Electrocardiogram in Friedreich's ataxia: A short‐term surrogate endpoint for treatment efficacy

Friedreich''s ataxia is a rare degenerative neuromuscular disorder, caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene, with a broad clinical phenotype characterized by progressive gait and limb ataxia, dysarthria, and loss of lower limb reflexes; cardiac involvement is represented by hypertrophic cardiomyopathy, ventricular arrhythmias, and sudden cardiac deaths. Currently, no definite therapy is available, while many drugs are under investigation; for this reasons, we need markers of short‐ and long‐term treatment efficacy acting on different tissue for trial evaluation. We describe the case of a 21‐year‐old patient affected by Friedreich''s ataxia on wheel‐chair, with initial cardiac involvement and electrocardiographic features characterized by thiamine treatment‐related negative T wave and QTc variations. We discuss plausible physiopathology and potential ECG role implications as an intermediate marker of treatment response in future clinical trials considering patients affected by Friedreich''s ataxia.     

Friedreich's ataxia associated with idiopathic hypertrophic subaortic stenosis

Friedreich's ataxia and idiopathic hypertrophic subaortic stenosis (IHSS), both diseases of unknown etiology, both result in hypertrophy and degenerative changes of the myocardium. Both diseases lead to nearly identical electrocardiographic changes. We report a patient who developed classical signs of Friedreich's ataxia several years after he was found to have moderately severe IHSS. This observation prompted a hemodynamic study of five other patients with Friedreich's ataxia in search of a more common association and thus a possible etiological link between the two diseases. Cardiac catheterization was performed under local anesthesia. Catheters were inserted into the right ventricle, the pulmonary artery, the left ventricle, and the aorta. Isuprel infusion up to 6 μg per minute was used in an attempt to induce an abnormal pressure gradient across the right or left ventricular outflow tract. Both right and left ventricular cineangiograms were obtained for evaluation of ventricular kinetics and wall thickness. Right and left heart pressures were normal at rest in all patients. During Isuprel infusion a 40 mm. pressure gradient was induced across the left ventricular outflow tract in only one patient. A second patient developed a 16 mm. gradient across the right ventricular outflow tract. All patients had low normal cardiac outputs. The angiograms demonstrated increased left ventricular wall thickness in all patients. It is concluded that systolic left and/or right ventricular out-flow tract obstruction is only infrequently present in Friedreich's ataxia and is mild in degree. An etiological link between Friedreich's ataxia and IHSS is not known at the present but may possibly exist and should be investigated.     

Hypertrophic obstructive cardiomyopathy and Friedreich's ataxia. Report of a case and review of literature

A case of Friedreich's ataxia with evidence of hypertrophic obstructive cardiomyopathy involving both ventricles is reported. A review of the previously reported cases leads us to believe that this association is not merely accidental, but that Friedreich's ataxia and hypertrophic obstructive cardiomyopathy are parts of the same syndrome.     

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich''s ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased “free iron” for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich''s ataxia.     

May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich's ataxia?

Background: Although heart involvement has been widely reported in Friedreich's ataxia (FA), which is the most prevalent of the spino-cerebellar degenerative diseases, the reason that cardiac abnormalities develop has not been yet established. Hypothesis: The investigation was undertaken to study the prevalence and characteristics of cardiac abnormalities in patients with FA and to evaluate whether the presence of left ventricular hypertrophy could be predicted. Methods: In all, 75 patients with FA and 16 patients with late onset FA (LOFA) disease were investigated for cardiac abnormalities using noninvasive methods. Results: A significant (p< 0.01) difference in the age onset (9.8 ±3.9 years) was found in 31 of the 75 patients with FA (41%) who showed left ventricular hypertrophy (LVH) at echocardiographic examination compared with the remaining 44 patients with FA without LVH (12.6 ± 4.3 years). Moreover, none of the 16 patients with LOFA (age onset 26.5 ± 4.2 years) showed abnormalities at echocardiographic examination. A significant (p<0.01) concordance in the familial distribution of hypertrophy was also found. Conclusion: These data suggest that the earlier the disease develops the more frequently LVH occurs.     

Chest pain during exercise as first manifestation of Friedreich's ataxia.

