[Ocular manifestation of an adult Niemann-Pick disease type B]. / Felnottkori B-típusú Niemann­Pick-betegség szemészeti manifesztációja.

Niemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick disease type B as a child, focusing on the ophthalmic manifestation of the disease. During the examination of the patient, fundus photographs and fundus autofluorescence imaging were taken, and optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and visual field (perimetry) examinations were performed. The characteristic macular halo and the cherry-red spot in the fovea were clearly visible during ophthalmoscopy and on the fundus photographs. The OCT images showed focal thickening with high reflectivity in the ganglion cell layer corresponding to the macular halo, and the area of the foveola was spared. With visual field examination, an intact field of vision was found on both eyes. Similar to the presented patient, symptoms in patients with the B subtype are milder, and besides the visceral symptoms, there are no neurological symptoms, and the specific ophthalmic abnormalities do not cause visual impairment. Currently, Niemann-Pick disease is considered a rare disease, and the diagnosis of the patients is often delayed or even missed due to non-specific or mild symptoms. Through consultation between medical specialties, ophthalmological examination can also contribute to the correct diagnosis in cases with mild general symptoms. Timely diagnosis can potentially lead to mitigation of symptoms thanks to the ever-expanding therapeutic options, stabilization of the disease progression, and increase of the patients' life expectancy. Orv Hetil. 2023; 164(46): 1838-1844.

Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency.

Acid sphingomyelinase deficiency (ASMD) is a rare LSD characterized by lysosomal accumulation of sphingomyelin, primarily in macrophages. With the recent availability of enzyme replacement therapy, the need for biomarkers to assess severity of disease has increased. Glycoprotein non-metastatic protein B (GPNMB) plasma levels were demonstrated to be elevated in Gaucher disease. Given the similarities between Gaucher disease and ASMD, the hypothesis was that GPNMB might be a potential biochemical marker for ASMD as well. Plasma samples of ASMD patients were analyzed and GPNMB plasma levels were compared to those of healthy volunteers. Visceral disease severity was classified as severe when splenic, hepatic and pulmonary manifestations were all present and as mild to moderate if this was not the case. Median GPNMB levels in 67 samples of 19 ASMD patients were 185 ng/ml (range 70-811 ng/ml) and were increased compared to 10 healthy controls (median 36 ng/ml, range 9-175 ng/ml, p < 0.001). Median plasma GPNMB levels of ASMD patients with mild to moderate visceral disease compared to patients with severe visceral disease differed significantly and did not overlap (respectively 109 ng/ml, range 70-304 ng/ml and 325 ng/ml, range 165-811 ng/ml, p < 0.001). Correlations with other biochemical markers of ASMD (i.e. chitotriosidase activity, CCL18 and lysosphingomyelin, respectively R = 0.28, p = 0.270; R = 0.34, p = 0.180; R = 0.39, p = 0.100) and clinical parameters (i.e. spleen volume, liver volume, diffusion capacity and forced vital capacity, respectively R = 0.59, p = 0.061, R = 0.5, p = 0.100, R = 0.065, p = 0.810, R = -0.38, p = 0.160) could not be established within this study. The results of this study suggest that GPNMB might be suitable as a biomarker of visceral disease severity in ASMD. Correlations between GPNMB and biochemical or clinical markers of ASMD and response to therapy have to be studied in a larger cohort.

Similarities and differences between Gaucher disease and acid sphingomyelinase deficiency: An algorithm to support the diagnosis.

