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Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations. [ABSTRACT FROM AUTHOR]

Background: Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease types A, A/B, and B is a progressive, life-limiting, autosomal recessive disorder caused by sphingomyelin phosphodiesterase 1 (SMPD1) gene mutations. There is a need to increase the understanding of morbidity and mortality across children to adults diagnosed with ASMD., Methods: This observational retrospective survey analysed medical records of patients with ASMD with retrievable data from 27 hospitals in France, diagnosed/followed up between 1 st January 1990 and 31 st December 2020. Eligible records were abstracted to collect demographic, medical/developmental history, and mortality data. Survival outcomes were estimated from birth until death using Kaplan-Meier survival analyses; standardised mortality ratio (SMR) was also explored., Results: A total of 118 medical records of patients with ASMD (type B [n = 94], type A [n = 15], and type A/B [n = 9]) were assessed. The majority of patients were males (63.6%); the median [range] age at diagnosis was 8.0 [1.0-18.0] months (type A), 1.0 [0-3] year (type A/B), and 5.5 [0-73] years (type B). Overall, 30 patients were deceased at the study completion date; the median [range] age at death for patients with ASMD type A (n = 14) was 1 [0-3.6] year, type A/B (n = 6) was 8.5 [3.0-30.9] years, and type B (n = 10) was 57.6 [3.4-74.1] years. The median [95% confidence interval (CI)] survival age from birth in patients with ASMD type A and type A/B was 2.0 [1.8-2.7] years and 11.4 [5.5-18.5] years, respectively. Survival analysis in ASMD type B was explored using SMR [95% CI] analysis (3.5 [1.6-5.9]), which showed that age-specific deaths in the ASMD type B population were 3.5 times more frequent than those in the general French population. The causes of death were mostly severe progressive neurodegeneration (type A: 16.7%), cancer (type B: 16.7%), or unspecified (across groups: 33.3%)., Conclusions: This study illustrated a substantial burden of illness with high mortality rates in patients with ASMD, including adults with ASMD type B, in France., (© 2024. The Author(s).)

Background: Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients., Methods: Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded., Results: Ten patients were included in the treated group (year of birth: 2006-2012), and 16 patients in the untreated group [born 1987-2005 (n = 15), 2012 (n = 1)]. The median age at neurological onset was 9 months (5-18) in the treated group, and 12 months (3-18) in the untreated group (p = 0.22). Miglustat therapy was started at a median age of 24.5 months (9-29) and median duration was 30 months (11-56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p = 0.11)., Conclusions: Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C., (© 2023. The Author(s).)

Background: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients., Methods: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process., Results: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research., Conclusion: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT)., (© 2023. The Author(s).)

Objective: To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder., Study Design: Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining., Results: At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68 + storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6 months of life, including 3 from liver involvement. In patients who survived beyond age 6 months (median follow-up, 6.1 years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients., Conclusions: Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3-55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5-25) vs. 18 cm (17-20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8-43.0) vs. 58.5 % (49.8-69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer ( p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.

Background: Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden over time in children and adults., Results: Fifty-nine patients (31 males/28 females) ranging in age from 7 to 64 years with chronic ASMD types A/B and B and at least two disease symptoms participated from 5 countries. Disease characteristics were assessed at baseline, after 1 year, and at the final visit (ranging from 4.5 to 11 years). Thirty patients (51%) were < 18 years at baseline (median age 12 years), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the final visit, 9 died, 9 discontinued, and 9 were lost to follow up. Common clinical characteristics that tended to worsen gradually with time were splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DL CO ), and dyslipidemia. Spleen volumes ranged from 4 to 29 multiples of normal at baseline, and splenomegaly was moderate or severe in 86%, 83%, and 90% of individuals at baseline, year 1, and final visits, respectively. The proportion of all individuals with interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the final visit, while median % predicted DL CO decreased by > 10% from baseline to the final visit. Nine patients died (15%), eight of causes related to ASMD (most commonly pneumonia); of these eight patients, five (63%) had symptom onset at or before age 2. Overall, six of the nine deaths occurred before age 50 with three occurring before age 20. Individuals with either severe splenomegaly or prior splenectomy were ten times more likely to have died during the follow-up period than those with smaller or intact spleens (odds ratio 10.29, 95% CI 1.7, 62.7). Most children had growth deficits that persisted into adulthood., Conclusions: This study provides important information about the natural history of chronic ASMD and provides a longitudinal view of the spectrum of disease manifestations and major morbidities in children and adults and supports the selection of clinically meaningful endpoints in therapeutic trials.

