MHS1

External Ophthalmoplegia, Facial Weakness, and Malignant Hyperthermia

Clinical Characteristics
Ocular Features: 

A subset of patients with malignant hyperthermia susceptibility (MHS) secondary to mutations in RYR1 has congenital ophthalmoplegia and ptosis.   Magnetic resonance imaging may reveal hypoplasia of extraocular muscles and intraorbital cranial nerves.

Systemic Features: 

The weakness in extraocular and levator muscles is sometimes associated with more generalized myopathy of a variable degree.  The myopathy may be progressive and individuals with extensive skeletal muscle weakness may have respiratory insufficiency and scoliosis. The clinical spectrum is broad and there is no consistent pattern in the degree of skeletal muscle weakness associated with ocular muscle involvement.  This may be explained in part by the variety of myopathies found among patients with mutations in RYR1 such as:  central core disease, multiminicore disease, congenital fiber type disproportion, centronuclear myopathy, and nemaline myopathy.

Malignant hyperthermia due to mutations in RYR1 is most commonly inherited as an autosomal dominant trait precipitated by exposure to certain volatile anesthetic agents such as halothane, isoflurane, and enflurane used in association with succinylcholine during general anesthesia.  Patients may experience acidosis, muscle rigidity, rhabdomyolysis and tachycardia with arrhythmias.  Myoglobinuria may lead to renal failure.

Exercise-induced heat stress rarely precipitates malignant hyperthermia.

Genetics

Ptosis, ophthalmoplegia, and susceptibility to malignant hyperthermia can occur as separate heritable conditions and it is uncommon for them to coexist as in the MHS1 syndrome described here.  Due to the heterogeneous signs of muscle disease reported among and between families, it is likely that MHS1 consists of more than one disorder.  Mutations in RYR1 are commonly associated with susceptibility to malignant hyperthermia while the co-occurrence of skeletal muscle disease is inconsistent and involvement of extraocular muscles is even rarer.

There is good evidence that at least 6 types of MHS exist.  A large number of responsible mutations in 2 genes, RYR1 (19q13.2) and CACNA1S (1q32.1), have been identified and there is good evidence that at least 4 additional loci exist.  Mutations in RYR1 are responsible for MHS1 and account for approximately 70% of susceptible individuals.  Families with both autosomal dominant and autosomal recessive inheritance patterns have been reported.  

It is not understood why some families with MHS1 have ocular and skeletal muscle abnormalities while others do not.  External ophthalmoplegia is most often secondary to mutations in mitochondrial DNA but the importance of presurgical recognition of the risk of malignant hyperthermia suggests that pre-surgery gene screening for RYR1 in such patients is warranted.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

The best treatment is prevention by using alternate anesthetic agents if the risk is recognized preoperatively.  Temperature should be monitored in all patients undergoing general anesthesia since prompt recognition of hyperthermia is essential.  Inhalation agents and succinylcholine must be discontinued and dantrolene sodium should be given promptly.  Metabolic abnormalities must be corrected and both external and internal body cooling should be initiated immediately.  Intravascular coagulation is an additional risk and coagulation profiles should be obtained.

A positive family history of MHS requires pre-anesthesia gene testing but failure to detect a mutation in known genes does not rule out susceptibility.

Ptosis surgery may be helpful in selected patients.

References
Article Title: 

Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization

Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerriere A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol. 2011 Apr;37(3):271-84.

PubMed ID: 
21062345
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