When symptoms don’t
add up, consider NPC
Luiz Felipe,
2 years old, living with infantile-onset NPC, and his dad, Tiago.
Niemann-Pick disease, type C (NPC), is a rare, progressive autosomal-recessive, neurodegenerative disorder caused by impaired cholesterol trafficking that leads to neurological decline and premature mortality.1-3
NPC: definition and mechanism
When neurological or developmental manifestations in young children seem unexplained or progressive, NPC should be considered. NPC is a rare, progressive, autosomal-recessive, neurodegenerative disorder and is estimated to affect 1 in 89,000 births in the United States, though it is likely underdiagnosed.1-4
In healthy individuals, functional NPC proteins enable cholesterol trafficking out of the LYSOSOME3
25% OF THE BODY’S CHOLESTEROL IS IN THE BRAIN5,6
Central nervous system levels are ~10x other areas
TIGHTLY REGULATED HOMEOSTATIC PROCESSES HOLD CHOLESTEROL LEVELS CONSTANT5,7
Including synthesis, intra- and intercellular trafficking, and excretion
Dysfunctional NPC proteins impair cholesterol
trafficking, leading to neurodegeneration1,3
HEALTHY FUNCTION
NPC1 and NPC2 are essential proteins for trafficking cholesterol out of the lysosome8,9
Cholesterol is distributed throughout the cell, enabling critical neuronal functions7,10
NPC
Cholesterol accumulates in the lysosome due to dysfunctional NPC proteins8,11
Impaired lysosomal function and insufficient cholesterol for normal cellular processes cause neuronal injury and cell death11-13
Even when the condition appears to be outwardly stable, cholesterol continues to accumulate, and irreversible neuronal loss continues to occur.3
Signs and symptoms of infantile-onset NPC1-3
When neurological symptoms begin before age 6, the condition is referred to as infantile-onset NPC. Infantile-onset NPC is the most aggressive form of the disease, with earlier neurological symptom onset predicting more rapid disease progression and earlier death. Manifestations of infantile-onset NPC can vary, but some carry greater diagnostic weight than others.
Determine whether NPC should be considered
Use this tool to evaluate clinical patterns and help determine whether infantile-onset NPC should be considered in your differential diagnosis.
This tool is intended to support clinical awareness and is not intended for diagnosis. It should be used for children with neurological symptoms beginning before 6 years of age.
Which neurological findings have you observed?
Select all neurological findings currently present or previously observed in your patient.1
Which current or historical visceral findings have you observed?
Select all current or historical visceral findings observed in your patient.1,2
Is there a known family history of NPC IN A BIOLOGICAL RELATIVE?
Select the option that best describes your patient's family history.
RESULTS
Genetic testing for NPC MAY BE APPROPRIATE
Based on the signs and symptoms selected, it may be appropriate to order genetic testing for NPC.
NEXT STEPS
Order genetic testing at no cost
Beren will provide patients meeting certain eligibility criteria with sponsored whole genome sequencing and familial variant testing.
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
*Isolated, or with neurological manifestations.
†Pulmonary infiltrates or respiratory failure in infancy.
This tool is intended to support clinical awareness and is not intended for diagnosis. It should be used for children with neurological symptoms beginning before 6 years of age.
Order genetic testing at no cost
Beren will provide patients meeting certain eligibility criteria with sponsored whole genome sequencing and familial variant testing.
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
RESULTS
Additional clinical evaluation may be needed.
Based on the information provided, additional assessment is needed to determine the level of suspicion for NPC. Consider referral to an NPC-experienced center for further evaluation.
NEXT STEPS
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
*Isolated, or with neurological manifestations.
†Pulmonary infiltrates or respiratory failure in infancy.
This tool is intended to support clinical awareness and is not intended for diagnosis.
It should be used for children with neurological symptoms beginning before 6 years of age.
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
RESULTS
Genetic testing for NPC MAY BE APPROPRIATE
Based on the signs and symptoms selected, it may be appropriate to order genetic testing for NPC.
NEXT STEPS
Order genetic testing at no cost
Beren will provide patients meeting certain eligibility criteria with sponsored whole genome sequencing and familial variant testing.
Access genetic testing
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
Find a specialist
*Isolated, or with neurological manifestations.
