Neurological outcome in long-chain hydroxy fatty acid oxidation disorders.

OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.

Management, vaccination status and COVID-19 morbidity of patients with Gaucher disease in Germany during the COVID-19 pandemic.

BACKGROUND: Continuation of standard management of Gaucher disease (GD) has been challenging during the COVID-19 pandemic, resulting in infrequent/missed infusions and follow-up appointments. Little data are available on the consequences of these changes and on the SARS-CoV-2 vaccinations in German GD patients. METHODS: A survey with 22 questions about GD management during the pandemic was sent to 19 German Gaucher centres. It was answered by 11/19 centres caring for 257 GD patients (almost ¾ of the German GD population); 245 patients had type 1 and 12 had type 3 GD; 240 were ≥ 18 years old. RESULTS: Monitoring intervals were prolonged in 8/11 centres from a median of 9 to 12 months. Enzyme replacement therapy (ERT) was changed to home ERT in 4 patients and substituted by oral substrate reduction therapy (SRT) in 6 patients. From March 2020 to October 2021, no serious complications of GD were documented. Only 4 SARS-CoV-2 infections were reported (1.6%). Two infections were asymptomatic and two mild; all occurred in adult type 1, non-splenectomized patients on ERT. Vaccination rate in adult GD was 79.5% (95.3% mRNA vaccines). Serious vaccination complications were not reported. CONCLUSIONS: The COVID-19 pandemic has lowered the threshold for switching from practice- or hospital-based ERT to home therapy or to SRT. No major GD complication was documented during the pandemic. Infection rate with SARS-CoV-2 in GD may rather be lower than expected, and its severity is mild. Vaccination rates are high in GD patients and vaccination was well tolerated.

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Radiofrequency Pulmonary Vein Isolation without Esophageal Temperature Monitoring: Contact-Force Characteristics and Incidence of Esophageal Thermal Damage.

Esophageal thermal lesions following pulmonary vein isolation (PVI) for atrial fibrillation (AF) potentially harbor lethal complications. Radiofrequency (RF)-PVI using contact force-technology can reduce collateral damage. We evaluated the incidence of endoscopically detected esophageal lesions (EDEL) and the contribution of contact force to esophageal lesion formation without esophageal temperature monitoring. One hundred and thirty-one AF patients underwent contact force-guided RF-PVI. Contact force, energy, force-time-integral, and force-power-time-integral were adopted. During PVI at the posterior segment of the wide antral circumferential line, limits were set for energy (30 W), duration (30 s) and contact force (40 g). Ablations were analyzed postero-superior and -inferior around PVs. Endoscopy within 120 h identified EDEL in six patients (4.6%). In EDEL(+), obesity was less frequent (17% vs. 68%, p = 0.018), creatinine was higher (1.55 ± 1.18 vs. 1.07 ± 0.42 mg/dL, p = 0.016), and exclusively at the left postero-inferior site, force-time-integral and force-power-time-integral were greater (2973 ± 3267 vs. 1757 ± 1262 g·s, p = 0.042 and 83,547 ± 105,940 vs. 43,556 ± 35,255 g·J, p = 0.022, respectively) as compared to EDEL(-) patients. No major complications occurred. At 12 months, arrhythmia-free survival was 74%. The incidence of EDEL was low after contact force-guided RF-PVI. Implementing combined contact force-indices on the postero-inferior site of left-sided PVs may reduce EDEL.

Percutaneous transhepatic or endoscopic ultrasound-guided biliary drainage in malignant distal bile duct obstruction using a self-expanding metal stent: Study protocol for a prospective European multicenter trial (PUMa trial).

BACKGROUND: Endoscopic ultrasound-guided biliary drainage (EUS-BD) was associated with better clinical success and a lower rate of adverse events (AEs) than fluoroscopy-guided percutaneous transhepatic biliary drainage (PTBD) in recent single center studies with mainly retrospective design and small case numbers (< 50). The aim of this prospective European multicenter study is to compare both drainage procedures using ultrasound-guidance and primary metal stent implantation in patients with malignant distal bile duct obstruction (PUMa Trial). METHODS: The study is designed as a non-randomized, controlled, parallel group, non-inferiority trial. Each of the 16 study centers performs the procedure with the best local expertise (PTBD or EUS-BD). In PTBD, bile duct access is performed by ultrasound guidance. EUS-BD is performed as an endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS), EUS-guided choledochoduodenostomy (EUS-CDS) or EUS-guided antegrade stenting (EUS-AGS). Insertion of a metal stent is intended in both procedures in the first session. Primary end point is technical success. Secondary end points are clinical success, duration pf procedure, AEs graded by severity, length of hospital stay, re-intervention rate and survival within 6 months. The target case number is 212 patients (12 calculated dropouts included). DISCUSSION: This study might help to clarify whether PTBD is non-inferior to EUS-BD concerning technical success, and whether one of both interventions is superior in terms of efficacy and safety in one or more secondary endpoints. Randomization is not provided as both procedures are rarely used after failed endoscopic biliary drainage and study centers usually prefer one of both procedures that they can perform best. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03546049 (22.05.2018).

Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria.

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 µmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 µmol/L planned vs. 467 µmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 µmol/L planned vs. 414 µmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy.

Diagnosis and management of secondary causes of steatohepatitis.

The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.

Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study.

BACKGROUND: Only few data on dietary management of adult phenylketonuria (PKU) patients are published. OBJECTIVES: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients. METHODS: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions. RESULTS: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of single-person households was higher (22 vs. 47%), the rate of childbirth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients. CONCLUSION: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low.

Cardiometabolic risk factor clustering in patients with deficient branched-chain amino acid catabolism: A case-control study.

Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.

[Secondary causes of fatty liver disease - an update on pathogenesis, diagnosis and treatment strategies]. / Sekundäre Ursachen der Fettleber ­ Neues zur Pathogenese, rationalen Diagnostik und Therapie.

Secondary causes of fatty liver disease are important to recognize since specific therapy options are available for some of these causes. Common causes of secondary fatty liver disease comprise hepatitis C virus infection (HCV), endocrinological diseases, nutritional and intestinal diseases as well as genetic liver and metabolic diseases. Certain drugs may also predispose to the development of fatty liver disease. Primary fatty liver disease, also known as non-alcoholic fatty liver disease (NAFLD) is defined by the presence of steatosis hepatis without relevant alcohol consumption or other causes of secondary fatty liver disease. NAFLD occurs more frequently in patients with metabolic syndrome and thus can be seen as the hepatic manifestation of the metabolic syndrome.Therefore, presence of features of the metabolic syndrome should be assessed in all patients with fatty liver disease. Furthermore, alcohol consumption should be determined to rule out alcoholic liver disease (ASH). Further diagnostic work up for secondary causes of fatty liver disease should include screening for HCV infection, for hypothyroidism and for drugs associated with steatosis development. In a next step screening for Wilson's disease, hemochromatosis, celiac disease and lipid metabolism disorders should be performed. An extended endocrinological workup and a liver biopsy should be considered if the etiology of fatty liver disease remains unclear.Common genetic polymorphisms have been identified in several genes, such as PNPLA3, TM6SF2 and MBOAT7, which may promote the development and the progression of fatty liver disease irrespective of the underlying etiology (e. g. metabolic syndrome, ASH or HCV). The risk variants in these genes have additive effects on steatosis development and diseases progression towards fibrosis and cirrhosis. The diagnosis of secondary causes of fatty liver disease may allow for therapeutic intervention and prevent disease progression. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of NAFLD patients.

Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative.

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.

Hepatocellular carcinoma in Gaucher disease: an international case series.

Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cirrhosis, one of the main risk factors for the development of HCC, was present in nine out of 14 patients for whom data was available. Three out of seven examined patients showed a transferrin saturation > 45%. In these three patients the presence of iron overload after histopathological examination of the liver was shown. Chronic hepatitis C infection was present in three of 14 examined cases. We summarized all findings and made a comparison to the literature. We recommend that GD patients, especially those with prior splenectomy or iron overload, be evaluated for signs of liver fibrosis and if found to be monitored for HCC development.

Low Incidence of Esophageal Lesions After Pulmonary Vein Isolation Using Contact-Force Sensing Catheter Without Esophageal Temperature Probe.

