Niemann-pick in children

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann-Pick disease...

BACKGROUND: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. RESULTS: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments...

The clinical manifestation of sphingolipidosis leads often to misclassification between acid sphingomyelinase deficiency (ASMD) and Gaucher disease. In this multicenter, prospective study, we investigated a cohort of 31,838 individuals suspected to have Gaucher disease, due to clinical presentation, from 61 countries between 2017 and 2022. For all samples, both Acid-β-glucocerebrosidase and acid sphingomyelinase enzyme activities were measured in dried blood spot specimens by tandem mass spectrometry followed by genetic confirmatory testing in potential positive cases...

BACKGROUND: There is limited information about the efficacy of ovarian tissue cryopreservation (OTC) in children. In the present study, we report eight patients with rare diseases who underwent OTC in China's first and largest ovarian tissue cryobank. PROCEDURE: Data from girls with rare diseases who underwent OTC between September 2020 and November 2022 were retrospectively analyzed. We also compared the number of cryopreserved cortex pieces, follicle number, and AMH in those with rare diseases and age-matched children with non-rare diseases who also underwent OTC in our cryobank...

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease with multi-systemic involvement, with no disease-modifying treatment available. Olipudase alfa is an investigational enzyme product developed to replace the deficient acid sphingomyelinase in ASMD patients. Several clinical trials have reported promising safety and efficacy results in adult and pediatric patients. However, no data have been reported outside of the clinical trial setting yet. This study aimed to evaluate major outcomes in pediatric chronic ASMD patients receiving olipudase alfa in the real-world setting...

BACKGROUND: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. METHODS: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data...

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically...

Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder. There are two types, NPC1, which is the predominant form (95%), and the rare NPC2, which represents less than 5% of the reported cases. Niemann-Pick disease type C2 usually presents with respiratory symptoms, cholestasis, neurological impairment, and hepatosplenomegaly. Case report: Here, we report a 3-year-old boy who presented to our hospital with exacerbation of chronic lung disease requiring invasive ventilatory support...

Infantile Krabbe disease is a rapidly progressive and fatal disorder of myelin, caused by inherited deficiency of the lysosomal enzyme β-galactocerebrosidase. Affected children lose their motor skills and other faculties; uncontrolled seizures are a frequent terminal event. Overexpression of the sphingolipid metabolite psychosine is a pathogenic factor, but does not fully account for the pleiotropic manifestations and there is a clear need to investigate additional pathological mechanisms. We examined innate immunity, caspase-11 and associated inflammatory pathways in twitcher mice, an authentic model of Krabbe disease...

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704)...

Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders...

Niemann-Pick C disease frequently presents as severe cholestatic disease in infants. However, it progressively becomes less of a problem as children age. We have found that, in an appropriate mouse model, liver cholesterol levels, which are initially very high, decrease while mitochondrial function, initially quite compromised, increases with age. The key mitochondrial regulator, MNRR1, increases in parallel with the increase in mitochondrial function. These changes appear to explain the amelioration of the liver disease that occurs with time in this disorder...

Niemann-Pick disease type C (NPC) is a rare autosomal recessive neuro-visceral lipid storage disease. We describe nine cases of infantile-onset NPC with various genetic mutations in the NPC1 gene, which presented with neonatal cholestasis. Serum alpha-fetoprotein (AFP) levels were obtained as part of their workup during the first four months of life. In eight of nine (89%) patients, serum AFP demonstrated elevated levels. Seven infants displayed marked elevations, ranging from 4 to 300 times the upper limit for age-adjusted norms...

Objective: Lysosomal storage disorders (LSDs) are becoming increasingly important in newborn screening, and tandem mass spectrometry (MS/MS) is widely used in newborn screening for LSDs through measurement of enzymatic activities in dried blood spots (DBSs). Overall, the determination of the cutoff value is important in such screening, and different laboratories have different methods of determining this value; most do not use a fixed cutoff value but rather calculate the corresponding batch cutoff value based on each batch of experimental data...

BACKGROUND AND AIMS: Niemann-Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. METHODS: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial...

Since the novel coronavirus (COVID-19) pandemic started, children and young adults have seldom been placed in high-risk groups, despite reports that they are at increased risk of severe forms of the disease and death in the presence of comorbidities. Herein we report an autopsy case of an 18-year-old female with a history of cerebral palsy (CP), recurrent respiratory infections, and newly diagnosed COVID-19, and who expired 22 days after presenting with symptoms of the disease. Gross findings were concurrent with CP-significant hypotrophy, with deep and wide brain sulci...

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These mutations cause the accumulation of unesterified cholesterol and other lipids in the lysosomes. NPC has a broad spectrum of clinical manifestations, depending on the age of onset. A 15-day-old infant presented at the Seoul National University Children's Hospital with neonatal cholestasis and hepatosplenomegaly, with the onset of jaundice at 5 days of age. Despite supportive treatment, the patient was considered for a liver transplant because of progressive liver failure...

BACKGROUND: To report on clinical presentation and outcomes of children who underwent liver transplantation (LTx) and were subsequently diagnosed to have Niemann-Pick type C (NPC). METHODS: Retrospective, descriptive, multi-centre review of children diagnosed with NPC who underwent LTx (2003-2018). Diagnosis was made by filipin skin test or genetic testing. RESULTS: Nine children were identified (six centres). Neonatal acute liver failure was the most common indication for LTx (seven children)...

Neurometabolic diseases are complex group of rare neurogenetic disorders, which are difficult to diagnose. Patients may have toxic metabolite accumulation, inadequate energy supply, or neurotransmitter deficiency, resulting in a variety of clinical manifestations and severity with enzyme activity or transporter function defects. Multiple organ involvement is frequently seen, among which neurological symptoms and signs are one of the most encountered problems. Ocular motor problems deserve special attention for it occurs in some inborn error of metabolism...

BACKGROUND: Neonatal cholestasis (NC) is one of the most serious diseases in newborns and infants and results from metabolic disorders, such as Niemann-Pick type C (NPC), among other causes. OBJECTIVE: We evaluated the incidence of NPC in our NC plus lysosomal storage disease (LSD) suspicious neonates and infants series. METHODS: The study included children (≤3 years old) with a history of NC together with a suspicion of LSD, referred from Spanish Hospitals during the period 2011-2020...