INTRODUCTION — Niemann-Pick disease (NPD) is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol.
This topic will review the classification, clinical manifestations, diagnosis, and management of NPD. Other lysosomal storage disorders are discussed separately. (See "Fabry disease: Neurologic manifestations" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Krabbe disease" and "Metachromatic leukodystrophy" and "Mucopolysaccharidoses: Clinical features and diagnosis".)
CLASSIFICATION AND CLINICAL FEATURES — Niemann-Pick disease (NPD), also called sphingomyelin-cholesterol lipidosis, is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol. Niemann-Pick disease originally was defined in terms of its histology as a reticuloendotheliosis. It now is subdivided into two major categories (table 1).
●Niemann-Pick disease type A (NPD-A) and type B (NPD-B) are allelic disorders caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 gene (SMPD1) and characterized by a primary deficiency of acid sphingomyelinase activity. NPD-A is the severe, early-onset form, and NPD-B is the less severe, later-onset form [1]. An intermediate phenotype between these two extremes has also been described [2,3]. Some authors have proposed using the term acid sphingomyelinase deficiency (ASMD) to embrace the NPD-A and NPD-B disease spectrum [1].
●Niemann-Pick disease type C is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol and other macromolecules, including glycosphingolipids.
NPD type A — Niemann-Pick disease type A (NPD-A; MIM 257200) is the acute neuronopathic form. The incidence of NPD-A is highest among Ashkenazi Jews, in whom the gene frequency is estimated to be 1:100. The overall prevalence of ASMD (types A and B combined) is estimated to be 1:250,000 [4].
Affected patients present with hepatosplenomegaly, feeding difficulties, and loss of early motor skills in the first few months of life. Rapid, progressive, and profound loss of neurologic function leading to death occurs by two to three years of age. A peripheral neuropathy is manifest as hypotonia and absent reflexes [5,6]. Storage of sphingomyelin in pulmonary macrophages leads to interstitial lung disease, frequent respiratory infections, and often to respiratory failure [1]. Macular cherry red spots (seen on funduscopic examination) are eventually present in all affected individuals (picture 1), although they may not be observed early in the course of the disease.
In a natural history study of 10 infants with NPD-A, all except one infant had a normal neonatal course and early development [7]. The one exception had jaundice that resolved without treatment. The first detected sign of the disease was organomegaly, noted at a median of three months (range two to four). The median age at diagnosis was six months. A cherry red spot was evident in all infants by 12 months of age but was absent in several on initial examination. No infant progressed beyond the gross motor milestone of sitting with support; none ever crawled on all fours or walked. Social smile was retained well into the disease course, and was lost at a median age of 19 months. Death (from respiratory failure in nine patients and bleeding in one) occurred at a median age of 27 months (range 19 to 35).
The laboratory findings may include lipid abnormalities such as decreased high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, and increased LDL cholesterol [8]. In the natural history study discussed above, all infants had low fasting HDL cholesterol values (mean 11.2 mg/dL [0.29 mmol/L]) from the earliest age at which they were obtained [7].
Large lipid laden foam cells are seen in the reticuloendothelial system of the spleen, bone marrow, lymph nodes, blood vessels, peripheral nerve Schwann cells, central nervous system, and retinal cells [9]. Electron microscopy reveals lysosomal inclusions and myelin inclusions in peripheral nerves, indicating a severe myelinopathy [6].
Type A disease is caused by pathogenic variants in the acid sphingomyelinase gene, also known as the SMPD1 gene, on chromosome 11p15, that result in complete absence of residual acid sphingomyelinase activity and subsequent lysosomal accumulation of sphingomyelin [10-12].
NPD type B — Niemann-Pick disease type B (NPD-B; MIM 607616) is generally later in onset and less severe than NPD-A, with a good prognosis for survival into adulthood [1]. It is present in all populations globally. The overall prevalence of ASMD (types A and B combined) is estimated to be 1:250,000 [4].
