[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.

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.

Hepatopulmonary Syndrome and Multiple Arteriovenous Fistulas in a Child with Niemann-Pick Disease.

Background: Niemann-Pick disease (NPD) is caused by abnormal storage of sphingomyelin. NPD may affect the pulmonary system and cause hypoxia. In the present case, both hepatopulmonary syndrome (HPS) and pulmonary arteriovenous fistulas (PAVFs) developed in a child with NPD and were successfully treated with repeated embolization. Case Presentation: We have reported the case of a 16-year-old-girl with NPD who suffered severe hypoxia, dyspnea, fatigue, had multiple PAVFs, and was diagnosed with type 2 HPS. To improve oxygenation, 10 PAVFs were embolized. She needed re-embolization after 9 months because of hypoxia redevelopment. Conclusions: Pulmonary involvement, HPS, and/or PAVFs could be responsible for hypoxemia in patients with NPD, who should, therefore, be investigated for HPS and PAVFs. Embolization could be beneficial. Some patients may need repeated embolization.

Homozygous pArg610del Mutation Unusually Associated With Severe Delay of Growth in 2 Acid Sphingomyelinase Deficiency-affected Sibs.

BACKGROUND: Typically, patients with Acid Sphingomyelinase Deficiency (ASMD) because of p.Arg610del mutation, have mild phenotype with normal linear growth. OBSERVATION: We reported the case of 2 Tunisian brothers who have been referred for splenomegaly, polyadenopathies, pubertal, and growth delay. Molecular testing of SMPD1 gene revealed the presence of a homozygous p.Arg610del mutation. Lysosphingomyelin and its isoform-509 were both increased confirming ASMD for both cases. Growth hormone deficiency was highly suspected but growth hormone response after stimulating tests was acceptable for both patients. CONCLUSIONS: There is no correlation between phenotype-genotype in case of p.Arg610del mutation that could be associated to a severe delay of growth.

Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist.

Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.

Cognition and anatomy of adult Niemann-Pick disease type C: Insights for the Alzheimer field.

Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). However, the cognitive, psychiatric, and neuropathological features of adult NPC and their relation to AD have yet to be explored. We systematically reviewed the literature on adult NPC with a particular focus on cognitive and neuroanatomical abnormalities. The careful study of cognition in adult NPC allows drawing critical insights in our understanding of the pathophysiology of AD as well as normal cognition.

Niemann-Pick disease type B: HRCT assessment of pulmonary involvement / Doença de Niemann-Pick tipo B: avaliação do comprometimento pulmonar por TCAR

ABSTRACT Objective: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics. Methods: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. The inclusion criteria were presence of abnormal HRCT findings and diagnosis of NPD type B confirmed by histopathological examination of a bone marrow, lung, or liver biopsy specimen. Results: The most common clinical findings were hepatosplenomegaly and mild to moderate dyspnea. The most common HRCT patterns were smooth interlobular septal thickening and ground-glass opacities, which were both present in all patients. Intralobular lines were present in 12 patients (92.3%). A crazy-paving pattern was observed in 5 patients (38.4%), and areas of air trapping were identified in only 1 case (7.6%). Pulmonary involvement was bilateral in all cases, with the most affected area being the lower lung zone. Conclusions: Smooth interlobular septal thickening, with or without associated ground-glass opacities, in patients with hepatosplenomegaly is the most common finding in NPD type B.

RESUMO Objetivo: Analisar os achados de TCAR em pacientes com doença de Niemann-Pick (DNP) tipo B a fim de avaliar a frequência dos padrões tomográficos e sua distribuição no parênquima pulmonar, além das características clínicas mais frequentes. Métodos: Foram estudados 13 pacientes (3 do sexo masculino e 10 do sexo feminino) com idades variando de 5 a 56 anos. As imagens de TCAR foram avaliadas por dois observadores de forma independente, e os casos discordantes foram resolvidos por consenso. Os critérios de inclusão foram presença de anormalidades na TCAR e diagnóstico confirmado de DNP tipo B por exame anatomopatológico através de biópsias de medula óssea, pulmão ou fígado. Resultados: Os achados clínicos mais comuns foram hepatoesplenomegalia e dispneia leve a moderada. Os padrões tomográficos mais frequentes foram espessamento liso de septos interlobulares e opacidades em vidro fosco, presentes em todos os pacientes. Linhas intralobulares estiveram presentes em 12 pacientes (92,3%). O padrão de pavimentação em mosaico foi observado em 5 pacientes (38,4%). Áreas de aprisionamento aéreo foram identificadas em 1 dos casos (7,6%). O comprometimento pulmonar foi bilateral em todos os casos, sendo o terço inferior dos pulmões a região mais envolvida. Conclusões: O achado de espessamento liso de septos interlobulares, com ou sem opacidades em vidro fosco associadas, em pacientes com hepatoesplenomegalia é o achado mais frequente na DNP tipo B.

Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick type C1 disease in a 7-week-old male with cholestasis.

Niemann-Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1 Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in NPC1 by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy.

Niemann-Pick disease type B: HRCT assessment of pulmonary involvement.

OBJECTIVE: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics. METHODS: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. The inclusion criteria were presence of abnormal HRCT findings and diagnosis of NPD type B confirmed by histopathological examination of a bone marrow, lung, or liver biopsy specimen. RESULTS: The most common clinical findings were hepatosplenomegaly and mild to moderate dyspnea. The most common HRCT patterns were smooth interlobular septal thickening and ground-glass opacities, which were both present in all patients. Intralobular lines were present in 12 patients (92.3%). A crazy-paving pattern was observed in 5 patients (38.4%), and areas of air trapping were identified in only 1 case (7.6%). Pulmonary involvement was bilateral in all cases, with the most affected area being the lower lung zone. CONCLUSIONS: Smooth interlobular septal thickening, with or without associated ground-glass opacities, in patients with hepatosplenomegaly is the most common finding in NPD type B.

Pulmonary Involvement in Niemann-Pick Disease: A State-of-the-Art Review.

Niemann-Pick disease is a rare autosomal recessive lysosomal storage disease with three subtypes. Types A and B result from a deficiency of acid sphingomyelinase activity, associated with the accumulation of lipid-laden macrophages (so-called Niemann-Pick cells) in various tissues, especially the liver and spleen. Type A is a fatal neurodegenerative disorder of infancy. Type B Niemann-Pick disease is a less severe form with milder neurological involvement, characterized by hepatosplenomegaly, hyperlipidemia, and pulmonary involvement; most patients live into adulthood. Type C Niemann-Pick disease is a complex lipid storage disorder caused by defects in cholesterol trafficking, resulting in a clinical presentation dominated by neurological involvement. Pulmonary involvement occurs in all three types of Niemann-Pick disease, but most frequently in type B. Respiratory manifestations range from a lack of symptoms to respiratory failure. Progression of respiratory disease is slow, but inexorable, due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls, and pleura, potentially leading to a progressively worsening restrictive pattern on pulmonary function testing. Bronchoalveolar lavage has important diagnostic value because it shows the presence of characteristic Niemann-Pick cells. Radiographic findings consist of a reticular or reticulonodular pattern and, eventually, honeycombing, involving mainly the lower lung zones. The most common changes identified by high-resolution computed tomography are ground-glass opacities, mild smooth interlobular septal thickening, and intralobular lines. The aim of this review is to describe the main clinical, imaging, and pathological aspects of Niemann-Pick disease, with a focus on pulmonary involvement.