Pulmonary vein isolation (PVI) is a cornerstone therapy for atrial fibrillation (AF). Although severe complications are rather rare, the development of an atrio-esophageal fistula (AEF) is a fatal complication with a very high mortality even after surgical treatment. The use of esophageal temperature probes (ETP) during PVI may protect the esophagus but it is still under debate since the ETP may also lead to esophageal lesions. The aim of this study was to evaluate the clinical safety of PVI using contact-force (CF) sensing catheter without esophageal temperature monitoring.We investigated 70 consecutive patients who underwent point-by-point PVI without usage of ETP and who underwent esophago-gastro-duodenoscopy (EGD) with detailed evaluation of the esophagus after the index PVI procedure. The operator attempted to keep CF within the 10-40 g range. The incidences of esophageal lesions (EDEL) detected by endoscopy were then analyzed.Two of 70 patients (2.9%) showed EDEL consisting of one longitudinal ulcer-like erythematous lesion with fibrin and a different one consisting of a round-shaped lesion surrounded by erythema and petechial hemorrhage. All EDEL healed within two weeks under high proton-pump inhibitor therapy without developing AEF as proven by a second EGD of the esophagus.Point-by-point PVI without usage of ETP showed a low incidence of EDEL (2.9%); atrio-esophageal fistula was absent. Further studies on the necessity of ETP under CF control are necessary.

Favourable Outcome in Two Pregnancies in a Patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency.

In patients with 3-hydroxy-3-methylglutaryl(HMG)-CoA lyase deficiency (OMIM 246450), five pregnancies have been described worldwide, which were either terminated or resulted in severe metabolic sequelae during pregnancy or delivery. Here, we report on a patient with HMG-CoA lyase deficiency, who underwent two uncomplicated pregnancies. The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status. Urine organic acid analysis showed an elevated excretion of 3-CH3-glutaric acid, 2,3-CH3-glutaconic acid, and 3-CH3-3-OH-glutaric acid. Oral treatment with carnitine and glucose wes administered intravenously during the period of nausea and vomiting. After clinical recovery, a diet with 0.89 g/kg of protein/d and 38 kcal/kg body weight/d was given. Meals were taken every 3 h. Additionally, 70 g of starch was given at midnight to maintain normoglycemia at night time. Peripartum, a complete parenteral nutrition, was delivered through a central venous catheter. The patient delivered a healthy male infant by Caesarean section at week 38 of gestation (Apgar 9/10/10) and remained metabolically stable throughout the peripartum period. Postpartum nutrition was gradually changed from parenteral to oral diet. Two years later, the patient became pregnant again and presented with hyperemesis gravidarum. With metabolic monitoring and treatment as before no decompensation occurred. At week 38 of gestation, she delivered a healthy female infant by elective Caesarian section (Apgar 9/10/10). This case report describes the metabolic and obstetric management of two pregnancies in a patient with HMG-CoA lyase deficiency with favorable outcome without metabolic complications.

Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe.

PURPOSE: In Gaucher disease, diminished activity of the lysosomal enzyme, acid ß-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management. RESULTS: Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. CONCLUSIONS: As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.

Understanding the natural history of Gaucher disease.

Gaucher disease is a rare and extraordinarily heterogeneous inborn error of metabolism that exhibits diverse manifestations, a broad range of age of onset of symptoms, and a wide clinical spectrum of disease severity, from lethal disease during infancy to first age of onset of symptoms in octogenarians. Before the advent of the International Collaborative Gaucher Group (ICGG) Gaucher Registry, the understanding of the natural history and phenotypic range of Gaucher disease was based on isolated case reports and small case series. Limited data hindered understanding of the full spectrum of the disease leading to some early misconceptions about Gaucher disease, notably, that nonneuronopathic (type 1) disease was a disease of adults only. The global scope of the ICGG Gaucher Registry, with its vast body of longitudinal data, has enabled a real appreciation of both the phenotypic spectrum of Gaucher disease and its natural history. This body of evidence represents the foundation for accurate assessment of the response to specific therapies for Gaucher disease and to the development of standard-of-care to monitor disease activity. Here, we outline the key developments in delineating the natural history of this highly complex disease and role of the ICGG Gaucher Registry in this effort.

Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism.

Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid ß-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment.

OBJECTIVE: We studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1). METHODS: The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance. RESULTS: As of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0 % vs. 42.8 %) and thrombocytopenia (14.2 % vs. 76.3 %), similar percentages of moderate or severe hepatomegaly (81.2 % vs. 80.0 %), and higher percentages of bone pain (88.9 % vs. 52.4 %) and bone crises (38.3 % vs. 16.0 %). After 10 years, both groups showed significant (p < 0.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2 weeks. After 10 years, the majority was receiving 15 to ≤45 U/kg every 2 weeks. CONCLUSION: Ten years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.