Heterozygosity in NPC may be associated with neurologic and systemic phenotypes

Tatiana Bremova-Ertl^1*Sabina Tahirovic²Silva Katusic Hecimovic³Kyriakos Martakis⁴Marianne Rohrbach⁵Matthias Gautschi⁶Radhika Dhamija⁷Jaya Ganesh⁸Melinda Peters⁹Mark Walterfang¹⁰Susanne A Schneider¹¹

• ¹Department of Neurology, University Hospital Bern, Bern, Switzerland
• ²German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
• ³Institut Ruđer Bošković, Zagreb, Croatia
• ⁴University of Giessen, Giessen, Germany
• ⁵University Children's Hospital Zurich, Zurich, Switzerland
• ⁶University of Bern, Bern, Bern, Switzerland
• ⁷Mayo Clinic, Rochester, Minnesota, United States
• ⁸Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁹Boston Children's Hospital, Boston, United States
• ¹⁰The University of Melbourne, Parkville, Victoria, Australia
• ¹¹University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany

Background: Niemann-Pick disease type C (NPC) is a pan-ethnic, progressive, recessively inherited lysosomal disorder that affects 1:100,000 live births. Emerging biochemical, genetic, and clinical evidence challenges the traditional view that disease-associated variants in the genes associated with the typical phenotype NPC manifest as an exclusively autosomal recessive disorder. While biallelic pathogenic variants cause the NPC disease phenotype, heterozygous carriers may exhibit phenotypic traits attributable to a partial loss of NPC1 or NPC2 function.We conducted a literature search of articles relevant to heterozygosity in NPC genes and genes associated with other lysosomal diseases. A narrative mini-review format was employed with the intention of providing a brief overview of the frequency of NPC carriers, as well as the biochemical, genetic, nonclinical, and clinical evidence available for readers seeking to understand the scientific basis for why NPC heterozygosity should be discussed and considered as a potential risk factor for the development of neurological phenotype or neurodegenerative diseases.Heterozygosity for many genes, including NPC1 variants, ("carriers" of a single variant in an NPC gene) can be clinically consequential. Recognizing the effects of NPC1 heterozygosity has profound implications for diagnosis, clinical monitoring, and potential early intervention. By broadening our understanding of the genetic and phenotypic spectrum of NPC, we can improve detection (which is straightforward in obligate heterozygotes, i.e., parents of NPC patients), reduce long-term health risks, and utilize targeted treatments that address the needs of carriers as well as affected individuals.