NPD-B is characterized by the development of hepatosplenomegaly during infancy or childhood. Most affected patients have thrombocytopenia secondary to hypersplenism. Liver involvement can be severe, with infiltration of foamy histiocytes, ballooning of hepatocytes, and fibrosis [13]. Other systemic manifestations include short stature with delayed skeletal maturation, interstitial lung disease, hyperlipidemia, and ocular abnormalities (macular halos and cherry red maculae, (picture 1)) [14-16]. The natural history is one of progressive hypersplenism and gradual deterioration of pulmonary function [17,18].
Most patients with NPD-B have no neurologic abnormalities. However, in those who survive early childhood, a minority of patients develop prolonged nerve conduction velocities and varying degrees of central nervous system, including cerebellar signs, nystagmus, extrapyramidal involvement, intellectual disability, psychiatric disorders, and peripheral neuropathy [1,2,19-22]. In one series of 64 patients with NPD-B, neurologic abnormalities were observed in 30 percent; these were minor and nonprogressive in 22 percent, and global and progressive in 8 percent [2]. In the latter group, the onset of neurologic abnormalities occurred between the ages of two and seven years.
Although data are limited, brain magnetic resonance imaging (MRI) may show pronounced cerebellar and mild supratentorial atrophy [22]. Other laboratory abnormalities may include liver dysfunction, decreased HDL cholesterol, hypertriglyceridemia, and increased LDL cholesterol [8]. The atherogenic lipid profile worsens over time, whereas the liver dysfunction remains stable [17].
NPD-B is associated with pathogenic variants of the SMPD1 gene that result in ASMD with some residual activity of the enzyme [11,12,23]. In two studies, for example, acid sphingomyelinase activity in patients with NPD-B was 4 percent of normal compared with undetectable activity in patients with NPD-A [11,23].
NPD type C — Niemann-Pick disease type C (NPD-C) can present from the perinatal period until late adulthood [24-28]. The disorder has an estimated minimal incidence of 1:120,000 live births in Europe [28]. NPD-C has two genotypes related to pathogenic variants in the NPC1 gene (NPD-C1; MIM 257220) or to pathogenic variants in the NPC2 gene (NPD-C2; MIM 607625). Systemic involvement of liver, spleen, or lung is present in ≥85 percent of patients, and precedes the development of neurologic symptoms [28]. The age on onset and clinical presentation of NPD-C is highly variable.
●Most patients with NPD-C have disease onset in middle to late childhood after normal early development. These patients typically have cerebellar involvement characterized by clumsiness and gait problems progressing to frank ataxia, and slow cognitive deterioration [26,29]. Vertical supranuclear ophthalmoplegia is another early manifestation (see "Ocular gaze disorders"). Progressive dystonia, dysarthria, and dysphagia occur, eventually impairing oral feeding, and approximately one-third of patients develop seizures. Death typically occurs from aspiration pneumonia in the second or third decade of life [26].
●Neonatal onset of NPD-C may occur, presenting with severe hepatic disease from infiltration of the liver [30]. In addition, pulmonary disease with respiratory failure secondary to alveolar proteinosis or an alveolar proteinosis-like syndrome may accompany neonatal hepatic disease or occur as the initial presentation [31,32]. Fetal onset of NPD-C is most often associated with ultrasonographic findings of splenomegaly, hepatomegaly, and ascites or fetal hydrops [27].
A separate infantile form presents with hypotonia and developmental delay with little or no hepatic and pulmonary involvement [33].
●Adult onset of NPD-C may present with ataxia, supranuclear vertical gaze palsy, cognitive impairment, and other symptoms similar to earlier onset disease, except that progression is generally much slower [26,34]. Other adults present with cognitive dysfunction or psychiatric disturbances [35-40]. In some cases of NPD-C, subtle premonitory signs or symptoms in childhood, such as splenomegaly, hepatomegaly, learning difficulty, deafness, or impaired vertical gaze, may precede neurologic deterioration in adulthood [40].
