence of dystrophin, N-CAM, MyoD and myogenin expression in these myogenic cells, compatible with a block of the complex transcriptional network necessary for correct embryonic muscle formation at an early stage of muscle development. These myopathological findings were absent in cardiac muscle, indicating that the defect exclusively affects skeletal muscle formation.

Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease.

Canavan disease is characterised as a rare, neurodegenerative disease that usually causes death in early childhood. It is an autosomal recessive disorder due to an aspartoacylase (ASPA) deficiency. The causative gene has been mapped to chromosome 17 pter-p13. Here we describe three affected children from two Greek families with an unusually mild course of Canavan disease. All children presented with muscular hypotonia and macrocephaly. Diagnosis was based on elevated N-acetylaspartate in urine, reduced aspartoacylase activity in fibroblasts, and marked white matter changes on cerebral imaging. All three affected individuals exhibited continuous psychomotor development without any regression. Genetic analyses revealed compound heterozygous mutations (Y288 C; F295 S) in two individuals. The Y288 C variant was previously described in a child with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia, partial cortical blindness and retinitis pigmentosa, and slightly elevated N-acetylaspartate in the urine. Demonstration of the same variant in two unusually mildly affected Canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild Canavan disease. In the third individual, two homozygous sequence variants were identified, which comprise the known G274R mutation and a novel K213E variant.

Identification of a novel LAMP2 mutation responsible for X-chromosomal dominant Danon disease.

Danon disease (DD) is a rare lysosomal glycogen storage disease with normal acid maltase activity, which is characterised clinically by cardiomyopathy and myopathy, and a variable degree of mental retardation. The causative gene, LAMP2, has been mapped to chromosome Xq24-q25. LAMP2 encodes a lysosome-associated membrane glycoprotein. We identified a novel LAMP2 mutation of the exon 8 splice acceptor site (IVS7-1G --> A) in an affected male and female, which predicts abnormal splicing. Both affected individuals presented solely with hypertrophic cardiomyopathy. Muscle weakness and mental impairment were absent. Diagnosis of Danon disease was established by muscle biopsy, when the male index patient developed transient severe muscle weakness following heart transplantation. Typical biopsy findings were also found in a heart muscle specimen. Demonstration of the LAMP2 mutation in affected male and female siblings is compatible with X-linked dominant inheritance. Danon disease should be actively looked for in cardiomyopathy patients.