Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease.

INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.

[Extensive digital necrosis during dermatomyositis associated with MDA-5 antibodies]. / Nécroses digitales étendues au cours d'une dermatomyosite avec anticorps anti-MDA-5.

BACKGROUND: Dermatomyositis (DM) is an inflammatory disease associated with auto-antibodies in 50 to 70% of cases. A new antibody, anti MDA-5, has been described in association with a specific type of DM involving severe interstitial lung disease and minimal muscle disease. We report the first case of DM with MDA-5 antibodies and with interstitial lung disease and rapidly extensive digital necrosis. PATIENTS AND METHODS: A 28-year-old male was hospitalized for asthenia, myalgia and subacute dyspnea. Examination demonstrated skin lesions with edema on every digit associated with purpuric and cyanotic lesions, as well as erythematous papules on the helix and the elbows, and Gottron's papules. Systemic corticosteroid therapy was initiated. The immunoprecipitation results indicated the presence of anti-MDA-5 antibodies. Despite corticosteroid therapy, the patient's respiratory status gradually deteriorated towards pulmonary fibrosis and rapidly extensive necrosis appeared on all fingers and toes. Theses effects were resistant to cyclophosphamide and immunoglobulin but were stabilized by cyclosporine. DISCUSSION: Anti-MDA-5 antibodies are specific to DM and constitute a risk factor for severe interstitial lung disease (70% of cases) with a higher risk of mortality (40%). The cutaneous presentation of this DM is specific with palmar papules and mucocutaneous ulceration. Rapidly extensive digital necrosis has not been previously reported. No treatment has demonstrated superiority. CONCLUSION: We report the first case of DM with anti-MDA-5 antibodies involving interstitial lung disease and massive digital necrosis. Because of the pulmonary risk, in the presence of clinical lesions containing anti-MDA-5 DM, screening for these antibodies should be carried out.

Impairment of quality of life in patients with antiphospholipid syndrome.

OBJECTIVES: Health-related quality of life (HRQoL) has not been fully explored in antiphospholipid syndrome (APS); therefore, we compared HRQoL between APS patients and the general population and assessed the impact of thromboembolic history. METHODS: HRQoL was measured in a multicentre cohort study by the Medical Outcomes Study Short-Form 36 (MOS-SF-36) questionnaire. HRQoL scores were compared to the French general population norms. Factors significantly associated with an impaired HRQoL were identified. RESULTS: A total of 115 patients with aPL and/or systemic lupus erythematosus (SLE) were included (mean age 42.7 ± 14.1 years old, 86 women). In 53 patients APS was diagnosed. Compared to general population norms, patients with APS had an impaired HRQoL. SLE-associated APS patients had the worst HRQoL scores (physical component summary (PCS)=40.8 ± 10.6; mental component summary (MCS)=40.6 ± 16.5) in comparison with SLE or aPL patients without thromboembolic history. In APS patients, history of arterial thrombosis significantly impaired HRQoL (PCS score: 42.2 ± 9.4 vs 49.2 ± 8.5; MCS score: 33.9 ± 13.7 vs 44.6 ± 10.3). CONCLUSION: Compared to the general population, APS patients experienced a lower HRQoL. In these patients, a history of arterial thrombosis significantly impaired HRQoL. Therefore, measurements of HRQoL should be included in APS patient management to assess the burden of the disease from a patient's perspective and to provide patients with the support they need.

Multidimensional analysis of clinical symptoms in patients with Fabry's disease.