Miglustat has been indicated for the treatment of Niemann-Pick disease type C (NP-C) since 2009. The aim of this observational study was to assess the effect of miglustat on long-term survival of patients with NP-C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat-treated and untreated patients overall and within sub-groups according to age-at-neurological-onset, that is, early infantile-onset (<2 years), late infantile-onset (2 to <6 years), juvenile-onset (6 to <15 years), and adolescent/adult-onset (≥15 years) were analysed and compared. Survival was analysed from the time of first neurological manifestation (Neurological onset group, comprising 669 patients) and from diagnosis (Diagnosis group, comprising 590 patients) using a Cox proportional hazard model adjusted for various covariates. Overall, 384 (57.4%) patients in the Neurological onset group and 329 (55.8%) in the Diagnosis group were treated with miglustat. Miglustat treatment was associated with a significant reduction in risk of mortality in both groups (entire Neurological onset group, Hazard ratio [HR] = 0.51; entire Diagnosis group, HR = 0.44; both P < .001). The effect was observed consistently in all age-at-neurological-onset sub-groups (HRs = 0.3 to 0.7) and was statistically significant for late infantile-onset patients in both groups (Neurological onset group, HR = 0.36, P < .05; Diagnosis group, HR = 0.32, P < .01), and juvenile-onset patients in the Diagnosis group only (HR = 0.30, P < .05). Despite the limitations of the data that urge cautious interpretation, the findings are consistent with a beneficial effect of miglustat on survival in patients with NP-C., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms. The cells were tested with multiple assays including NPC1 mRNA expression levels and allele expression ratios, assessment of NPC1 promoter haplotypes, NPC1 protein levels, cellular cholesterol staining, localization of the mutant NPC1 proteins to lysosomes, and cholesterol/cholesteryl ester ratios. These results were correlated with phenotypes of the individual patients., Results: Overall we identified 5 variant promoter haplotypes. Three of them showed reporter activity decreased down to 70% of the control sequence. None of the haplotypes were consistently associated with more severe clinical presentation of NP-C. Levels of transcripts carrying null NPC1 alleles were profoundly lower than levels of the missense variants. Low levels of the mutant NPC1 protein were identified in most samples. The protein localised to lysosomes in cultures expressing medium to normal NPC1 levels. Fibroblasts from patients with severe infantile phenotypes had higher cholesterol levels and higher cholesterol/cholesteryl ester ratios. On the contrary, cell lines from patients with juvenile and adolescent/adult phenotypes showed values comparable to controls., Conclusion: No single assay fully correlated with the disease severity. However, low residual levels of NPC1 protein and high cholesterol/cholesteryl ester ratios associated with severe disease. The results suggest not only low NPC1 expression due to non-sense mediated decay or low mutant protein stability, but also dysfunction of the stable mutant NPC1 as contributors to the intracellular lipid transport defect.

Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Results: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n   = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n  = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date., Methods: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed., Results: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02)., Conclusion: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.

