Another step towards defining the genetic landscape of rhabdomyolysis

This scientific commentary refers to ‘MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline high serum creatine kinase’, by Lopes Abath Neto et al. (doi:10.1093/brain/awab275).

In this issue of Brain, Lopes Abath Neto and co-workers¹ describe the identification of biallelic loss-of-function variants in MLIP, the gene encoding muscular LMNA interacting protein, in a paediatric cohort of patients with myopathy characterized by rhabdomyolysis, myalgia and hyperCKemia. The study includes deep phenotyping via comprehensive clinical examinations of a cohort of seven patients from six unrelated families with MLIP-related myopathy.

Rhabdomyolysis refers to the acute breakdown of myofibres. Affected individuals usually present with systemic symptoms, such as tachycardia, fever and muscle aches. But often the symptoms are mild and the rhabdomyolysis episode is only detected due to unusual colour of urine or high serum creatine kinase (CK) levels. Acute triggers of rhabdomyolysis can include drugs, toxins or strenuous exercise. However, specific genetic defects involving skeletal muscle can predispose an individual to experience episodes of rhabdomyolysis under situations that would not cause them in others.

Most of these genetic defects involve metabolic pathways. The affected muscle works normally during rest and until the type of exercise performed requires activation of the metabolic pathway that is impaired, or there is an increased energy demand due to intercurrent processes. In that situation the muscle is not able to produce enough energy, in the form of ATP. The resulting malfunction of sarcolemma proton pumps leads to activation of Ca²⁺-dependent proteases, triggering the digestion of myofibres. The muscle breakdown releases the contents of myofibres to the circulation. This includes CK, causing the defining rise of serum CK. Potassium and other electrolytes are also released, which can cause arrhythmia and other systemic complications.

After the trigger has disappeared and the individual has recovered, CK levels should return to normal, unless there is ongoing muscle damage.² Chronic muscle conditions, such as some dystrophies associated with sarcolemmal instability (e.g. those caused by mutations in CAV3³ or GMPPB⁴) can predispose patients to acute attacks of rhabdomyolysis. In these individuals, the muscle is not normal to begin with, and the patient commonly displays muscle weakness and higher levels of basal CK, over which the acute systemic symptoms and CK peak superimpose. If the characteristic symptoms of rhabdomyolysis are mild or absent, it is important to differentiate an acute episode of rhabdomyolysis from fluctuations in basal CK levels associated with muscle damage caused by other events, such as an unusual bout of exercise—perhaps gardening or an atypical visit to the gym.

Some molecular defects that affect control of Ca²⁺ release from the sarcoplasmic reticulum can also cause acute episodes of rhabdomyolysis. Episodes may be triggered by exercise⁵ or by certain drugs that cause malignant hyperthermia. This is the case with specific RYR1 and CACNA1S variants, among others. In these cases, basal CK levels are generally within the normal range, although they can fluctuate.⁶ However, patients with congenital myopathies caused by variants in the same genes can also be at increased risk of malignant hyperthermia.⁷

Quite often, no causative molecular defects are identified in patients with rhabdomyolysis, particularly in those with only episodic symptoms. A genetic diagnosis is more frequently obtained in patients who present in childhood compared to those with adult-onset disease. There are probably a number of rhabdomyolysis-associated genes still to be identified, and it is possible that sequencing techniques have not yet uncovered all molecular defects in the known genes. However, it is also likely that many of these individuals do not have any molecular defects, as rhabdomyolysis would occur in any healthy individual in response to certain triggers. It is sometimes difficult to decide when ‘strenuous exercise’ should not have been strenuous enough to cause rhabdomyolysis, meaning that further investigation is warranted.⁸

Lopes Abath Neto and colleagues¹ describe a new gene associated with predisposition to rhabdomyolysis in patients with a subtle, chronic myopathic process. This broadens our understanding of rhabdomyolysis, not just by adding another gene to the list, but by revealing a new disease phenotype. Age of onset in the cohort ranged from 8 months to 7 years. The patients displayed mild and somewhat non-specific symptoms, including myalgia. Muscle strength was normal or only mildly reduced, such that it did not limit the patients’ daily activities and they were even able to play sports. Muscle MRI did not show fat replacement at any level. On muscle biopsy, some patients did show regions of degeneration and regeneration suggestive of a dystrophic pattern. However, muscle biopsies were generally either within normal limits or showed non-specific changes. After recent rhabdomyolysis episodes, muscle biopsy showed changes typical of myofibre necrosis, with all fibres at the same stage of the degeneration process. Basal CK levels, however, were elevated in all patients, demonstrating that there was chronic damage to the muscle from early in life. Since all patients were under the age of 20, it is also possible that symptoms and signs of a muscular dystrophy or other presentation of a chronic muscle condition will develop over time.

The pathomechanism by which MLIP variants cause a chronic muscle disease, and particularly rhabdomyolysis episodes, is unclear. Little is known about the function of MLIP protein, but recent data show that it may act as a transcription factor involved in myotube differentiation.⁹ Individuals with other muscle diseases involving abnormalities in myoblast proliferation and differentiation, such as those caused by TRIM32 variants, develop a muscular dystrophy, which is evident both clinically and pathologically, although no susceptibility to rhabdomyolysis has been reported.¹⁰

As Lopes Abath Neto et al.¹ note, in the patients with MLIP variants, disruption of a GSK3 phosphorylation site within the protein may contribute to rhabdomyolysis in situations of high energy demand. GSK is thought to have a role in glucose homeostasis. Thus, it is tempting to speculate that MLIP-mediated disease may occur via two mechanisms; an arrest in muscle differentiation causing a chronic myopathic process, and disturbances in glucose metabolism resulting from loss of the GSK phosphorylation site, predisposing to rhabdomyolysis.

The study has some limitations, mainly the lack of functional data to support the pathogenicity of the variants as the cause of the disease. The fact that all patients studied had biallelic loss-of-function variants in MLIP, whereas those same variants were rare or absent in control population databases, strongly suggests that the variants are pathogenic. The MLIP gene is predominantly expressed in muscle. However, it also has multiple isoforms and a complex expression pattern, and the significance of this variation is as yet unclear. Furthermore, the authors were unable to demonstrate the absence of the MLIP protein in patients’ muscle, owing to the lack of a reliable antibody. Future functional studies to explore the pathomechanism of MLIP-associated myopathy and rhabdomyolysis are therefore needed.

Funding

G.R. is supported by a Fellowship from the Australian NHMRC (APP1122952).

Competing interests

The authors report no competing interests.

References