AIM: Fabry's disease is an X-linked inherited lysosomal storage disorder caused by the deficient activity of alpha-galactosidase A. The interrelationships between clinical symptoms in Fabry patients have not yet been fully established. Using cluster and multivariate analysis, the aim of the study was to determine the relationships among clinical symptoms and organ involvement, and predictive clinical symptoms for disease severity. METHODS: Clinical data obtained from 108 French Fabry patients were retrospectively collected and analysed using multiple correspondence analysis and hierachical ascendant classification. Multivariate analysis was also performed to determine among clinical symptoms predictors for cardiac disease (HRT), renal involvement (KDN) and brain complication (STR). RESULTS: The cohort comprised 41 male patients (aged 28.9 ± 11.6 years) and 67 female patients (aged 40.4 ± 15.5 years). Three main clusters of clinical symptoms could be delineated, characterising disease progression: the first cluster grouped digestive disorders (found in 30% of the patients) and exercise intolerance (32%), the second, cluster dyshidrosis (47%), acroparesthesia (67%), angiokeratoma (44%) and cornea verticillata (54%), the third, cluster grouped KDN (30%), HRT (39%) and STR (25%) and hearing loss (44%). In univariate analysis, the patient age predicted HRT and KDN, dyshidrosis predicted HRT and STR, angiokeratoma predicted KDN and cornea verticilla and hearing loss predicted KDN, HRT and STR. In multivariate analysis, hearing loss and age were independent predictors of organ complication. CONCLUSION: Among the various interrelated clinical symptoms occurring in Fabry disease, patients with dyshidrosis and particularly hearing disorders appear to be at higher risk of organ complications.

Fabry disease 'The New Great Imposter': results of the French Observatoire in Internal Medicine Departments (FIMeD).

Fabry disease (FD) is an X-linked lysosomal storage disorder due to α-galactosidase A deficiency. It is associated with a broad range of clinical symptoms, resulting in frequent misdiagnosis and diagnostic delay, which may impact on patient outcomes. This retrospective observational study of 58 FD patients referred to 10 internal medicine departments in France aimed to review differential diagnoses received prior to diagnosis and examines diagnostic delay. The average age at the time of diagnosis was 27.6 years (range: 10-60) and 42.2 years (range: 9-77) among the 23 males and 35 females analyzed, respectively. Most common symptoms that led to FD diagnosis were family history of FD (12 males and 27 females), followed by pain in extremities (10 males and 5 females), and angiokeratoma (8 males and 4 females). Eighteen patients had received alternative diagnoses prior to FD diagnosis, including a female patient with four previous diagnoses. Four case reports are presented, which illustrate the diagnostic 'odyssey' and delayed diagnosis often experienced by patients. Clinicians should consider a diagnosis of FD when presented with a wide range of symptoms, thus helping to shorten the diagnostic delay and facilitating early therapy with enzyme replacement therapy to improve patient outcomes.

[Muscular disability and organ impairments in myotonic dystrophy type 1]. / Fonction musculaire et atteinte d'organes dans la dystrophie myotonique de type 1.

BACKGROUND: Myotonic dystrophy (DM1) is a multisystemic disorder characterized by myotonic muscular weakness, and numerous organ impairments, especially cardiac and respiratory disorders. The goal of this study was to evaluate in DM1 patients the relationships between a new muscular disability scale, the motor function measure (MFM), and functional measurements of organ involvements. PATIENTS AND METHODS: The MFM and MDRS, as well as spirometry, blood gases, echocardiography, electrocardiogram, and ophthalomological examination were performed in 69 consecutive DM1 patients. RESULTS: Significant relationships were found between MDRS and MFM (p < 0.001) as well as between both and age and BMI of the patients. Patients with total MFM below 76 had a higher risk of respiratory insufficiency, conduction disorders, left ventricular dysfunction, hypoxemia and cataract than the other DM1 patients. CONCLUSION: The MFM provides an effective evaluation of muscular disability in DM1 patients. Cardiac and respiratory involvements are correlated with lower MFM.

[Diagnostic journey of type 1 Gaucher Disease patients: A survey including internists and hematologists]. / Parcours diagnostique des patients atteints de maladie de Gaucher de type 1 : enquête auprès de médecins internistes et hématologues.

INTRODUCTION: Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by a beta-glucocerebrosidase deficiency and responsible for a lysosomal storage disorder. GD is characterized by haematological, visceral and bone involvements. The aim of this study was to describe the diagnostic journey of type 1 GD patients as well as the role of the internist. METHODS: A retrospective multicentric study involving type 1 GD patients has been conducted in 16 centers, between 2009 and 2011. RESULTS: Fifty-five type 1 GD patients were included, under the care of an internist or an haematologist. They were originally hospitalized in 8 different specialized units. Diagnosis was established by bone-marrow aspiration in 22 patients (40%), by enzymatic assay of glucocerebrosidase activity in 15 patients (27%), and by bone-marrow biopsy in 9 patients (16%). The use of enzymatic assay became more frequent after 1990. The delay between first hospitalization due to GD symptoms and definitive diagnosis was less than one year for 38 patients. Patients with suspected GD were mainly referred to an internist physician. CONCLUSION: GD seems to be better recognized and quickly diagnosed since 1990 in spite of the multiplicity of journeys. The role of the internist seems important.