Cardiac function is affected in up to 90% of patients with Friedreich's ataxia, the most common spinocerebellar degenerative disease. Friedreich's ataxia typically causes motor abnormalities of the extremities, mainly impairing walking and the coordination of the legs and arms. The myocardium is affected at a later stage of the disease. The extent and timing of myocardial involvement determines the clinical course. Some patients have no cardiac symptoms and cardiac involvement can be established only by electrocardiographic or echocardiographic examination. In addition some pathological studies have found evidence of coronary abnormalities, mainly in the small vessels. There are no reports that such lesions cause angina. In a 16 year old patient chest pain on exercise had been the presenting symptom of Friedreich's ataxia at the age of 9. Considerable alterations in ventricular repolarisation on the electrocardiogram suggested a congenital coronary abnormality or hypertrophic myocardiopathy. The results of a Doppler echocardiography, Holter monitoring, and a haemodynamic study with coronary arteriography were all normal. An exercise test when the boy was 13 indicated significant changes in ventricular repolarisation. Myocardial scintigraphy (99mTc-MIBI) at that time, however, was normal. He improved slightly when he was treated with verapamil. When he was 15 neurological symptoms developed and Friedreich's ataxia was diagnosed. Typical angina during exercise seems to have been the first symptom of Friedreich's ataxia.     

Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans

Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner.     

Maladie de Whipple et infections à Tropheryma whipplei. Quand l’interniste doit y penser ? Comment les traiter ?

Tropheryma whipplei culture and genome sequencing have, thanks to new tools, rationalized both diagnosis and treatment of Whipple's disease. Whipple's disease involves mainly Caucasian male, approximately 50-years-old, suffering from arthralgia, weight loss and diarrhea. A worsening of clinical manifestations after immunosuppressive therapy is frequently observed while antibiotics prescribed for another infection improves the clinical status. Clinical manifestations may more rarely suggest lymphoma or sarcoidosis. Positive T. whipplei performed on both saliva and stool samples are strongly suggestive of Whipple's disease. The diagnosis is confirmed by positive periodic acid Schiff staining or immunohistochemistry performed on small-bowel biopsies. Localized chronic infections are defined by the absence of histological duodenal involvement. Endocarditis mainly occurs in 60-years-old men with arthralgia, cardiac failure or embolic events. Encephalitis causes mainly cognitive and psychiatric involvement, and sometimes dementia, ataxia and weight gain. Uveitis and arthritis evolve chronically, and are frequently resistant to immunosuppressive treatment. PCR and culture (particularly for cerebrospinal fluid) performed on various tissues and fluids allow the localized infections diagnosis. In classic Whipple's disease, the treatment with doxycycline (200 mg/day) and hydroxychloroquine (600 mg/day) for a length of 12 months followed by a lifetime treatment by doxycycline (200 mg/day) should be recommended to avoid reinfection. In localized infections, a treatment with doxycycline (200 mg/day) and hydroxychloroquine (600 mg/day) is proposed for 12 to 18 months followed by a lifetime follow-up.     

Multicentric reticulohistiocytosis: Rheumatology perspective

Multicentric reticulohistiocytosis (MRH) is a rare, multisystemic non-Langerhans cell histiocytosis characterized by skin and articular involvement, and rarely involves various other organs. There are no specific laboratory findings for MRH. Diagnosis is based on clinical findings and skin or synovial biopsy results. There is currently no consensus for the treatment of MRH. Here, we review the differential diagnosis and treatment options of MRH from the rheumatologist's perspective. We also report an index case of MRH associated with Sjögren's syndrome and pulmonary embolism.     

Cardiac involvement in Wegener's granulomatosis.

Wegener''s granulomatosis is a systemic inflammatory disorder of unknown aetiology. The protean clinical presentations depend on the organ(s) involved and the degree of progression from a local to a systemic arteritis. The development of serological tests (antieutrophil cytoplasmic antibodies) allows easier diagnosis of a disease whose incidence is increasing. This is particularly helpful where the presentation is not classic--for example "overlap syndromes"--or where the disease presents early in a more localised form. This is true of cardiac involvement, which is traditionally believed to be rare, but may not be as uncommon as has hitherto been thought (< or = 44%). This involvement may be subclinical or the principal source of symptoms either in the form of localised disease or as part of a systemic illness. Pericarditis, arteritis, myocarditis, valvulitis, and arrhythmias are all recognised. Wegener''s granulomatosis should therefore be considered in the differential diagnosis of any non-specific illness with cardiac involvement. This includes culture negative endocarditis, because Wegener''s granulomatosis can produce systemic upset with mass lesions and vasculitis. Echocardiography and particularly transoesophageal echocardiography can easily identify and delineate cardiac and proximal aortic involvement and may also be used to assess response to treatment.     

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich''s ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.     

