The etiology of rhabdomyolysis: an interaction between genetic susceptibility and external triggers.

BACKGROUND AND PURPOSE: Rhabdomyolysis is a medical emergency characterized by acute skeletal muscle breakdown with a sudden rise and subsequent fall of serum creatine kinase (CK) levels. Rhabdomyolysis events are provoked by exposure to external triggers, possibly in combination with an increased genetic susceptibility. We aimed to describe comprehensively the external triggers and potentially pathogenic genetic variants possibly implicated in increased rhabdomyolysis susceptibility. METHODS: We performed a retrospective single-center study, including a total of 1302 patients with an acute CK level exceeding 2000 IU/l. RESULTS: Anoxia was the most frequently reported trigger (40%). A subset of 193 patients were clinically suspected of an underlying genetic disorder (recurrent episodes, a positive family history, very high or persistently increased CK levels). In 72 of these patients, an unequivocal genetic defect was identified. A total of 22 genes with pathogenic variants were identified, including 52 different variants. Of those, 11 genes have been previously associated with rhabdomyolysis (ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, RYR1). Eleven genes are probably implicated in increased susceptibility (including AGL, CAPN3, CNBP, DMPK, MAGT1, ACADM, SCN4A, SGCA, SGCG, SMPD1, TANGO2). CONCLUSION: These findings suggest that the spectrum of genetic susceptibility for rhabdomyolysis has not yet been completely clarified. With the increasing availability of next-generation sequencing in a diagnostic setting, we expect that in more cases a genetic defect will be identified.

HyperCKemia and rhabdomyolysis in the neuroleptic malignant and serotonin syndromes: A literature review.

Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with other syndromes that have a clear genetic background, in particular RYR1-related malignant hyperthermia. Through a literature review, performed according to the PRISMA guidelines, we aimed to report the clinical features of both syndromes, and the results of genetic testing performed. 10 case series and 99 case reports were included, comprising 134 patients. A male predominance of 58% was found. The median age was 35 (range 4-84) years. Eight patients experienced recurrent episodes of rhabdomyolysis. Genetic analysis was performed in eleven patients (8%), revealing four RYR1 variants, three likely benign (p.Asp849Asn, p.Arg4645Gln, p.Arg4645Gln) and one variant of uncertain significance (p.Ala612Thr). This review underlines that a subset of patients with neuroleptic malignant syndrome and serotonin syndrome develop recurrent episodes of rhabdomyolysis. This recurrent pattern suggests a possible underlying (genetic) susceptibility. However, the genetic background of neuroleptic malignant syndrome and serotonin syndrome has only been investigated to a very limited degree so far. The increasing availability of next generation sequencing offers an opportunity to identify potentially associated genetic backgrounds, especially in patients with recurrent episodes or a positive family history.

The prolactin response to sulpiride in major depression: the role of the D2 receptor in depression.

Multiple lines of investigations have implicated the role of the dopaminergic system in depression. The aim of the study was to characterise the Dopamine D2 receptor sensitivity status in depressed patients versus controls by means of a novel neuro-endocrine challenge test, the prolactin response to sulpiride. In this intervention, ten patients and ten age matched male volunteers were studied. The patients were diagnosed according to DSM-IV criteria, and Montgomery Asberg and Zung scales were done. There was no significant difference in baseline levels of prolactin between the depressed and control groups. Significantly higher prolactin levels after sulpiride challenge were however found in depressed patients than controls at all time points after sulpiride administration. This neuroendocrine challenge paradigm suggests that the prolactin response to sulpiride, a D2 receptor antagonist, is enhanced in depression, which suggests that this receptor might be supersensitive in depression compared to controls. This adds to the data implicating the dopaminergic system in the pathophysiology of depression, and suggests that dopaminergic mechanisms might be a target of therapeutic interest.

Clozapine associated neutropenia and cytomegalovirus colitis.

Both diarrhea and colitis associated with clozapine have been reported. We present a case of clozapine-associated neutropenia complicated by cytomegalovirus colitis. The definitive diagnosis was suggested on biopsy which showed eosinophilic intranuclear inclusions suggestive of cytomegalovirus infection, and confirmed on immunohistochemistry. Neutropenia or agranulocytosis in association with clozapine treatment may be complicated by colitis. In such cases, investigations for cytomegalovirus may be indicated.