Serum parathormone profile during surgical treatment of hyperfunctioning parathyroid adenoma: a multicompartmental model.

Patterns of intact parathyroid hormone (iPTH) elimination and subsequent recovery of parathyroid function were studied in seven patients undergoing surgical removal of solitary hyperfunctioning parathyroid adenoma. Using a sensitive two-site immunoradiometric assay, iPTH levels were measured pre, peri-, and postoperatively. Blood samples were taken at very early and at late stages, including 3, 6, 9, and 15 minutes and 48, 72, and 96 h after adenomectomy. A biexponential formula was calculated to fit the decreasing values of iPTH in all patients. The PTH half-life in the early phase was 1.4 +/- 1.1 minutes (95% confidence limits). The PTH half-life in the second phase was 64.45 +/- 32.19 minutes (95% confidence limits). A third phase is represented by a slow, linear increase in plasma iPTH values as a result of the recovery of healthy suppressed parathyroid glands. The extrapolation to baseline of the later phase shows that the recovery of normal parathyroid function begins as soon as 240 minutes after adenomectomy and is independent of the decrease in PTH of adenomatous origin. All individual results were consistent with this model. Five patients had iPTH values below 5 pg/ml, one had 15 pg/ml, and the last had 27 pg/ml 5 h after parathyroid adenomectomy. The recovery of the hormonal activity of the remaining glands occurred rapidly. By the postoperative hour 24 the mean serum iPTH concentration was 12.28 +/- 8.07 pg/ml. The intraoperative serum iPTH concentration offers a model to assess both recovery of hormonal secretion from functionally suppressed parathyroid glands and disappearance of parathyroid hormone.

Energetic metabolism in hypothyroid skeletal muscle, as studied by phosphorus magnetic resonance spectroscopy.

Phosphorus nuclear magnetic resonance spectroscopy was used to investigate the muscle bioenergetics in different hypothyroid states. Using the thenar muscle group as reference, 2 patients with chronic and severe hormonal deficiency, 3 patients with subacute hypothyroidism, and 8 patients with moderate thyroid insufficiency with isolated high blood TSH levels were studied at rest, during exercise, and during subsequent recovery. The patients were compared with 15 control subjects. Only 1 patient presented a clinical myopathy. The intracellular pH and the relative measurements of inorganic phosphate, phosphocreatine, phosphodiesters, and ATP were directly calculated from phosphorus spectra. Resting muscle showed a significant rise in the inorganic phosphate to ATP ratio. In working hypothyroid muscle, a more important decrease in phosphocreatine levels was noted in patients with chronic and subacute thyroid deficiency, while the intracellular pH fall was greater in all hypothyroid patients than in control subjects. The phosphocreatine recovery rate was lower in all deficient patients, reflecting a probable mitochondrial metabolism impairment. These results are consistent with a defect of the high energy phosphate metabolism in hypothyroidism, even in moderate or recent hormonal deficiency.

Sarcoid reactions in cystic duct carcinoma.

A diagnosis of sarcoidosis was evoked in a 61-year-old man on clinical and histologic bases. Nevertheless, a bile duct carcinoma was disclosed in association with the discovery of generalized sarcoid-like granulomas. This is only the third time that such an association has been described. HLA-B8, DR3, and DRw52 antigens were found, suggesting that altered immunologic mechanisms could play a role in the pathogenesis of this sarcoid-like reaction.

The effect of salbutamol treatment on the cellular immunity of the offspring of pregnant mice: spleen cell activity.