Association between psychiatric disorders and marfan's syndrome in a large sardinian family with a high prevalence of cardiac abnormalities

Background: Marfan's syndrome is an inherited disorder of connective tissue associated with characteristic abnormalities of the skeletal, ocular, and cardiovascular systems. Marked clinical variability and age dependency of all manifestations of Marfan's syndrome may render the unequivocal diagnosis difficult in mildly affected, young subjects. Hypothesis: The study and care of a 32-year-old woman with evidence of Manfan's syndrome, several cardiac abnormalities, and paranoid schizophrenia led to an investigation of her consenting relatives to verify the penetrance of Marfan's syndrome and the degree of comorbidity between the disease and psychiatric disorders. Methods: The patient and 12 subjects belonging to three generations of her family underwent cardiovascular, skeletal, ophthalmologic, and psychiatric examinations. Two-dimensional and Doppler echocardiography were performed. Results: One female index patient and six of her first-degree relatives were found to be affected by Marfan's syndrome. All seven patients were found to have mitral valve prolapse associated with other cardiac abnormalities. Four of these patients were affected by the following psychiatric disorders: generalized anxiety disorder, major depressive disorder, paranoid schizophrenia (two cases). Six more relatives without Marfan's syndrome showed mitral valve prolapse in association with other echocardiographic features. Two of these were found to be affected by a major depressive disorder. Conclusions: The present data support the hypothesis that a psychiatric condition, associated with a significantly high frequency of cardiac involvement, may be part of the phenotype of Marfan's syndrome.     

Cardiac involvement in Friedreich's heredo-ataxia

The frequency and characteristics of cardiac involvement have been evaluated in 22 patients with Friedreich's ataxia and in 10 patients with non Friedreich's ataxia (Strumpell-Lorraine 5 cases; Pierre Marie 5 cases), classified according to the severity and the lasting of neurological disease. In a high percentage (45%) of patients with Friedreich's ataxia, the results show left ventricular hypertrophy as proved echocardiographically by an increase of the interventricular septum thickness and of the posterior wall thickness. On the contrary, no patient with non Friedreich's ataxia had left ventricular hypertrophy. In the patients with Friedreich's ataxia, left ventricular hypertrophy was of concentric type in 27% of the cases and of asymmetric type in 18% of the cases; left ventricular systolic indexes were not reduced. The left ventricular end-diastolic diameter was normal in all the patients. Furthermore, in 4 patients with Friedreich's ataxia (18% of the cases) without left ventricular hypertrophy, mitral valve prolapse has been found. No correlation exists between the severity and the lasting of neurologic disease and the presence of cardiac hypertrophy. This supports the hypothesis that the cardiac abnormality is a primary expression of a genetic defect and not a secondary manifestation of spinocerebellar degeneration. It is therefore necessary to always consider a patient with Friedreich's ataxia as affected with a cardiac disease even if it is not clinically evident.     

Primary Cardiac Sarcoidosis with Syncope and Refractory Atrial Arrhythmia: A Case Report and Review of the Literature

We discuss the case of a 38-year-old black man who presented at our hospital with his first episode of syncope, recently developed atrial arrhythmias refractory to pharmacologic therapy, and a left atrial thrombus. He was diagnosed with primary cardiac sarcoidosis characterized by predominant involvement of the epicardium that caused atrial fibrillation and atrial flutter. Histologic analysis of his epicardial lesions yielded a diagnosis of sarcoidosis. This patient''s atrial arrhythmia was successfully treated with a hybrid operation that involved resection of his atrial appendage, an Epicor maze procedure, and radiofrequency ablation during a catheter-based electrophysiologic study. The cardiac sarcoidosis was successfully managed with corticosteroid therapy.Our case report shows that sarcoidosis can initially manifest itself as syncope with new-onset atrial arrhythmia. Sarcoidosis is important in the differential diagnosis because of its progressive nature and its potential for treatment with pharmacologic, surgical, and catheter-based interventions.     

Isolated Cardiac Involvement in Primary Amyloidosis: Presenting as Sick Sinus Syndrome and Heart Failure

