RYR1-related malignant hyperthermia with marked cerebellar involvement - a paradigm of heat-induced CNS injury?

Heat-induced CNS injury has been recognized for more than 50 years but the biological basis for the marked selectivity of CNS damage is currently uncertain. We present clinical, imaging, autopsy and genetic findings of a 14-year-old male who developed fatal cerebellar swelling in the course of a malignant hyperthermia (MH) episode caused by triggering anaesthetics. Unaccustomed intense exercise in the days prior to general anaesthesia was a probable confounding factor for the MH reaction. Autopsy findings demonstrated pronounced degeneration of cerebellar Purkinje cells. Post mortem genetic analysis revealed a mutation (c.6502G>A; p.Val2168Met) in the skeletal muscle ryanodine receptor (RYR1) gene previously associated with the MH trait. RYR1 mutations appear to be associated with heat-induced CNS injury in a distribution compatible with known expression pattern of the RyR1 isoform in cerebellar Purkinje cells. Recent exercise in genetically predisposed individuals may prime abnormal muscle prior to general anaesthesia and contribute to the severity of MH reactions.

Infantile onset myofibrillar myopathy due to recessive CRYAB mutations.

Mutations in the αB-crystallin (CRYAB) gene, encoding a small heat shock protein with chaperone function, are a rare cause of myofibrillar myopathy with autosomal-dominant inheritance, late-onset and moderate severity. We report a female infant presenting from 4 months with profound muscle stiffness, persistent creatine kinase elevation and electromyography characterized by spontaneous electrical activity and pseudomyotonic discharges. Muscle biopsy suggested a myofibrillar myopathy and genetic testing revealed homozygosity for the CRYAB mutation c.343delT (p.Ser115ProfsX14). These findings suggest a severe, recessively inherited form of CRYAB-related myofibrillar myopathy. Profound muscle stiffness as the main presenting feature indicates αB-crystallin as a potent modifier of muscle contractility.

Benefit of corticosteroid therapy in Angelman syndrome.

Angelman syndrome is often associated with an intractable seizure disorder. We describe 4 children who demonstrated an excellent response to corticosteroid therapy. The benefits included not only reduction in clinical seizures but also modification of the "typical'' Angelman electroencephalogram. In addition, there was improvement in the myoclonic jerks, sleep pattern, and developmental progress. Corticosteroids appeared to have a broad benefit on the epileptic encephalopathy. We believe that these cases pose a challenge to the conventional management of intractable epilepsy in Angelman syndrome.

High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial.

This is the first study to evaluate the efficacy of riboflavin for migraine prophylaxis in children. This was a randomized, double-blind study of riboflavin (200 mg daily) versus placebo in 48 children. The primary efficacy measure was the number of patients achieving a 50% or greater reduction in the number of migraine attacks per 4 weeks. Other outcome measures were the mean severity of migraine per day, mean duration of migraine, days with nausea or vomiting, analgesic use, and adverse effects. A 50% or greater reduction in headaches was seen in 14/21 patients in the placebo group and 12/27 patients in the riboflavin group (not significant P = .125). There were no differences between riboflavin and placebo for primary or secondary outcome variables. These results suggest that riboflavin is not an effective therapy for preventing migraine in children. A high placebo responder rate was seen, with implications for other studies of migraine in children.