Niemann-Pick Disease, Type B

Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients.

This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan-Meier survival analyses from birth until death.

The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD "non-type A" (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications.

Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Chronic visceral hypersensitivity is closely associated with irritable bowel syndrome (IBS), a very common disorder which significantly impairs quality of life, characterized by abdominal pain, and distension. Imaging studies have found that IBS patients show higher metabolic activities and functional differences from normal controls in the anterior cingulate cortex (ACC), in response to visceral pain stimulation. Non-clinical data and clinical data suggest that medicinal products containing essential oils such as peppermint or caraway oil exert beneficial effects on IBS symptoms.

We assessed acute and long-term treatment effects of a mixture of peppermint and caraway essential oils (Menthacarin) on brain electrophysiological markers of gut pain sensitivity in two rat models of visceral hypersensitivity.

Chronic administration of corticosteroids and acute repeated mechanical hyperstimulation under anesthesia induced hyperalgesia and hypersensitivity, characterized by an increase in electrophysiological excitatory responses of ACC neurons to colorectal distension (CRD) and an increase in the proportion of neurons responding to otherwise subthreshold stimulation, respectively. Long-term, but not acute, oral administration of Menthacarin (60 mg kg^-1  day^-1 ) significantly reduced the net excitatory response to CRD in normally responsive control animals and counteracted the development of visceral hyperalgesia and hypersensitivity induced by repeated corticosterone administration and acute mechanical stimulation.

The present study shows that, using the CRD method, chronic Menthacarin administration at a clinically relevant dose attenuates the neuronal discharge associated with visceral pain stimuli in the rat ACC, particularly in models of hypersensitivity, suggesting a potential for treating exaggerated visceral pain sensitivity.

Niemann-Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.