Drug-induced hyperthermia with rhabdomyolysis in CLN3 disease.

CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by blindness, epilepsy, dementia, psychiatric manifestations, and motor deterioration. Problems related to behavior, emotions and thought are among the main features. Antidepressant and antipsychotic drugs have been employed with variable results. Neuroleptic malignant syndrome (NMS) has previously been described in two patients with NCL, one with CLN3 disease and one with adult onset NCL of unclear genetic origin. Our aims were to describe the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 disease from West and South Sweden and to delineate the range of associated clinical features. Our study identified four patients presenting with seven episodes of severe drug-induced hyperthermia and either NMS-like or Serotonin syndrome (SS)-like features. Possibly provoking drugs were risperidone, clozapine, olanzapine, haloperidol, quetiapine, and sertraline. The course was atypical, frequently prolonged, associated with rhabdomyolysis and status dystonicus, and resulted in the death of three of the patients. Our study points to a vulnerability to drug-induced hyperthermia in patients with CLN3 disease which we believe could be underreported. Interestingly the proposed pathophysiological mechanisms behind NMS and SS on one hand and CLN3 on the other hand seem to converge in a common mechanism involving dysregulation of the sympathetic nervous system.

Polymorphisms of the TNF-alpha and ACE genes, and renal scarring in infants with urinary tract infection.

PURPOSE: Susceptibility to renal scarring is increasingly investigated through polymorphisms of genes regulating inflammation and fibrosis. TNF-alpha and ACE gene polymorphisms have been studied in chronic renal conditions but their role in urinary tract infection and vesicoureteral reflux associated renal scarring is unclear. We investigated the relationship between TNF-alpha A/G and ACE I/D polymorphisms, and renal scarring after urinary tract infection in infants. MATERIALS AND METHODS: ACE I/D and TNF-alpha -308 A/G polymorphisms were investigated with restriction fragment length polymorphism analysis in 39 boys and 25 girls with a first urinary tract infection before age 2 years and in 77 controls. Genotype and allele frequencies were compared among children with urinary tract infection with and without renal scarring, and controls. RESULTS: ACE I/D genotype frequencies were similar among infants with urinary tract infection with and without renal scarring, and controls. However, all 6 children with severe renal scarring and impaired renal function bore a D allele, 5 of which were DD homozygotes. D allele was more common in these severely affected children than in their peers with urinary tract infection and mild or no renal scarring (OR 9.92, 95% CI 1.24-79, p = 0.012), and controls (OR 8.03, 95% CI 1.01-64, p = 0.029). No differences were observed in TNF-alpha A/G genotype frequencies among the 3 groups. Presence of vesicoureteral reflux was not related to phenotypes or allele frequencies. CONCLUSIONS: Our findings suggest that D allele polymorphism of the ACE gene is associated with urinary tract infection related severe renal scarring in young children.