Cardiac amyloidosis is an infiltrative cardiomyopathy with a grave prognosis. Its clinical manifestations include restrictive cardiomyopathy, diastolic heart failure, conduction defects, and arrhythmias. Isolated cardiac involvement and significant conduction disturbances are reported very infrequently. We report a rare case of isolated cardiac involvement in primary amyloidosis, in a 76-year-old man who initially presented with sick sinus syndrome that necessitated permanent pacemaker insertion. Subsequent symptoms of heart failure led to additional evaluation, including an endomyocardial biopsy that revealed primary cardiac amyloidosis. Medical therapy improved the patient''s symptoms, and he was discharged from the hospital in stable condition. In addition to discussing the patient''s case, we review the relevant medical literature.Key words: Amyloidosis/complications/drug therapy/pathology, cardiomyopathies/complications/pathology, heart failure/diagnosis/etiology, prognosis, treatment outcomeCardiac amyloidosis is an infiltrative cardiomyopathy caused by the deposition of proteinaceous material, called amyloid, in the extracellular space of the heart. Clinical manifestations can include restrictive cardiomyopathy, diastolic heart failure, conduction defects, and arrhythmias.¹ We describe a rare case of primary cardiac amyloidosis in an elderly man who initially presented with sick sinus syndrome that necessitated permanent pacemaker insertion. Subsequent symptoms of heart failure prompted additional evaluation that established a diagnosis of primary cardiac amyloidosis.     

Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra‐renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one‐third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment‐related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.     

Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

Adult-onset Still''s disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy.The authors describe a case of adult-onset Still''s disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity.     

The heart and cardiac pacing in Steinert disease

Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert''s disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3'' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.Key words: myotonic dystrophy type 1, arrhythmias, cardiac pacing     

一个假肥大型肌营养不良症伴心脏扩大家系的遗传学及临床研究

背景假肥大型进行性肌营养不良是由抗肌萎缩蛋白基因突所致的一种X连锁隐性遗传神经肌肉疾病,又称为杜氏或贝克肌营养不良（Duchenne’s or Becker’s muscular dystrophy;DMD or BMD）,是以缓慢进行性加重的对称性肌无力和肌萎缩为特点的遗传性肌肉病变,其中DMD病情严重,预后差;BMD病情进展相对缓慢,可累及心脏。目的总结假肥大型肌营养不良症伴心脏扩大患者的临床特征并进行基因分析和系统治疗,为临床诊治提供借鉴。方法：对先证者和家系成员进行临床观察、血清酶、肌电图、心电图、心脏彩色超声检查及心脏核磁检查,采用直接测序的方法进行抗肌萎缩蛋白基因突变的检测,尚需对100例无血缘关系的健康人群进行该位点的基因扩增测序,以排除所发现的突变为未知人群多态位点的可能。对确诊患者根据病情进行对症治疗并对其进行随访。结果先证者符合BMD诊断,基因检测结果提示先证者携带dystrophin基因突变（c.4998_5000DelGCA,p.1667del）。家系成员中检测出3例患者携带以上突变,携带者均表现为四肢近端肌肉萎缩、无力,双腓肠肌假性肥大,血清肌酶水平显著增高,心脏受累,先证者接受心脏移植术,恢复良好。结论本研究通过基因检测为先证者明确诊断,并对家系成员进行基因筛查,心脏移植术是治疗BMD晚期患者的可行有效的方法。     

Speed and efficiency but not accuracy or timing deficits of limb movements in alcoholic men and women

BACKGROUND: Lesions of the cerebellum, a concomitant of alcoholism, can disrupt quality and regularity of movement. Whether evidence for such dysfunction lingers in patients with uncomplicated alcoholism, which is known to affect cerebellar structural integrity, is controversial. METHODS: We used quantitative measures to examine component processes of five classes of movement associated with regional cerebellar function: limb ataxia (alternated finger tapping and variants of the finger-to-nose and heel-to-shin tests), paced tapping, eye-hand coordinated tracing, timed response reflecting preparation and execution time, and postural stability. The subjects examined were 39 abstinent alcoholics (13 men and 26 women) and 21 age-matched controls (9 men and 12 women). For limb ataxia, the dependent measures were the trajectory deviation from the subject's own average movement path and the speed of travel from beginning points to endpoints. RESULTS: Repeated-measures analysis of variance comparing movement speed of finger to nose and heel to shin yielded significant interactions in all conditions (p < 0.007); this indicated that the alcoholics were relatively slower in the upper- than lower-limb tasks. Movements by the alcoholic men were significantly slower but less deviant from an ideal trajectory in all upper-limb conditions than those of the control men (p < 0.002). Although measures of lower-limb movement trajectory did not distinguish the groups, tests of ataxia of stance and gait did. The groups did not differ, however, on tests of timed tapping or sinusoid tracing. CONCLUSIONS: Alcohol-related postural instability in abstinent alcoholics is functional evidence supporting the postulated damage to the anterior superior vermis. Altered speed or accuracy trade-offs, with alcoholics moving slower to attain equivalent or even smaller trajectory deviations, are symptomatic of cerebellar hemisphere dysfunction that is characterized by deliberation of otherwise automatic movements.