Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States.

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an ultra-rare progressive neurodegenerative disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes that lead to premature death, with most individuals dying between 10 and 25 years of age. NPC can present at any age and many individuals with NPC may be misdiagnosed or undiagnosed. A key challenge with recognizing NPC is the heterogeneous and nonspecific clinical presentation. Currently, there are no approved treatments for NPC in the United States; miglustat, an FDA-approved treatment for Gaucher disease, is used off-label for NPC and GM1 gangliosidosis. OBJECTIVES: To estimate the number of people in the United States that 1) have an NPC diagnosis 2) have an NPC diagnosis and/or are treated off-label with miglustat for NPC and 3) are likely to have NPC. METHODS: For the first two objectives, patients were identified using the Symphony Integrated DataVerse database (Oct 2015-Jan 2020). To identify the number of people with NPC for Objective 1, cases of NPC were defined as any patients with an ICD-10 code of E75.242 (NPC) during the study period. Objective 2 expands upon Objective 1, including (a) patients from Objective 1 and (b) patients with documented miglustat use (NDC 43975-0310 or 10,148-0201) who did not have any claim with Gaucher disease (ICD-10 E75.22) or GM1 gangliosidosis (ICD-10 E75.1) during the study period. For the third objective, published NPC incidence (1 per 89,000 live births) and expected mortality estimates were applied to the 2018 United States birth rate (11.6 per 1000) and population size (326.7 million). RESULTS: A total of 308 million unique individuals were represented in the database. Of these, 294 individuals had an NPC diagnosis, yielding an identified NPC prevalence of 0.95 per million people in the United States. 305 individuals were diagnosed with NPC and/or were treated with miglustat without having a diagnosis for either Gaucher or GM1 gangliosidosis, yielding an NPC diagnosed or treated prevalence of 0.99 per million people in the United States. Based on the published literature, there are an estimated 42 new NPC cases per year. Applying this number to the distribution of NPC type (based on age of neurologic symptom onset) and corresponding mortality estimates generates an estimated 943 prevalent cases of NPC, or 2.9 cases of NPC per million people in the United States. CONCLUSIONS: NPC is an ultra-rare, progressive neurodegenerative disease with approximately 1 per million people in the United States diagnosed with or treated off-label for NPC. Given that NPC is often misdiagnosed or undiagnosed, the estimated prevalence from the epidemiology calculations (2.9 per million) approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.

Molecular microdomains in a sensory terminal, the vestibular calyx ending.

Many primary vestibular afferents form large cup-shaped postsynaptic terminals (calyces) that envelope the basolateral surfaces of type I hair cells. The calyceal terminals both respond to glutamate released from ribbon synapses in the type I cells and initiate spikes that propagate to the afferent's central terminals in the brainstem. The combination of synaptic and spike initiation functions in these unique sensory endings distinguishes them from the axonal nodes of central neurons and peripheral nerves, such as the sciatic nerve, which have provided most of our information about nodal specializations. We show that rat vestibular calyces express an unusual mix of voltage-gated Na and K channels and scaffolding, cell adhesion, and extracellular matrix proteins, which may hold the ion channels in place. Protein expression patterns form several microdomains within the calyx membrane: a synaptic domain facing the hair cell, the heminode abutting the first myelinated internode, and one or two intermediate domains. Differences in the expression and localization of proteins between afferent types and zones may contribute to known variations in afferent physiology.

Quantal and nonquantal transmission in calyx-bearing fibers of the turtle posterior crista.

Intracellular recordings were made from nerve fibers in the posterior ampullary nerve near the neuroepithelium. Calyx-bearing afferents were identified by their distinctive efferent-mediated responses. Such fibers receive inputs from both type I and type II hair cells. Type II inputs are made by synapses on the outer face of the calyx ending and on the boutons of dimorphic fibers. Quantal activity, consisting of brief mEPSPs, is reduced by lowering the external concentration of Ca2+ and blocked by the AMPA-receptor antagonist CNQX. Poisson statistics govern the timing of mEPSPs, which occur at high rates (250-2,500/s) in the absence of mechanical stimulation. Excitation produced by canal-duct indentation can increase mEPSP rates to nearly 5,000/s. As the rate increases, mEPSPs can change from a monophasic depolarization to a biphasic depolarizing-hyperpolarizing sequence, both of whose components are blocked by CNQX. Blockers of voltage-gated currents affect mEPSP size, which is decreased by TTX and is increased by linopirdine. mEPSP size decreases severalfold after impalement. The size decrease, although it may be triggered by the depolarization occurring during impalement, persists even at hyperpolarized membrane potentials. Nonquantal transmission is indicated by shot-noise calculations and by the presence of voltage modulations after quantal activity is abolished pharmacologically. An ultrastructural study shows that inner-face inputs from type I hair cells outnumber outer-face inputs from type II hair cells by an almost 6:1 ratio.