Volumetric changes on brain MRI in patients with NPD-C include gray matter reductions involving the thalamus, hippocampus, striatum, cerebellum, and insular cortex, as well as white matter reductions involving the corpus callosum and widespread reductions in fractional anisotropy of white matter tracts [41-43]. Magnetic resonance spectroscopy (MRS) may show early changes prior to MRI findings, but data are limited. Reported findings include decreased n-acetyl aspartate/creatine ratios in the frontal and parietal cortex, centrum semiovale and caudate nucleus with increased choline/creatinine ratios in the frontal cortex and centrum semiovale [44].
Genetics of NPD-C — NPD-C is inherited in an autosomal recessive pattern [26]. There are two separate disease gene loci for NPD-C: the NPC1 gene on chromosome 18q11-q12, and the NPC2 gene (also called the HE1 gene) on chromosome 14q24.3 [25,45,46].
Pathogenic variants in the NPC1 gene can be identified in approximately 95 percent of NPD-C cases, while pathogenic variants in NPC2 account for approximately 4 percent [47-50]. So-called Niemann-Pick type D is an allelic variant of NPD-C that results from a pathogenic point variant of NPC1 and occurs in descendants of an Acadian couple who were born in the late 1600s in Nova Scotia [51,52].
NPC1 encodes a large membrane glycoprotein primarily located to late endosomes; this protein plays a role in the intracellular trafficking, levels, and distribution of LDL-cholesterol [53-56]. Disruption of this trafficking leads to lipid accumulation and neuronal degeneration [57]. NPC2 encodes a small soluble lysosomal protein previously known as cholesterol-binding protein [46].
Pathogenic variants in both the NPC1 and NPC2 genes result in the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. The biochemical pattern is identical. The precise functions and relationship of the two genes remains unclear [58].
Heterozygous carriers of NPC1 pathogenic variants may have abnormal brain metabolism and clinically silent manifestations of NPD-C, including oculomotor abnormalities, hepatosplenomegaly, elevated cholestane triol, and cognitive impairment [59].
DIAGNOSIS — The diagnosis of Niemann-Pick disease (NPD) first depends upon an appreciation of the variable phenotypic manifestations. The specific diagnostic tests and criteria for Niemann-Pick disease type A (NPD-A), Niemann-Pick disease type B (NPD-B), and Niemann-Pick disease type C (NPD-C) are reviewed below. (See 'Diagnosis of NPD-A and NPD-B (acid sphingomyelinase deficiency)' below and 'Diagnosis of NPD-C' below.)
NPD is often erroneously omitted from the differential diagnosis in cases that lack organomegaly, but this is not a universal feature. In addition, common screening tests for metabolic diseases such as amino or organic acids are typically normal in NPD.
Diagnosis of NPD-A and NPD-B (acid sphingomyelinase deficiency) — The diagnosis of NPD-A is suggested by the following clinical features [1]:
●Hepatosplenomegaly
●Interstitial lung disease
●Macular cherry red spot
●Developmental delay
The diagnosis of NPD-B is suggested by the following clinical features [1]:
●Hepatosplenomegaly
●Thrombocytopenia
●Interstitial lung disease
●Hyperlipidemia
The diagnosis of acid sphingomyelinase deficiency (ASMD), including NPD-A or NPD-B depending on clinical context, is confirmed when molecular genetic testing identifies both disease-causing alleles in sphingomyelin phosphodiesterase-1 gene (SMPD1) or when residual acid sphingomyelinase activity in peripheral blood leukocytes or cultured skin fibroblasts is <10 percent of controls [1,60]. In rare cases, the use of a so-called "artificial" substrate rather than the natural sphingomyelin substrate has led to falsely normal or enhanced laboratory determination of sphingomyelinase activity [61].