Sandhoff disease (SD) is a rare inherited disorder caused by a deficiency of β-hexosaminidase activity which is fatal because no effective treatment is available. A mouse model of Hexb deficiency reproduces the key pathognomonic features of SD patients with severe ubiquitous lysosomal dysfunction, GM2 accumulation, neuroinflammation and neurodegeneration, culminating in death at 4 months. Here, we show that a single intravenous neonatal administration of a self-complementary adeno-associated virus 9 vector (scAAV9) expressing the Hexb cDNA in SD mice is safe and sufficient to prevent disease development. Importantly, we demonstrate for the first time that this treatment results in a normal lifespan (over 700 days) and normalizes motor function assessed by a battery of behavioral tests, with scAAV9-treated SD mice being indistinguishable from wild-type littermates. Biochemical analyses in multiple tissues showed a significant increase in hexosaminidase A activity, which reached 10-15% of normal levels. AAV9 treatment was sufficient to prevent GM2 and GA2 storage almost completely in the cerebrum (less so in the cerebellum), as well as thalamic reactive gliosis and thalamocortical neuron loss in treated Hexb-/- mice. In summary, this study demonstrated a widespread protective effect throughout the entire CNS after a single intravenous administration of the scAAV9-Hexb vector to neonatal SD mice.

Purpose of Review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice., Recent Findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified., Summary: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: The biological diagnosis of sphingolipidoses currently relies on the measurement of specific enzymatic activities and/or genetic studies. Lysosphingolipids have recently emerged as potential biomarkers of sphingolipidoses and Niemann-Pick type C in plasma., Methodology: We developed a sensitive and specific method enabling the simultaneous quantification of lysosphingolipids by LC-MS/MS: lysoglobotriaosylceramide for Fabry disease, lysohexosylceramide (i.e. lysoglucosylceramide and/or lysogalactosylceramide) for Gaucher and Krabbe diseases, lysosphingomyelin and its carboxylated analogue lysosphingomyelin-509 for Niemann-Pick type A or B, and C diseases, lysoGM1 ganglioside for GM1gangliosidosis and lysoGM2 ganglioside for GM2 gangliosidosis., Findings: The diagnostic performances were validated in plasma samples analysing a large series of patients affected with sphingolipidoses and Niemann-Pick type C disease (n = 98), other inborn errors of metabolism (n = 23), and controls (n = 228). The multiplex measurement of lysosphingolipids allowed the screening of Fabry (including female patients and late-onset variants), Gaucher and infantile Krabbe, Niemann-Pick type A/B and C diseases with high sensitivity and specificity. LysoGM1 and LysoGM2 were elevated in most of the patients affected with GM1 and GM2 gangliosidosis respectively. In amniotic fluid supernatant from pregnancies presenting non-immune hydrops fetalis (n = 77, including previously diagnosed Gaucher (n = 5), GM1 gangliosidosis (n = 4) and galactosialidosis (n = 4) fetuses) and from normal pregnancies (n = 15), a specific and dramatic increase of lysohexosylceramide was observed only in the Gaucher amniotic fluid samples., Interpretation: This multiplex assay which allows the simultaneous measurement of lysosphingolipids in plasma modifies the diagnostic strategy of sphingolipidoses and Niemann-Pick type C. Furthermore, in pregnancies presenting non-immune hydrops fetalis, lysohexosylceramide measurement in amniotic fluid offers a rapid screening of fetal Gaucher disease without waiting for glucocerebrosidase activity measurement in cultured amniocytes.

Background: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse., Methods: The study population consisted of two Greek NPC patients and their extended pedigree. Patients' clinical, biochemical, molecular profiles and the possible correlations are presented. Genotyping was performed by direct sequencing. Mutations' origin was investigated through selected exonic NPC1 polymorphisms encountered more frequently in a group of 37 Greek patients with clinical suspicion of NPC disease and in a group of 90 healthy Greek individuals, by the use of Haplore software., Results: Two novel NPC1 mutations, [IVS23 + 3insT (c.3591 + 3insT) and p. K1057R (c.3170A > C)] were identified and each mutation was associated with a specific haplotype. One of the patients was entered to early treatment with miglustat and has presented no overt neurological impairment after 11.5 years., Conclusions: The splicing mutation IVS23 + 3insT was associated in homozygocity with a severe biochemical and clinical phenotype. A possible founder effect for this mutation was demonstrated in the Greek Island, as well as a different origin for each novel mutation. Longitudinal follow-up may contribute to clarify the possible effect of early miglustat therapy on the patient compound heterozygous for the two novel mutations.

