Identifying Niemann–Pick type C in early-onset ataxia: two quick clinical screening tools

• DOI: 10.1007/s00415-016-8178-0
• Publication Date: 2016-06-17T02:08:18Z
• Authors: Matthis Synofzik; Zofia Fleszar; Ludger Schöls; Jennifer Just; Peter Bauer; Juan V. Torres Ma...; Stefan Kolb
• Keywords: Adult; Male; Adolescent; diagnosis [Niemann-Pick Disease, Type C]; Clinical Neurology; Statistics, Nonparametric; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Humans; Mass Screening; methods [Mass Screening]; ddc:610; Child; complications [Niemann-Pick Disease, Type C]; Retrospective Studies; Original Communication; Niemann-Pick Disease, Type C; Middle Aged; 3. Good health; Neurology; ROC Curve; Child, Preschool; Ataxia; Female; complications [Ataxia]

Niemann-Pick disease type C (NP-C) is a rare multisystemic lysosomal disorder which, albeit treatable, is still starkly underdiagnosed. As NP-C features early onset ataxia (EOA) in 85-90 % of cases, EOA presents a promising target group for undiagnosed NP-C patients. Here, we assessed the ability of the previously established NP-C suspicion index (SI) and a novel abbreviated '2/3 SI' tool for rapid appraisal of suspected NP-C in unexplained EOA. This was a retrospective observational study comparing 'NP-C EOA' cases (EOA patients with confirmed NP-C) with non-NP-C EOA controls (EOA patients negative for NP-C gene mutations). NP-C risk prediction scores (RPS) from both the original and 2/3 SIs were calculated and their discriminatory performance evaluated. Among 133 patients (47 NP-C EOA cases; 86 non-NP-C EOA controls), moderate (40-69 points) and high (≥70 points) RPS were common based on original SI assessments in non-NP-C EOA controls [16 (19 %) and 8 (9 %), respectively], but scores ≥70 points were far more frequent [46 (98 %)] among NP-C EOA cases. RPS cut-off values provided 98 % sensitivity and 91 % specificity for NP-C at 70-point cut-off, and ROC analysis revealed an AUC of 0.982. Using the 2/3 SI, 90 % of NP-C EOA cases had scores of 2 or 3, and RPS analysis showed an AUC of 0.961. In conclusion, the NP-C SI and the new, quick-to-apply 2/3 SI distinguished well between NP-C and non-NP-C patients, even in EOA populations with high background levels of broadly NPC-compatible multisystemic disease features. While the original SI showed the greatest sensitivity, both tools reliably aided identification of patients with unexplained EOA who warranted further investigation for NP-C.