Lysosomal storage disorders are a group of inborn errors of metabolism due to defects in proteins crucial for lysosomal function. Gaucher disease is the most common autosomal recessive lysosomal storage disorder due to mutations in the GBA1 gene, resulting in the lysosomal deficiency of glucocerebrosidase activity. Gaucher disease is characterized by the toxic accumulation of glucosylceramide in the reticuloendothelial system. Acid sphingomyelinase deficiency (ASMD), previously known as Niemann Pick A/B disease, is also an autosomal recessive lysosomal storage disorder due to mutations in the SMPD1 gene, which result in acid sphingomyelinase deficiency and the accumulation of sphingomyelin in mononuclear phagocytic system and hepatocytes. The phenotypic expression of Gaucher disease type 1 (GD1), the most common type, and chronic visceral ASMD may overlap for several signs or symptoms. Splenomegaly is detectable in approximately 90% of the patients in both conditions; however, since GD1 is more frequent than ASMD, clinicians are more prone to suspect it, often neglecting the diagnosis of ASMD. Based on previous experience, a group of experts in the clinical and laboratory diagnosis, management, and treatment of lysosomal storage disorders developed an algorithm for both GD1 and ASMD to support physicians, including primary care providers, internists, and specialists (e.g., hepatologists, hematologists, and pulmonologists) to suspect and differentiate GD1 and ASMD and to provide the appropriate referral.

Three-years misdiagnosis of Niemann Pick disease type B with novel mutations in SMPD1 gene as Budd-Chiari syndrome.

BACKGROUND: The chronic visceral subtype of acid sphingomyelinase deficiency, commonly known as Niemann Pick disease type B (NPDB), is a relatively rare autosomal recessive genetic disorder that is caused by mutations in the SMPD1 gene. NPDB with sea-blue histiocytes (SBH) clinically mimics Budd-Chiari syndrome (BCS), as it lacks specific clinical characteristics. This makes its diagnosis difficult. CASE PRESENTATION: Here, we report a case of NPDB with SBH that was misdiagnosed as BCS for three years. A 20-year-old female with abdominal distension, hepatosplenomegaly, and haematological anomalies was initially diagnosed with BCS based on her imaging finding of a thin hepatic vein and rapid blood flow at the confluence of the hepatic vein and inferior vena cava. Her bone marrow cytology found sea-blue histiocytes. Liver biopsy showed foamy cytoplasm in hepatocytes surrounded by numerous Kupffer cells. Sequencing analysis of the SMPD1 gene led to the finding of two missense mutations in the heterozygous state: C.829 T > C (p.Trp277Arg) in exon 2 (novel) and c.1805G > A (p.Arg602His) in exon 6 (already described). These findings established the diagnosis of NPDB. CONCLUSION: The patient presented with hepatosplenomegaly, haematological anomalies, and dyslipidaemia. Thus, NPDB should be considered following the exclusion of related diseases. The diagnosis of NPDB was suspected by clinical symptoms and routine laboratory tests and was confirmed by liver biopsy and gene sequencing. The novel mutation c.829 T > C in exon 2 of the SMPD1 gene has never been reported and needs to be further investigated.

Spontaneous splenic rupture as the first clinical manifestation of Niemann-Pick disease type B: A case report and review of the literature.

Splenomegaly is the most common phenotype for Niemann-Pick disease type B (NPD-B), an autosomal recessive lipid storage disease caused by deficiency of the lysosomal enzyme acid sphingomyelinase. Although a spleen of massive volume is common in NPD-B, splenic rupture in this disease is rarely reported. We describe a patient with NPD-B who initially presented with spontaneous splenic rupture. Microscopic examination of the spleen specimen revealed expansion of the red pulp by abundant foamy histiocytes. A literature review revealed that splenic rupture resulting from latent splenomegaly may occur in middle adulthood in a mild form of NPD-B associated with SMPD1 variants of lower pathogenicity. We suggest that unexplained splenomegaly or splenic rupture should raise the possibility of a lysosomal storage disease, including NPD. For patients with NPD-B, spleen size should be evaluated periodically, and the risk of splenic rupture should always be considered.

Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family.

OBJECTIVES: Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). CASE PRESENTATION: Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). CONCLUSIONS: Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

Niemann-Pick Disease Type B in Traumatic Splenic Rupture.

