We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.

Markedly increased ferritin levels in a clinically septic patient with an underlying rheumatic disease indicates a hemophagocytotic syndrome. High dosage steroid should be started before there is biopsy confirmation of the disease.