We describe the ninth variant of neuronal ceroid lipofuscinosis (NCL) or Batten disease, due to defects in a putative new gene, CLN9. We therefore refer to the new variant as CLN9-deficient. Two Serbian sisters and two German brothers are described. Their clinical history is characteristic for juvenile NCL. They show similar gene expression patterns. The existence of this variant is supported by the presence of curvilinear inclusions, fingerprint profiles, and granular osmiophilic deposits in neurons, lymphocytes, and conjunctival cells. Enzyme screening and sequencing of the coding regions of other NCL genes was negative. CLN9-deficient cells have a distinctive phenotype. They have rounded cell bodies, have prominent nucleoli, attach poorly to the culture dish, and are sensitive to apoptosis but have increased growth rates. Gene expression of proteins involved in cell adhesion and apoptosis is altered in these cells. Sphingolipid metabolism is also perturbed. They have decreased levels of ceramide, sphingomyelin, lactosylceramide, ceramide trihexoside, and globoside and increased activity of serine palmitoyl transferase.