Three common SMPD1 pathogenic variants account for approximately 90 percent of NPD-A cases among Ashkenazi Jews [62], and another common SMPD1 pathogenic variant accounts for approximately 90 percent of NPD-B cases among patients of North African descent [63]. Thus, for patients of Ashkenazi Jewish or North African descent, targeted analysis for pathogenic variants is the preferred initial method of molecular genetic testing [1].
Sequence analysis of SMPD1 is appropriate if targeted analysis does not identify both pathogenic variants in patients with confirmed ASMD. In such patients, the pathogenic variant detection rate of sequence analysis is >95 percent [1].
Diagnosis of NPD-C — The diagnosis of NPD-C is suspected based upon the clinical features and biomarker screening for oxysterols; it is confirmed when genetic testing identifies both disease-causing alleles in NPC1 or NPC2.
The following clinical features are associated with NPD-C:
●Newborns may present with ascites, abnormal liver function tests, prolonged jaundice, and pulmonary infiltrates. Infants may show persistent hypotonia [24].
●In early childhood, hepatosplenomegaly is common. In late childhood, vertical supranuclear gaze palsy, ataxia, dystonia, or seizures may be prominent [24,64].
●Gelastic cataplexy (ie, cataplexy triggered by laughter) with abnormal polysomnograms is a prominent feature in up to 50 percent of children [65,66].
●In adults, dementia, depression, bipolar disease [39], or schizophrenia may be the only symptoms [38].
A Suspicion Index tool (figure 1) may be useful as a screen for NPD-C [67]. A risk prediction score of ≥70 indicates a strong suspicion for NPD-C. The index was derived by a retrospective review that compared the clinical features of patients with NPD-C confirmed by filipin staining (n = 71), noncases excluded from the diagnosis of NPD-C by negative filipin staining (n = 64), and control patients who had at least one characteristic symptom of NPD-C (n = 81). Individual signs and symptoms were analyzed by logistic regression to develop prediction scores for NPD-C.
The clinical features most strongly associated with NPD-C were vertical supranuclear gaze palsy, gelastic cataplexy, isolated unexplained splenomegaly, prolonged neonatal jaundice or cholestasis, and premature cognitive decline or dementia (figure 1) [67]. Gelastic cataplexy had a high specificity but low sensitivity for NPD-C, and was noted to be rare among adults. Premature cognitive decline or dementia was common in NPD-C but was not highly specific.
●Biomarker screening – For patients with a high clinical suspicion of NPD-C, measurement of oxysterols is the first-line screening test [68]. Our preferred oxysterol biomarker is cholestane triol. The assay for cholestane triol has a high sensitivity and acceptable specificity [69-71]. Biomarker screening for oxysterols has largely replaced skin biopsy and fibroblast culture for screening and diagnosis of NPD-C.
●Genetic testing – The diagnosis of NPD-C is confirmed by genetic testing [68]. Pathogenic variants in the NPC1 gene (mapped at 18q11) are found in approximately 90 percent of NPD-C cases. Pathogenic variants in the NPC2 gene defect (mapped at 14q24.3) are found in fewer than 5 percent of cases [49].
●Skin biopsy – In cases where the diagnosis remains uncertain after biomarker screening of oxysterols and initial genetic testing, skin biopsy with fibroblast cell culture and filipin staining can confirm the diagnosis. Filipin staining is performed on fibroblasts obtained at skin biopsy that have been cultured in lipoprotein-deficient serum, then exposed to a pulse of LDL-derived cholesterol. When positive, filipin staining shows an intense punctuate pattern of fluorescence concentrated around the nucleus, consistent with unesterified cholesterol. Formal esterification studies demonstrate delayed low-density lipoprotein-derived cholesterol esterification [33,72,73]. At centers with appropriate expertise, electron microscopy of skin biopsy can demonstrate polymorphous cytoplasmic bodies, which are diagnostic of NPD-C when present.