Preterm delivery is one of the greatest problems in obstetric care. One of the most commonly used treatments for high risk cases is salbutamol, a beta-2-adrenoceptor agonist. The aim of the present study was to determine if such treatment causes any changes in the neonatal immune system which should therefore be a concern in the care of the newborn. The experiments were performed on 4 to 5 or 6 to 7-week old female and male offspring of salbutamol-treated C3H/W inbred mice. In the first part of the study, the number of spleen cells, phenotypes and activity (phytohemagglutinin-induced proliferation, ability to induce local graft versus host reaction) were determined. We observed lowering of cell number and lowered proportions of cluster of differentiation (CD)3, CD4 and CD8 positive lymphocytes in spleens of progeny of salbutamol-treated mice. However, CD4+ to CD8+ ration was higher in the progeny of salbutamol-treated mothers than in the corresponding controls. In addition, reactivity to phytohemagglutinin and ability to induce local graft vs. host reaction were higher (popliteal lymph node test) or undisturbed (lymphocyte-induced angiogenesis test) in this group of mice.

[Nervous system borreliosis with pseudo-lymphoma cells in cerebrospinal fluid]. / Neuroborréliose avec cellules pseudolymphomateuses dans le liquide céphalorachidien.

We report the case of a 44-year-old woman, who experienced acute back pains, leg paraesthesia, and diplopia. Analysis of the cerebrospinal fluid revealed, in addition to increased protein and decreased glucose levels, an elevated number of large atypical cells, resembling lymphoma cells. Magnetic resonance imaging of the brain and spine was normal. High levels of antibodies against Borrelia burgdorferi were found in both serum and cerebrospinal fluid. The patient completely recovered with ceftriaxone therapy.

[Magnetic resonance imaging in lupic chorea]. / Imagerie par résonance magnétique dans une chorée lupique.

A case of disseminated lupus erythematosus with chorea is reported. CT was normal. Magnetic resonance imaging showed multiple focal lesions on T2-weighted sequences, predominating in the periventricular white matter. This MRI pattern did not change in a second MRI investigation, 7 months later. The contribution of MRI to our understanding of the neurolupus pathophysiology is discussed.

[Abnormalities of the muscular bioenergetics in Steinert's disease]. / Anomalies de la bioénergétique musculaire dans une maladie de Steinert.

The thenar muscles and gastrocnemius of a patient with myotonic dystrophy were investigated, at rest, by phosphorus nuclear magnetic resonance spectroscopy. A decrease in phosphocreatine level and an increase in inorganic phosphate and phosphodiester levels were found in the gastrocnemius, which was clinically spared, whilst the thenar muscles, which were wasted and affected by myotonia, exhibited only an increased inorganic phosphate level and an elevated pH. These findings were comparable with those found in other muscular disorders, such as Duchenne's and Becker's dystrophies, as well as in limb girdle dystrophy. They suggested that the abnormalities observed were unrelated to myotonia or wasting, and the possibility of a secondary mitochondrial disorder in myotonic dystrophy, is to be considered.

[High dose intravenous immunoglobulins in therapeutic arsenal in autoimmune and systemic diseases]. / Les immunoglobulines intraveineuses à fortes doses dans l'arsenal thérapeutique des maladies auto-immunes et des maladies de système.

Immune globulin are extracted from plasma pooled from 1000 or more donors. Each lot should contain at least 90% of intact IgG. Intravenous immune globulin are recommended unequivocally for some diseases: acute autoimmune thrombocytopenic purpura of childhood, autoimmune erythroblastopenia, haemophilia with anti-VIII antibodies, Kawasaki's syndrome, and perhaps, Guillain-Barré syndrome. Nevertheless, this therapy has been reported to be beneficial for more than 35 diseases thought to be produced by immunopathology. Large amounts of immune globulin, such as 400 to 2000 mg/kg are proposed over a period of two to five days. The safety of this treatment, which may be introduced without any special structure, is a very interesting quality of the intravenous immune globulin therapy. However, comparative efficacy against reference therapy, surveillance for long-term positive and adverse effects and cost-effectiveness should be carried out.

[Physiopathology of inorganic lead poisoning]. / Physiopathologie de l'intoxication par le plomb inorganique.