Introduction: Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease with a clinical spectrum ranging from a neurovisceral infantile form (Niemann-Pick disease type A) to a chronic visceral form also encountered in adults (Niemann-Pick disease type B, NP-B)., Methods: Retrospective multicentric analysis of French adult patients with ASMD over the period 1985-March 2015. Clinical, biological, and imaging data were analyzed., Results: Twenty-eight patients (19 males, 9 females) were analyzed. Diagnosis was made before the age of 10 years in 16 cases. Main symptoms at diagnosis were spleen/liver enlargement and interstitial lung disease. Biological abnormalities included: thrombocytopenia (platelet count <150 000/mm 3 ) in 24 cases including 4 patients with platelet count <60 000/mm 3 , constantly low high-density lipoprotein (HDL) cholesterol, polyclonal hypergammaglobulinemia (n=6), monoclonal gammopathy of unknown significance (n=5), normal prothrombin level discordant with low factor V (n=5), elevated chitotriosidase level (n=11). The diagnosis was confirmed in all cases by deficient acid sphingomyelinase enzyme activity. SMPD1 gene sequencing was performed in 25 cases. The frequent p.R610del mutation was largely predominant, constituting 62% of the non-related alleles. During the follow-up period, three patients died before 50 years of age from cirrhosis, heart failure and lung insufficiency, respectively., Conclusion: ASMD in adulthood (NP-B) associates spleen/liver enlargement and interstitial lung disease. Early diagnosis and appropriate management are essential for reducing the risk of complications, improving quality of life, and avoiding inappropriate procedures such as splenectomy. To date, only symptomatic therapy is available. A phase 2/3 therapeutic trial with IV infusion of recombinant enzyme is on-going., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5-50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.

Niemann-Pick disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the wide range in age of onset of NP-C and clinical presentation of the disease, combined with the complexity of the cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations, notably with unidentified mutations and the classification of new variants. This review is intended to increase awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress, definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical markers do not provide a clear answer. Expertise and reference laboratories thus remain essential, and further work is still required to fulfill unmet needs., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Niemann-Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the 'continued' subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat.

Objective: Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease-relevant substrates that could pertain to mechanism., Methods: NPC disease mice treated for 2 weeks with nine different CDs were evaluated for UC, and GM2 and GM3 ganglioside accumulation using immunohisto/cytochemical and biochemical assays. Auditory brainstem responses were determined in wild-type mice administered CDs. CD complexation with UC, gangliosides, and other lipids was quantified., Results: Four HPβCDs varying in degrees of substitution, including one currently in clinical trial, showed equivalent storage reduction, while other CDs showed significant differences in relative ototoxicity and efficacy, with reductions similar for the brain and liver. Importantly, HPγCD and two sulfobutylether-CDs showed efficacy with reduced ototoxicity. Complexation studies showed: incomplete correlation between CD efficacy and UC solubilization; an inverse correlation for ganglioside complexation; substantial interaction with several relevant lipids; and association between undesirable increases of UC storage in Kupffer cells and UC solubilization., Interpretation: CDs other than HPβCD identified here may provide disease amelioration without ototoxicity and merit long-term treatment studies. While direct interactions of CD-UC are thought central to the mechanism of correction, the data show that this does not strictly correlate with complexation ability and suggest interactions with other NPC disease-relevant substrates should be considered.

Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-β-cyclodextrin (HPβCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPβCD into clinical trials., (Copyright © 2015, American Association for the Advancement of Science.)