MANAGEMENT — There is no treatment for Niemann-Pick disease (NPD) that is proven to modify the onset or neurologic progression of the disease, or to prolong lifespan. However, some patients with Niemann-Pick disease type C (NPD-C) may benefit from treatment with miglustat (see 'Miglustat for NPD-C' below). Cholesterol lowering agents lower the free cholesterol in the liver but the clinical course is unchanged [74].
Supportive care — The management of all forms of NPD is supportive.
Support groups for people and families affected by Niemann-Pick disease include:
●International Niemann–Pick Disease Alliance
●National Niemann-Pick Disease Foundation
●Ara Parseghian Medical Research Fund
NPD-A — Infants with Niemann-Pick disease type A (NPD-A) may temporarily benefit from physical and occupational therapy, periodic nutritional assessments, and possibly a feeding tube for nutrition. Sedatives may be helpful for sleep difficulty and irritability [1].
NPD-B — Suggested surveillance for patients with Niemann-Pick disease type B (NPD-B) includes periodic assessment (every 6 to 12 months) of height and growth in children, weight in patients of all ages, nutrition, changes in activity level, bleeding, shortness of breath, abdominal pain, and neurologic function [1]. Concomitantly, the following tests should be monitored [1]:
●Platelet count
●Liver enzymes
●Fasting lipid profile
●Pulmonary function tests
●Chest radiography
●Skeletal evaluation with dual-energy x-ray absorptiometry (DXA)
Patients with NPD-B who have symptomatic pulmonary disease may benefit from supplemental oxygen. Severe bleeding from thrombocytopenia can lead to the need for transfusion of blood products. In adults with hyperlipidemia, treatment is suggested to correct elevated total cholesterol. Avoidance of contact sports is suggested for patients with splenomegaly [1].
NPD-C — In patients with NPD-C, physical therapy may be beneficial for maintaining mobility. Swallowing function should be monitored periodically, and gastrostomy tube placement may be useful to prevent aspiration and/or inadequate nutrition in patients with progressive dysphagia. The treatment of seizures, dystonia, and cataplexy is suggested and may be partially effective. Bowel regimens may be helpful for preventing severe constipation in patients with reduced mobility [26].
Evidence from a single case report suggests that bronchoalveolar lavage can improve pulmonary function in children with pulmonary infiltrates and recurrent pulmonary infections [75]. Some experts suggest the use of chest physical therapy and aggressive bronchodilation therapy with antibiotic treatment of intercurrent infections for preventing secondary pulmonary complications [26].
Disease-modifying therapies
Olipudase alfa for ASMD (NPD-A and NPD-B) — Olipudase alfa is an enzyme replacement therapy that provides an exogenous source of acid sphingomyelinase. It was approved by the US Food and Drug Administration (FDA) in August 2022 for the treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD), the cause of NPD-A and NPD-B [76].
●Dose and administration – Olipudase alfa is given every two weeks by intravenous (IV) infusion. The starting dose for children is 0.03 mg/kg IV; the dose is gradually titrated up to the recommended maintenance dose of 3 mg/kg IV by the ninth dose (week 16). The starting dose for adults is 0.1 mg/kg IV, which is gradually titrated up to the recommended maintenance dose of 3 mg/kg by the eighth dose (week 14).
Details for the recommended dose escalation schedule and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions are contained in the FDA prescribing label [77].
Before starting treatment, pregnancy status should be verified for females of reproductive potential, and baseline transaminase levels should be obtained [77]. Pretreatment with antihistamines, antipyretics, and/or glucocorticoids may be used to prevent infusion reactions.
●Adverse effects – The most common adverse effects in adult patients are headache, cough, diarrhea, hypotension, and ocular hyperemia. In children, the most common adverse effects are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis.
There is a black box warning of severe hypersensitivity reactions, including anaphylaxis. Other warnings include the risk of infusion reactions, elevated transaminases, and risk of fetal malformations with use during pregnancy.