This paper gives an overview of the hypotheses concerning the mechanisms of inorganic lead toxicity on cells and tissues, with emphasis on the effect of low-concentration lead. Inhibition of heme synthesis is responsible not only for lead-induced anaemia, but also for accumulation of delta-aminolaevulinic acid (ALA) and for lowering the concentration of cytochromes contained in the mitochondrial respiratory chain. Auto-oxidation of ALA is thought to result in the formation of free radicals. On the other hand, lead replaces ionic calcium in its role as second cell messenger. This mechanism would explain the abnormalities observed in synaptic transmission, arteriolar vasoreactivity and functioning of such cells as osteoclasts and osteoblasts. Nuclear toxicity, with abnormal expression of DNA genes and inhibition of certain enzymes such as membrane Na+/K+ ATPase, are also considered. The mechanisms of tissue toxicity are discussed.

[Gaucher's disease: current aspects]. / La maladie de Gaucher: aspects actuels.

Gaucher's disease is an autosomal recessive inherited disorder, characterized by genetic deficiency of lysosomial glucocerebrosidase. Its substrate (glycosylceramide) subsequently accumulates in cells of monocyte/macrophage origin, resulting in enlargement of the spleen and liver, skeletal lesions, and, in the most severe phenotypes, in neurological disorders. Thirty-six mutations have been at present documented in the gene encoding for the glucocerebrosidase, but four of them (N370S, L444P, 84GG and IVS2+1) are really frequent, particularly in ashkenaze population. Gaucher's disease is diagnosed by the presence of Gaucher cells, especially in bone marrow aspirate, and by assessing the glucocerebrosidase activity. The prognosis has been considerably improved by enzyme replacement therapy.

[Pancoast-Tobias syndrome disclosing a primary pulmonary non-Hodgkin lymphoma]. / Syndrome de Pancoast-Tobias révélant un lymphome non hodgkinien pulmonaire primitif.

INTRODUCTION: Pancoast's syndrome is generally due to superior sulcus tumors, generally bronchial cancer. In rare cases, other causes are found, but these are potentially curable. CASE-REPORT: A 78-year old woman with a long history of tobacco intake presented with Pancoast's syndrome in the form of a locally invasive left apical lung mass. Despite her advanced age and the diagnosis of the high probability of lung cancer, a transparietal biopsy procedure was nevertheless performed, with the subsequent diagnosis of primary malignant pulmonary lymphoma. The patient was satisfactorily treated by combined chemotherapy. CONCLUSION: The present study has shown that malignant non-Hodgkin lymphomas should be considered in the etiology of the disease, and as a rare but potentially treatable cause of Pancoast's syndrome.

[Current diagnosis and treatment of lead poisoning]. / Diagnostic et traitements actuels du saturnisme.

Lead may be an industrial and an environmental hazard which becomes of greater importance every year. Classical symptoms of plumbism are rare, whenever minor clinical signs increase in frequency. Erythrocyte zinc protoporphyrin and delta-aminolaevulinic acid dehydratase are reliable indicators of the importance of the lead poisoning in individuals. The concentration of lead in blood is also a suitable biological indicator as is EDTA mobilization test. The treatment is based on the use of chelating agents such as calcium EDTA or DMSA, but the only solution is reduction or removal of the sources of lead exposure.

[Dilated cardiomyopathy and panuveitis as presenting symptoms of Lyme disease. General review of one case]. / Cardiomyopathie dilatée et panuvéite bilatérale révélant une maladie de Lyme. Revue générale à propos d'un cas.

INTRODUCTION: The clinical expression of Lyme disease is highly variable. If a patient presents clinical findings consistent with a systemic Lyme borreliosis, this disease must be considered in an endemic area because of its favorable outcome with adequate treatment. EXEGESIS: The authors report and discuss the case of a patient with an unusual history of dilated cardiomyopathy and supraventricular fibrillation followed by bilateral panuveitis. Enzyme-linked immunosorbent assay and Western blot were positive for Borrelia burgdorferi antigens. The diagnosis of Lyme disease was made after other infectious, inflammatory and autoimmune disorders were excluded by clinical, instrumental and biological investigations. The treatment by ceftriaxone and amoxicillin resolved the ophthalmologic manifestations and improved the cardiac condition. CONCLUSION: This report underlines the possibility of an unusual presentation of Lyme disease. Ophthalmologic and cardiac involvement should be known by clinicians.