Identifying Niemann-Pick type C in early-onset ataxia: two quick clinical screening tools.
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.
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.
Matthis
M
Synofzik
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Zofia
Z
Fleszar
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Ludger
L
Schöls
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Jennifer
J
Just
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Peter
P
Bauer
Syntax for Science SL, Basel, Switzerland.
Juan V
JV
Torres Martin
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Stefan
S
Kolb
D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000150:complications*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D052556:Niemann-Pick Disease, Type C / Q000150:complications* / Q000175:diagnosis*; D012372:ROC Curve; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D055815:Young Adult
Diagnosis; Early onset ataxia; Niemann–Pick disease type C; Suspicion index