●Efficacy – A randomized controlled trial of 36 adults with ASMD randomly assigned participants in a 1:1 ratio to treatment with olipudase alfa or placebo. At one year, olipudase alfa treatment led to a greater increase in the mean percent predicted diffusing capacity of the lung for carbon monoxide (DLCO) (22 percent, versus 3 percent for the placebo) as well as a greater reduction in spleen volume (39 percent decrease, versus 0.5 percent increase with placebo) and liver volume (28 vs 1.5 percent decrease) [78]. In an open-label trial of 20 pediatric patients with ASMD, one-year results showed that, olipudase alfa treatment was associated with an increased mean percent predicted DLCO of 33 percent in patients able to perform the test and with decreased mean spleen volume and liver volume of >40 percent each [79]. All patients had growth retardation at enrollment, and olipudase alfa was associated with an improvement in mean height Z-scores of 0.56 at one year.
Miglustat for NPD-C — Miglustat inhibits the synthesis of glycolipids and may delay the progression of the neurologic manifestations of NPD-C in children without severe neurologic symptoms at the start of treatment, as reviewed below. However, expert consensus guidelines note that miglustat should not be given to patients who have no neurologic manifestations because some remain asymptomatic for long periods of time [80].
In accord with these guidelines, we suggest miglustat for patients with NPD-C who have mild to moderate neurologic, psychiatric, or cognitive manifestations. The optimum time to start treatment is as soon as any neurologic manifestations emerge [81]. Patients and their families and caregivers should be informed that the effectiveness of miglustat for NPD-C is unproven and that the best attainable outcome of therapy is neurologic stabilization or a slower rate of neurologic disease progression.
●Dose - The suggested dose for adults and adolescents (age ≥12 years) is 600 mg daily given in three divided doses. The miglustat dose in children 4 to 11 years of age is based upon body surface area (BSA):
•600 daily in three divided doses for BSA >1.25 m2
•400 mg daily in two divided doses for BSA 0.89 to 1.25 m2
•300 mg daily in three divided doses for BSA 0.74 to 0.88 m2
•200 mg daily in two divided doses for BSA 0.48 to 0.73 m2
•100 mg once daily for BSA ≤0.47 m2
Few children <4 years old with NPD-C have been treated with miglustat and optimal dosing is uncertain; one study used miglustat 250 mg/m2 per day [82].
The most common adverse effects of miglustat include gastrointestinal symptoms (eg, diarrhea, flatulence), weight loss, and tremor.
●Efficacy – Based upon the observation that glycolipids were increased in NPD-C cells, substrate reduction therapy with miglustat, an inhibitor of glycosphingolipids biosynthesis, was shown to decrease lipid storage, improve endosomal uptake, and normalize lipid trafficking in B lymphocytes [83]. In a preliminary open-label randomized controlled trial, 29 patients ≥12 years old with NPD-C were randomly assigned to miglustat 200 mg three times daily (n = 20) or to standard care (n = 9) [84]. Patients assigned to miglustat demonstrated nonsignificant improvement in horizontal saccadic eye movement velocity (the primary outcome measure) at 12 months; the difference between groups was statistically significant after excluding patients taking benzodiazepines. Improvement or stabilization with miglustat, statistically nonsignificant in most cases, was also seen in clinically relevant secondary outcome measures, including swallowing capacity, hearing acuity, and ambulation. In addition, several observational studies have reported that miglustat treatment is associated with stabilization of swallowing function and other neurologic manifestations of NPC [85-89], including improved survival [90].
Early miglustat treatment did not prevent neurologic involvement in two children with NPD-C one a girl with early infantile onset and mild axial hypotonia who started treatment at age 7 months, and the second a boy with no neurologic symptoms who started treatment at age 19 months [82,91]. After the first seven and five years of therapy, respectively, both children remained without neurologic symptoms [82]. However, over the ensuing three years, the girl developed cognitive impairment, a cherry red spot, vertical gaze paresis, ataxia, dysmetria, and gelastic cataplexy, while the boy developed mild cognitive decline, hyperreflexia, and mild incoordination, but no gaze paresis [91].
