Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use - Is There an Acquired Form?

OBJECTIVE: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease-causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non-genetic causes. METHODS: We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed. RESULTS: We identified 9 patients diagnosed with late-onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. INTERPRETATION: Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024.

Skeletal muscle immunohistochemistry of acquired and hereditary myopathies.

PURPOSE OF REVIEW: The continued development in the field of immunohistochemistry (IHC) has improved the ability to diagnose muscle diseases. Many hereditary diseases are diagnosed by the absence or abnormal localization of proteins. Detection of secondary pathological protein expression is also used in diagnostics, and to study disease processes. We relate and discuss recent reports, where IHC has been an important tool in the investigation of muscle diseases. RECENT FINDINGS: In idiopathic inflammatory myopathies, IHC has extended its role to diagnose subgroups. This is most evident concerning immune-mediated necrotizing myopathy and antisynthetase syndrome. The availability of new antibodies has increased the sensitivity of a muscle biopsy to diagnose several hereditary myopathies. The introduction of protein restoration therapies in muscular dystrophies also comes with the need to detect and measure protein levels. For the study of disease processes at the protein level, in both acquired and hereditary myopathies IHC, often combined with gene studies, PCR-based methods, western blotting and electron microscopy, continues to bring forth interesting results. SUMMARY: IHC is an integrated tool in muscle pathology, where recent studies contribute to improved diagnostic skills and increased insights into disease processes.

Apoptosis in idiopathic inflammatory myopathies with partial invasion; a role for CD8+ cytotoxic T cells?

Polymyositis and inclusion body myositis are idiopathic inflammatory myopathies, with a pathology characterized by partial invasion of non-necrotic muscle fibres by CD8+ cytotoxic T-cells, leading to fibre degeneration. Although the main effector pathway of CD8+ T-cells is to induce apoptosis of target cells, it has remained unclear if apoptosis occurs in these diseases, and if so, if it is mediated by CD8+ T-cells. In consecutive biopsy sections from 10 patients with partial invasion, muscle fibres and inflammatory cells were assessed by immunohistochemistry and apoptotic nuclei by the TUNEL assay. Analysis of muscle fibre morphology, staining pattern and quantification were performed on digital images, and they were compared with biopsies from 10 dermatomyositis patients and 10 controls without muscle disease. Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8+ T-cells, granzyme B+ cells and macrophages, but lacked FAS receptor expression. In contrast, apoptotic myonuclei were rare in dermatomyositis and absent in controls. The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8+ cytotoxic T- cells, acting in parallel to the process of partial invasion.

Luminescent conjugated oligothiophenes for sensitive fluorescent assignment of protein inclusion bodies.

Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.

The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice.

Methylmercury (MeHg) is a common environmental pollutant due to both natural and anthropogenic sources. Although the central nervous system (CNS) is considered the critical organ for the toxic effect of MeHg, it has recently been suggested that the immune system might be at least as sensitive as the CNS. We have examined the effects of MeHg on the immune system in genetically metal-susceptible mice. Subcutaneous (sc) injections of 2 mg MeHg/kg body weight (bw) every third day (internal dose ca. 540 microg Hg/kg bw/day) to A.SW mice of the H-2(s) haplotype, caused during the first week a 47 and 9% reduction of B- and T-cells, respectively, which indicates immunosuppression. Subsequently, an autoimmune syndrome developed which shared certain features with the syndrome induced by inorganic mercury in H-2(s) mice, including antibodies targeting the 34 kDa nucleolar protein fibrillarin, increased expression of IL-4 mRNA, increase of Th2-type of immunoglobulins (IgE and IgG1), and increased MHC class II expression on B-cells. However, the response using MeHg was attenuated compared with even lower doses of Hg in the form of inorganic mercury, and specifically lacked the increased expression of IL-2 and IFN-gamma mRNA, the polyclonal B-cell activation (PBA), and the systemic immune-complex (IC) deposits which are induced by inorganic mercury. Increasing the dose of MeHg increased the titre of anti-nucleolar antibodies and shortened the induction time, but did not lead to stronger immunostimulation or systemic IC-deposits. The kidney and liver selectively accumulated MeHg, while the blood, spleen and lymph nodes showed lower levels of MeHg. The accumulation of MeHg and Hg(2+) increased throughout the 30-day period. The fraction of Hg(2+) in the kidney varied between 4 and 22%, and the lymph nodes showed a maximum of 30% Hg(2+). We conclude first that MeHg has quantitatively different effect on the immune system compared with inorganic mercury, and secondly that an initial immunosuppression induced by a xenobiotic does not preclude subsequent immunostimulation and autoimmunity.

Medin and medin-amyloid in ageing inflamed and non-inflamed temporal arteries.

Small amyloid deposits commonly occur along the internal elastic lamina of the temporal artery. In temporal artery biopsies from 22 patients with histological signs of giant cell arteritis and 25 without, amyloid deposits were found in 14 and 21 biopsies, respectively. Two specific peptide antisera show that this amyloid is identical to the recently identified medin-amyloid in the ageing aorta. On immunoelectron microscopy, the amyloid appeared topographically closely related to the elastic material. Furthermore, fragmented elastic material was often immunolabelled for medin and found to be engulfed by giant cells. Medin is an internal fragment of the larger precursor lactadherin and is presumably formed by specific enzymatic cleavage events. In situ hybridization showed that lactadherin is expressed locally by smooth muscle cells of the temporal artery. Given the potential role of lactadherin as a mediator for the adhesion of cells, including macrophages, to other cells or surfaces, lactadherin or its fragment medin may be important in the inflammatory process in giant cell arteritis.