Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function.

PURPOSE: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures. METHODS: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded. RESULTS: A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive. CONCLUSIONS: Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations.

OBJECTIVE: To describe seizure phenotypes associated with the hyperinsulinism/hyperammonemia syndrome (HI/HA), which is caused by gain of function mutations in the enzyme glutamate dehydrogenase (GDH). STUDY DESIGN: A retrospective review of records of 14 patients with HI/HA. RESULTS: Nine patients had seizures as the first symptom of HI/HA, and six had seizures in the absence of hypoglycemia. No electroencephalogram (EEG) background abnormalities were identified. In four patients, EEG recordings during seizures in the setting of normal blood glucose contained generalized epileptiform discharges. EEGs of three of these patients showed 0.5- to 2-second generalized irregular spike-and-wave discharge at 3 to 6 Hz corresponding to eye blinks, eye rolling, or staring. The EEG of the fourth patient consisted of 20 seconds of generalized regular spike-and-wave discharge at 3 Hz in the clinical context of staring and unresponsiveness. In two patients, seizure control worsened with carbamezapine or oxcarbezapine treatment. CONCLUSIONS: In patients with HI/HA, generalized seizures are common and can occur in the absence of hypoglycemia. The drugs carbamazepine and oxcarbazepine should be used with caution for treatment. Pathogenesis of epilepsy in these patients may be related to effects of GDH mutations in the brain, perhaps in combination with effects of recurrent hypoglycemia and chronic hyperammonemia.