A case series of 16 symptomatic children of different ages treated with miglustat for six months to four years for NPD-C reported that patients with more severe disease, generally those with infantile NPD-C, showed greater deterioration during miglustat therapy than patients with less severe disease, generally those with juvenile-onset NPD-C [92].
Experimental therapies — There is a persistent search for new treatment approaches. Evaluation of novel therapies is ongoing and may offer some hope for the future. The following reports illustrate the range of experimental therapies for NPD:
●Hematopoietic stem cell transplantation (HSCT) did not modify the neurological course in an ASMD mouse model, although increased Purkinje cells were noted in the cerebellum and decreased sphingomyelin storage was noted in spinal cord neurons [93].
●In utero stem cell transplant in NPD has been shown to have only a transitory benefit [94]. Allogeneic or bone marrow treatment has generally not modified the neurologic course in patients [95,96]. However, there are rare case reports of successful HSCT in children with NPD-B [96,97]. Transplant related complications included chronic graft versus host disease of the skin, and renal tubular dysfunction.
●Direct intracerebral transplant of neural progenitor cells into the mouse model of NPD-A resulted in up to five times more acid sphingomyelinase activity and lead to reversal of distended lysosomal pathology in transplanted cells in vivo [98].
●Another approach is based on the observation that neurosteroids, made in the central nervous system, affect neuronal growth and differentiation, and modulate brain functions [99]. Disordered cholesterol trafficking might disrupt neurosteroidogenesis, thereby contributing to the NPD-C phenotype. Treatment with allopregnanolone in the NPD-C mouse delayed neurological symptoms, increased Purkinje cells, decreased cortical ganglioside storage and doubled life span [100]. Subsequent studies found that the effects originally attributed to allopregnanolone were actually caused by its vehicle, cyclodextrin [101]. There is evidence from animal models of NPC that cyclodextrin reduces lysosomal cholesterol accumulation, slows the progression of neurodegeneration, and improves survival [102-105]. In a small preliminary open-label study of 14 patients with NPD-C1, intrathecal 2-hydroxypropyl-beta-cyclodextrin seemed to slow disease progression [106], and a small preliminary trial found that intravenous 2-hydroxypropyl-beta-cyclodextrin reduced liver cholesterol and improved peripheral biomarkers of cholesterol metabolism [107]. Larger clinical trials are needed to determine if cyclodextrin is beneficial and safe for patients with NPD-C.
●Glial activation may be important in pathogenesis of neurodegenerative disorders such as NPD. In support of this hypothesis, intracerebral transplantation of bone marrow-derived mesenchymal stem cells in NPD-C mice suppressed neuroglial inflammation and resulted in reduced cerebellar pathology [108].
●Other investigational agents for NPC include vorinostat [109], N-acetyl-l-leucine [110], and arimoclomol [111].
Genetic counseling — All types of NPD are autosomal recessive disorders. At the time of conception, siblings of an affected patient with NPD have a 25 percent chance of being affected with the disease, a 50 percent chance of being an unaffected carrier and 25 percent chance of being unaffected and not a carrier. (See "Genetic counseling: Family history interpretation and risk assessment".)
Prenatal testing for pregnancies at 25 percent risk of NPD-A or NPD-B can be accomplished by measuring sphingomyelinase activity in amniotic fibroblasts [58,112], or by molecular genetic testing if both disease-causing sphingomyelin phosphodiesterase-1 (SMPD1) gene alleles have been identified in an affected family member [1]. Additionally, screening for population-specific pathogenic variants is feasible for individuals of Ashkenazi Jewish descent and North African descent [1]. (See "Preconception and prenatal carrier screening for genetic disease more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Niemann-Pick disease type A'.)
