Metabolic Myopathies: Experience of a Reference Center of Inherited Metabolic Diseases.

INTRODUCTION: Metabolic myopathies (MM) are a heterogeneous group of genetic disorders affecting metabolic pathways involved in energy production during rest, exercise and physiologic stress (fever, fasting, …). Impairments in the pathways of glycolysis/ glycogenolysis, fatty acid transport/oxidation or in the mitochondrial respiratory chain present primarily with exercise intolerance, myalgias, weakness, cramps, or rhabdomyolysis. Depending on aetiology, the diagnosis can be made through neonatal screening, pre-symptomatic or in the set of clinical manifestations for which a high level of suspicion is important. METHODS: Retrospective descriptive study of the clinical, biochemical, and molecular features of patients with a confirmed diagnosis of MM followed by the multidisciplinary team of the Reference Center of Inherited Metabolic Diseases of Centro Hospitalar Universitário de Lisboa Central from 2009 to 2022. RESULTS: Twenty-three patients with MM were included: 9 (39%) glycogen storage diseases (7 McArdle and 2 Pompe), 7 (30%) fatty acid oxidation disorders (3 CPT2, 3 LCHAD and 1 MAD deficiencies), 6 (26%) mitochondrial disease with significant muscle involvement (2 Pearson, 1 Kearns Sayre, 1 VARS2, 1 SUCLA2 and 1 MT-TL1 deficiencies), and 1 myoadenylate deaminase deficiency. Ages varied from 15 months to 35 years. Eighteen (78%) patients were diagnosed by clinical symptoms, 3 by newborn screening (LCHAD) and 2 were asymptomatic (1 Pompe and 1 McArdle). Frequent symptoms were rhabdomyolysis triggered by illness or exercise 12 (52%), fatigue 11 (48%), exercise intolerance 10 (43%), and myalgia 9 (43%). Eight (35%) patients (LCHAD and mitochondrial) had multisystemic involvement. In 20 (87%) patients, the diagnosis was confirmed by biochemical and/or genetic analysis and 3 (McArdle) by muscle biopsy. CONCLUSION: MM are a heterogeneous set of disorders, but a careful history may guide the differential diagnosis among biochemical pathways and other etiologies. Nowadays, molecular testing has become a powerful tool for diagnosis confirmation, surpassing muscular biopsy in most cases. Accurate diagnosis is important to identify who may benefit from specific therapeutic options, such as enzyme replacement therapy, restricted diets, emergency regime and cofactors. All patients benefit from adequate lifestyle modifications, individualized exercise prescription, nutritional intervention, and genetic counselling.

Inhibitory effect of contralateral noise on transient otoacoustic emissions in infants with congenital syphilis.

OBJECTIVES: Analyze the inhibitory effect of contralateral noise on transient otoacoustic emissions in infants with congenital syphilis (CS). METHODS: Cross-sectional study, approved by the Research Ethics Committee n° 3.360.991. Infants with treated CS at birth and infants without risk indicators for hearing impairment were selected. Both groups had the waves I, III and V presence at 80 dB nHL with click BAEP and the presence of response in the nonlinear TEOAEs at 80 dB NPS bilaterally. For suppression, TEOAE were analyzed without the contralateral noise, with the linear stimulus at 60 dB SPL. The neonates who presented a response in three frequencies per ear performed the second TEOAE collection with the contralateral white noise at an intensity of 60 dB SPL. Inferential analysis were performed using the Mann-Whitney and Wilcoxon test, adopting a significance level p < 0.05. RESULTS: The sample consisted of 30 subjects divided into two groups, the Study Group (SG), consisting of 16 infants, and the Control Group (CG), consisting of 14 infants with no risk indicators for hearing loss. No differences were observed between the groups and the inhibition values, in the SG 30.8% presented inhibition and 25% for the CG in the right ear, in the left ear it was 46.7% in the SG and 38.5% in the CG. The SG demonstrated greater inhibition in the RE for the frequency bands from 1.5 to 4 KHz. CONCLUSIONS: The analyses adopted in this study point out that the inhibitory effect of contralateral noise on TEOAEs in infants with CS does not differ from infants without risk indicators for hearing loss.

Boundaries of a systemic disease: a protean presentation of giant cell arteritis.

A 60-year-old man was hospitalised with persistent fever, arm pain, dry cough and cholestasis. Diagnostic workup was remarkable for elevated inflammatory markers. Infectious diseases and autoimmune screening were negative. Imaging modalities excluded a neoplastic aetiology. Liver biopsy was negative for granulomatous or lymphomatous infiltrations. Giant cell arteritis (GCA) was suspected, but temporal artery Doppler ultrasound and biopsy were non-diagnostic. A positron emission tomography scan showed intense metabolic uptake in large vessels suggesting the diagnosis of GCA. Prednisolone was initiated with clinical and analytical improvement. At 1-year follow-up, there were no relapses and the patient remains symptom free.