The rupture of spleen is common in clinical and forensic practice. Trauma is the most common cause of splenic rupture. Although rare, traumatic splenic rupture may occur in these individuals with asymptomatic underlying disease, and clinical and forensic pathologists may neglect the disease and diagnose only the traumatic splenic rupture. Here, we present a case of postinjury splenic rupture resulting in splenectomy, where the patient was diagnosed with Niemann-Pick disease type B through histopathological examination and genetic testing. In forensic practice, in cases of isolation splenic rupture, full microscopy should be done to differentiate traumatic rupture from a spontaneous bleed due to an underlying disease process.

Multimodal imaging including optical coherence tomography angiography in patients with type B Niemann-Pick disease.

PURPOSE: To evaluate accumulation patterns of deposits in retinal layers of type B Niemann-Pick patients by multimodal imaging. METHODS: Seven patients with type B Niemann-Pick disease were included in this study. All participants underwent a complete ophthalmologic evaluation, high-resolution digital colour imaging, spectral-domain optical coherence tomography, blue light fundus autofluorescence and optical coherence tomography angiography (OCTA). RESULTS: We demonstrated different accumulation patterns in the retinal ganglion cell layer, the retinal nerve fibre layer and the subfoveolar region by multimodal imaging. Local retinal capillary nonflow areas in the superficial plexus, increased vascular tortuosity and deformed foveal avascular areas were shown in OCTA scans. CONCLUSION: Multimodal imaging including OCTA is a useful technique for the identification of different types of accumulation patterns, diagnosis and follow-up of type B Niemann-Pick patients.

Utility of amniotic fluid chitotriosidase in the prenatal diagnosis of lysosomal storage disorders.

OBJECTIVE: Plasma chitotriosidase is a documented biomarker for certain lysosomal storage disorders. However, its clinical utility for prenatal samples is not elucidated yet. METHODS: We have established Reference intervals for amniotic fluid chitotriosidase using control amniotic fluids (n = 47) and compared the activity with amniotic fluids affected by lysosomal storage disorders (n = 25). RESULTS: The reference interval established was 0-6.76 nmol/h/ml. The amniotic fluids affected with LSDs exhibited elevation of chitotriosidase. The area under the curve (AUC) of receiver operating characteristic curve for affected vs. healthy was 0.987 indicating 98.6% accuracy of chitotriosidase in identifying pregnancies affected with LSDs. Among the different LSDs, Gaucher (202.00 ±â€¯35.27 nmol/h/ml) and Niemann-pick A/B (60.33 ±â€¯21.59 nmol/h/ml) showed very high levels of chitotriosidase. CONCLUSION: Amniotic fluid chitotriosidase has the potential to serve as a diagnostic marker for lysosomal storage disorders, more specifically for Gaucher and Niemann-Pick A/B.

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases. BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement. PURPOSE AND METHODS: An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes. CONCLUSIONS: Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD.Genet Med advance online publication 13 April 2017.

Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases.

Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.

[Acid sphingomyelinase deficiency (Niemann-Pick disease type B) in adulthood: A retrospective multicentric study of 28 adult cases]. / Déficit en sphingomyélinase acide (maladie de Niemann-Pick B) : une étude rétrospective multicentrique de 28 patients adultes.

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/mm3) in 24 cases including 4 patients with platelet count <60 000/mm3, 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.

Niemann-Pick Disease Type B in a 21 Year Old Male.

Niemann-pick disease is a group of autosomal recessive disorder of lipid storage with progressive accumulation of sphingomyelin and other lipids in the lysosomes of various tissues. We are reporting a 21 year old male who had hepatosplenomegaly, cherry red macula and normal cognitive function. Bone marrow biopsy showed plenty of foam cells and sphingomyelinase level was low, thus conforming our diagnosis. Survival into adulthood and absence of gross neurological involvement suggests Niemann-Pick disease type B.

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.

PURPOSE: Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important. METHOD: We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency. RESULTS: Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,000-1/36,000. CONCLUSION: We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

Niemann-Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease-causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus-specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B.