Prenatal testing for pregnancies at 25 percent risk of NPD-C is available using chorionic villus sampling at 10 to 12 weeks or fetal cells obtained by amniocentesis at 15 to 18 weeks. Biochemical testing can be done only when the proband has the typical biochemical phenotype. Molecular genetic testing is possible when the two disease-causing NPC1 (or NPC2) pathogenic variants have been identified in the proband, or when family studies have shown informative linked markers [26,58]. Pathogenic variant testing allows early and fast (48 hours) prenatal diagnosis on the proband [113,114].
Carrier detection can be offered by molecular testing if the NPC1 or NPC2 gene has been identified in the proband.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Niemann-Pick disease".)
SUMMARY AND RECOMMENDATIONS
●Niemann-Pick disease (NPD; also called sphingomyelin-cholesterol lipidosis) is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of sphingomyelin (table 1). Niemann-Pick disease types A and B are allelic disorders caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene, and characterized by a primary deficiency of acid sphingomyelinase activity. Type C is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol. (See 'Classification and clinical features' above.)
●Niemann-Pick disease type A (NPD-A) is the acute neuronopathic form. The incidence of NPD-A is highest among Ashkenazi Jews. Affected patients present with hepatosplenomegaly, feeding difficulties, and loss of early motor skills in the first few months of life. Rapid, progressive, and profound loss of neurologic function leading to death occurs by two to three years of age. Additional manifestations include peripheral neuropathy, hypotonia, loss of reflexes, and interstitial lung disease. Macular cherry red spots are eventually present in all affected individuals (picture 1). (See 'NPD type A' above.)
●Niemann-Pick disease type B (NPD-B) is pan-ethnic and generally later in onset and less severe than NPD-A, with a good prognosis for survival into adulthood. Hepatosplenomegaly develops during infancy or childhood. Other systemic manifestations include short stature with delayed skeletal maturation, interstitial lung disease, hyperlipidemia, and ocular abnormalities (picture 1). The natural history is one of progressive hypersplenism and gradual deterioration of pulmonary function. (See 'NPD type B' above.)
●Niemann-Pick disease type C (NPD-C) can present from the perinatal period until late adulthood. Most patients with NPD-C have disease onset in middle to late childhood, typically with cerebellar symptoms, slow cognitive deterioration, vertical supranuclear gaze palsy, and progressive dystonia, dysarthria, and dysphagia. (See 'NPD type C' above.)
●The diagnosis of NPD first depends upon an appreciation of the variable phenotypic manifestations. The definitive diagnosis of NPD-A and NPD-B is made by detection of both disease-causing alleles in SMPD1 or by demonstration of acid sphingomyelinase deficiency (ASMD). The diagnosis of NPD-C is based upon abnormal biomarker screening for oxysterols and genetic confirmation of a pathogenic variants involving both alleles of NPC1 or NPC2. (See 'Diagnosis' above.)
●The management of all forms of NPD is supportive. (See 'Management' above.)
●There is no treatment for NPD that is proven to modify the onset or neurologic progression of the disease, or to prolong lifespan. However, limited data suggest that olipudase alfa may improve certain non-neurologic manifestations of ASMD (NPD-A and NPD-B) and that miglustat may delay the progression of the neurologic manifestations of NPD-C in children without severe neurologic symptoms at the start of treatment.
•For children and adults with ASMD, the cause of NPD-A and NPD-B, we suggest treatment with olipudase alfa (Grade 2C). (See 'Olipudase alfa for ASMD (NPD-A and NPD-B)' above.)
•For children and adults with NPD-C who have mild to moderate neurologic, psychiatric, or cognitive manifestations, we suggest miglustat treatment (Grade 2C). (See 'Miglustat for NPD-C' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Cruse, DO, who contributed to earlier versions of this topic review.