†Pulmonary infiltrates or respiratory failure in infancy.
This tool is intended to support clinical awareness and is not intended for diagnosis.
It should be used for child ren with neurological symptoms beginning before 6 years of age.
©2026 Beren Therapeutics P.B.C. All rights reserved. Beren and Mandos are trademarks of Beren Therapeutics P.B.C. DSA-1384-US-EN-v1 07/2026
RESULTS
Additional clinical evaluation may be needed.
Based on the information provided, additional assessment is needed to determine the level of suspicion for NPC. Consider referral to an NPC-experienced center for further evaluation.
NEXT STEPS
Refer to an NPC-experienced center
Referral to NPC-experienced centers supports diagnosis, ongoing management, and multidisciplinary care coordination.
Find a specialist
*Isolated, or with neurological manifestations.
†Pulmonary infiltrates or respiratory failure in infancy.
This tool is intended to support clinical awareness and is not intended for diagnosis.
It should be used for child ren with neurological symptoms beginning before 6 years of age.
©2026 Beren Therapeutics P.B.C. All rights reserved. Beren and Mandos are trademarks of Beren Therapeutics P.B.C. DSA-1384-US-EN-v1 07/2026
DON’T RISK MISSING NPC
The signs and symptoms of NPC are nonspecific and overlap with a range of other conditions, including1,14,15:
- Neurodevelopmental/neurodegenerative/neuromuscular disorders
- Inherited metabolic/lysosomal disorders
- Liver disorders
- Infectious diseases
- Hematologic/oncologic disorders
- Psychiatric disorders
Given the irreversible nature of disease progression, early consideration is critical even when only a subset of features is present.3
ORDER GENETIC TESTING AT NO COST
Beren will provide patients meeting certain eligibility criteria with sponsored whole genome sequencing and familial variant testing.
References: 1. Hiwot T, Porter FD, Bremova-Ertl T, et al. 2025 Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C. J Inherit Metab Dis. 2026;49(3):e70185. doi:10.1002/jimd.70185 2. Pineda M, Mengel E, Jahnová H, et al. A suspicion index to aid screening of early-onset Niemann-Pick disease type C (NP-C). BMC Pediatr. 2016;16:107. doi:10.1186/s12887-016-0641-7 3. Berry-Kravis E. Niemann-Pick disease, type C: diagnosis, management and disease-targeted therapies in development. Semin Pediatr Neurol. 2021;37:100879. doi:10.1016/j.spen.2021.100879 4. Burton BK, Ellis AG, Orr B, et al. Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States. Mol Genet Metab. 2021;134(1-2):182-187. doi:10.1016/j.ymgme.2021.06.011 5. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12(2):105-112. doi:10.1097/00041433-200104000-00003 6. Vance JE. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech. 2012;5(6):746-755. doi:10.1242/dmm.010124 7. Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem. 2009;390(4):287-293. doi:10.1515/BC.2009.035 8. Pfeffer SR. NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes. J Biol Chem. 2019;294(5):1706-1709. doi:10.1074/jbc.TM118.004165 9. Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci U S A. 2008;105(40):15287-15292. doi:10.1073/pnas.0807328105 10. Li D, Zhang J, Liu Q. Brain cell type-specific cholesterol metabolism and implications for learning and memory. Trends Neurosci. 2022;45(5):401-414. doi:10.1016/j.tins.2022.01.002 11. Lee D, Hong JH. Niemann-Pick Disease type C (NPDC) by mutation of NPC1 and NPC2: aberrant lysosomal cholesterol trafficking and oxidative stress. Antioxidants (Basel). 2023;12(12):2021. doi:10.3390/antiox12122021 12. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16. doi:10.1186/1750-1172-5-16 13. Karten B, Vance DE, Campenot RB, Vance JE. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J Neurochem. 2002;83(5):1154-1163. doi:10.1046/j.1471-4159.2002.01220.x 14. Bremova-Ertl T, Patterson M. Niemann-Pick disease type C. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews® [Internet]. Updated November 20, 2025. Accessed August 10, 2026. https://www.ncbi.nlm.nih.gov/books/NBK1296/ 15. Geberhiwot T, Moro A, Dardis A, et al. Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C. Orphanet J Rare Dis. 2018;13(1):50. doi:10.1186/s13023-018-0785-7
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