Meglumine antimoniate combination treatment for relapsing Kala-azar after treatment and secondary prophylaxis failure with liposomal amphotericin B in two HIV-coinfected patients.

Visceral leishmaniasis (VL) is a protozoan infection caused by Leishmania infantum and L. donovani with a higher incidence and severity in HIV-infected patients due to its synergistic effect on hampering the immune response, often leading to death after treatment failure. Literature regarding the management of relapsing VL in HIV-coinfected patients is lacking. Many experts recommend a combined therapy with liposomal amphotericin B and miltefosine. The use of pentavalent antimonials is often discouraged due to their toxicity. We report two cases of successful response to treatment with combined therapy with meglumine antimoniate followed by secondary prophylaxis with miltefosine and atovaquone on relapsing VL in two HIV-coinfected patients despite treatment and monthly prophylaxis with appropriate doses of liposomal amphotericin B.

Estudo comparativo da atividade antiinflamatória, ulcerogênica e citotóxica do S-ibuprofeno e ibuprofeno racêmico / Comparative study of anti-inflammatory, ulcerogenic and cytotoxic activities of racemate and S-ibuprofen

Ibuprofen is widely commercialized in racemic form. Although metabolic chiral inversion occurs through the conversion of R(-)-ibuprofen to S(+)-ibuprofen and the latter enantiomer is considered the active form, clinical trials involving the administration of a racemate to S-enantiomer dosage ratio of 1:0.5 have demonstrated that S(+)-ibuprofen is as efficacious as the racemic formulation. Moreover, the R(-)-enantiomer has been implicated in adverse gastrointestinal effects found with the racemic form, but the mechanisms involved in this process are not yet fully understood. The aim of the present study was to evaluate the anti-inflammatory activity of a racemate to S(+)-ibuprofen dosage ratio of 1:0.5 using the carrageenan air pouch model of inflammation and determine both ulcerogenic activity and the chiral conversion rate in rats. An in vitro study of the cytotoxicity of racemate and S(+)-ibuprofen in gastric cells was also performed. Although the plasma level of S(+)-ibuprofen was raised after racemate administration, no significant difference was found in anti-inflammatory activity, as assessed by exudate formation, PGE2 production and leukocyte migration to the air pouches. Fewer gastric lesions were found after S(+)-ibuprofen administration, despite the low gastric PGE2 content. In the in vitro study, the racemic compound proved more cytotoxic than S(+)-ibuprofen. The present findings suggest that the S-enantiomer of ibuprofen could be considered a therapeutic alternative to minimize gastrointestinal side effects, since the chiral inversion of R(-)-ibuprofen to S(+)-ibuprofen did not result in an improved anti-inflammatory response.

O Ibuprofeno é normalmente comercializado na forma racêmica. Embora ocorra inversão quiral convertendo a forma R(-)- em S(+)-ibuprofeno e, a última seja considerada a forma ativa, a administração da proporção 1:0,5 (racemato: S-enantiômero) demonstrou que o S(+)-ibuprofeno é mais eficaz que a formulação racêmica. Adicionalmente, o R(-)-enantiômero está envolvido nos efeitos adversos gastrintestinais descritos para a formulação racêmica, embora os mecanismos não sejam complemente compreendidos. O objetivo deste estudo foi avaliar a atividade antiinflamatória da proporção 1:0,5 (racemato:S-ibuprofeno) utilizando o modelo experimental de bolsa de ar, a atividade ulcerogênica e a taxa de conversão quiral em ratos. Também estudamos in vitro, a citotoxicidade provocada pelo racemato e S(+)-ibuprofeno em células gástricas. Embora os níveis plasmáticos de S(+)-ibuprofeno tenham aumentado após a administração do racemato, a atividade antiinflamatória avaliada pela formação de exsudato, produção de PGE2 e migração de leucócitos para a bolsa de ar não foram diferentes. As lesões gástricas foram reduzidas após a administração de S(+)-ibuprofeno, apesar da inibição de PGE2 gástrica. In vitro, o composto racêmico foi mais citotóxico que o S(+)-ibuprofeno. Nossos resultados sugerem que o S-enantiômero do ibuprofeno pode ser considerado uma alternativa terapêutica visando a redução dos efeitos colaterais gastrintestinais, visto que a inversão quiral do R(-)- para o S(+)-ibuprofeno não resultou em melhora do efeito antiinflamatório observado.