Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfall in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292 K.

This study describes a diagnostic pitfall in the laboratory diagnosis of patients with sphingomyelinase deficiency (SMD; Niemann-Pick disease types A and B; NPA and NPB), in cases where sphingomyelinase activity was not determined with sphingomyelin as the natural enzymic substrate. Four of 24 SMD patients studied had falsely normal or enhanced activity, when a so-called artificial sphingomyelinase substrate, 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine (HNP), was used, whereas SMD was clear with the sphingomyelin substrate. Those four patients had the Q292 K mutation of the acid sphingomyelinase gene (SMPD1) on at least one allele. Three of the four patients (no data available from one) experienced only late-infantile or juvenile, though distinct, neurological involvement, where learning disabilities, hypo- or areflexia or mild ataxia were initial signs. The laboratory pitfall with HNP substrate, which is used in many laboratories, raises the risk that some SMD patients are overlooked, and it prevents the consideration of a late-manifesting neurological course in some patients as well as the planning of enzyme substitution therapy in non-neurological SMD (NPB) patients. Since classical NPB is very rare, it is suggested that SMD patients with late- or mild-manifesting neurological symptoms should better be assigned to additional SMD subgroups than grouped with NPB.