Niemann-Pick disease type C (NPC) is an atypical neurovisceral lysosomal storage disorder resulting from mutations in either the NPC1 or the NPC2 gene, currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a key element of the pathogenesis. The resulting accumulation of unesterified cholesterol in the LE/L compartment can be visualized by fluorescence microscopy after staining with filipin. The "filipin test," performed on cultured fibroblasts, is the historical gold standard method to establish the diagnosis in patients. The authors provide methodological details of the protocol developed and used in their laboratory since 1988, in which two sources of low-density lipoproteins (LDL) (total serum and pure LDL) are used in parallel to facilitate the final interpretation. Methodological caveats and variability of patterns encountered in patients with proven Niemann-Pick C disease (typical "classic" or "intermediate," atypical "variant") are described. An overview of the past 5 years referrals (533 subjects tested, 57 NPC cases, but also 74 mildly/weakly positive tests not due to NPC) is discussed, leading to a proposed algorithm for interpretation of results in the filipin test. This tool takes into account the limits of the method. In up to 15% of all referrals, the filipin test was inconclusive in absence of molecular analysis. Patients diagnosed in the adult age preferentially showed an "intermediate" or "variant" pattern. Well conducted, the filipin test remains an efficient approach for diagnosing NPC, and it is a good functional test to study the pathogenicity of novel mutations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".

Acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) includes the severe neuronopathic type A, the non-neuronopathic type B, and rare intermediate cases. Here we report on such an atypical type B patient who died at 31 years of age from liver failure. This male subject was first seen in a paediatric department at the age of 3 years because of significant hepatosplenomegaly. Foam cells in bone marrow, interstitial pneumonitis, a slight facial dysmorphy and normal psychomotor development were additional findings. Acid sphingomyelinase studies in lymphocytes (and later SMPD1 gene studies [c.151&#95;154delGACT; c.1341-21&#95;1341-18delAATG]) established the diagnosis of ASMD. Between the ages 6-27, he developed growth retardation, peripheral neuropathy, kyphoscoliosis, alopecia, and aortic valve insufficiency requiring valve replacement. Surgery for bilateral inguinal hernias was performed twice, when the patient was 10 and 21 years of age, respectively. At the age of 28, he was noted to have hepatosplenomegaly and follow-up investigations revealed ascites and gastric varices. Liver biopsy showed cirrhosis without areas of necrosis (A6 in Child-Pugh classification). He developed haematemesis and worsening encephalopathy leading to his death at age 31. In conclusion, cirrhosis should be considered as a possible complication of ASMD in adult patients, even if hepatic tests are normal.

Niemann-Pick type C (NPC) disease is a rare autosomal recessive lysosomal storage disease, exhibiting an extremely heterogeneous clinical phenotype. It is a cellular lipid trafficking disorder characterized by the accumulation in the lysosomal/late endosomal system of a variety of lipids, especially unesterified cholesterol. So far two genes, NPC1 or NPC2, have been linked to the disorder. It is a panethnic disease for which two isolates have been described. We present a novel NPC1 mutation (p.A1132P; c.3394G>C) identified in homozygosity in two patients originating from the same small town of an Aegean Sea island and the results of the broad screening of their extended families. Overall 153 individuals have so far been investigated and a total of 64 carriers were identified. Moreover a common descent of the individuals tested was revealed and all carriers could be traced back to a common surname, apparently originating from a common ancestor couple six generations back. The mutation was found associated with an uncommon haplotype in the island that is also present in other populations., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Niemann-Pick type C disease (NPC) is a recessive neurolipidosis. We report five adolescent and adult NPC cases to underscore the frequency and heterogeneity of movement disorders in NPC. Clinical, morphologic, biochemical and genetic study was performed in the five patients. Disease onset was between 8 and 50 years. Movement disorders were present in all cases, were heterogeneous and often combined [cerebellar ataxia (5/5), myoclonus (3/5), dystonia (2/5), chorea (1/5) and tremor (1/5)] and were the first sign in 4/5. Two patients were reported to have no vertical supranuclear gaze palsy (VSGP) at the first examination. Two patients experienced acute neuropsychiatric signs leading to death in one case due to myoclonic storm. Filipin staining was always positive. Two NPC1 mutations were identified in three patients, only one in two siblings. NPC should be considered in case of unexplained movement disorders, even when VSGP or cataplexy are not reported. Filipin staining remains a strong support for the diagnosis. Treatment with miglustat should be considered which is currently the only approved disease-specific treatment of NPC in children and adults.

Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.