Enzyme replacement therapy in two patients with classic Fabry disease from the same family tree:Two case reports

BACKGROUND The pathophysiology of Fabry disease(FD)-induced progressive vital organ damage is irreversible.Disease progression can be delayed using enzyme replacement therapy(ERT).In patients with classic FD,sporadic accumulation of globotriaosylceramide(GL-3)in the heart and kidney begins in utero;however,until childhood,GL-3 accumulation is mild and reversible and can be restored by ERT.The current consensus is that ERT initiation during early childhood is paramount.Nonetheless,complete recovery of organs in patients with advanced FD is challenging.CASE SUMMARY Two related male patients,an uncle(patient 1)and nephew(patient 2),presented with classic FD.Both patients were treated by us.Patient 1 was in his 50s,and ERT was initiated following end-organ damage;this was subsequently ineffective.He developed cerebral infarction and died of sudden cardiac arrest.Patient 2 was in his mid-30s,and ERT was initiated when the patient was diagnosed with FD,during which the damage to vital organs was not overtly apparent.Although he had left ventricular hypertrophy at the beginning of this treatment,the degree of hypertrophy progression was limited to a minimal range after>18 years of ERT.CONCLUSION We obtained discouraging ERT outcomes for older patients but encouraging outcomes for younger adults with classic FD.

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21^(st) century

Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes,(e.g., giving unprotected enzymes at the start of the mealand acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy.

Motor Development as a Potential Marker to Monitor Infantile Pompe Disease on Enzyme Replacement Therapy

After Enzyme Replacement Therapy (ERT) using recombinant human acid alpha-glucosidase (rhGAA), survival of Infantile Pompe Disease (IPD) patients through the first 18 months of age has been documented and acquisitions of motor development are an important outcome, but description of its course is scarce. Objective: To describe the motor development in an IPD patient and its correlation with clinical conditions during the first 18 months on ERT with rhGAA. Methods: By longitudinal observational study of an IPD case at early stage. Clinical and biochemical characteristics were obtained from patient records. Echocardiogram assessed cardiac indexes and the urinary biomarker—glucose tetrasaccharide (Glc4)—was obtained by HPLC/UV, following sample derivatization with butyl 4-amino benzoate and analysis on a C18 stationary phase column. Motor skills were evaluated with Alberta Infant of Motor Scale (AIMS) and motor delay was considered as motor percentile (p) below 10. Descriptive statistical analysis was carried out and t-test was used to calculate the differences among means, with significance level defined as p value < 0.05. Results: After ERT beginning amelioration of the cardiomyopathy with reduced left ventricle mass index (LVMI) from the 2nd month onwards was observed, but above the upper normal limit for healthy children and CRIM-positive IPD patients. Although GAA antibodies level remained above the recommended titers and fluctuating elevation of Glc4 quantified, motor development analysis showed an ascendant curve expected for age within achievement of independent ambulation. Motor delay after pneumonia and maintenance of hypotonia were noted. Variation of Glc4 appeared long after a transitory intercurrence. Conclusion: In an IPD case, motor development can have normal evolution despite hypotonia. Motor analysis seems to be sensitive to follow-up clinical intercurrences. To elucidate the interaction among prognostic factors and outcomes, further clinical studies need to be conducted.

Clinical and Technological Dependence Characteristics on a Series of Brazilian Cases with Infantile Onset Pompe Disease in Enzyme Replacement Therapy

Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.

Fabry Disease: Update, Focusing on Heart Disease by Multimodal Imaging

Fabry disease (FD) is a rare X-linked lysosomal accumulation disorder caused by a deficiency in the enzyme alpha-galactosidase A (Gal A), resulting in excessive storage of glycosphingolipids, particularly globotriaosylceramide (Gb3). This leads to cellular dysfunction in various organs, with cardiovascular compromise being the major cause of morbidity and mortality. This study aimed to provide a comprehensive overview of FD focusing on its genetic, epidemiological, clinical, diagnostic, and therapeutic aspects. This study explored the genetic mutations associated with FD, its epidemiology, clinical phenotypes, cardiac manifestations, diagnostic approaches, and current treatment options. Background: FD is caused by mutations in GLA on the X chromosome, with over 1000 identified variants. Neonatal screening and specific studies have shown an increased incidence of FD. The clinical presentation varies between classic and late phenotypes, with cardiac involvement being a major concern, particularly in late-onset FD. Purpose: This study aimed to summarize the current knowledge on FD, emphasizing cardiac involvement, diagnostic modalities, and treatment options. Methods: A literature review of relevant studies on FD, including genetics, epidemiology, clinical presentation, diagnostic methods, and treatment options, was conducted. Results: Cardiac manifestations of FD included left ventricular hypertrophy (LVH), heart failure, arrhythmias, and sudden death. Diagnostic approaches such as electrocardiography, echocardiography, and cardiac magnetic resonance imaging play crucial roles in the early detection and monitoring of cardiac involvement. Enzyme replacement therapy (ERT) and emerging treatments have shown promise in managing FD, although challenges remain. Conclusions: FD remains a challenging condition in cardiology, with under-diagnosis being a concern. Early detection and specific therapy are essential to improve patient outcomes. Echocardiography and cardiac MRI are valuable tools for diagnosis and follow-up. Despite the advances in treatment, accessibility remains an issue. More research is needed to deepen our understanding of FD and to improve therapeutic strategies.

The Diagnostic and Therapeutic Challenges of Fabry Nephropathy—A Review of the Literature, Illustrated by a Clinical Case

Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical to milder nonclassical or late-onset phenotypes. Renal involvement, termed Fabry Nephropathy (FN), can vary from mild proteinuria to kidney failure. FN diagnosis, especially in nonclassical cases with a genetic Variant of Unknown Significance (VUS) in the GLA gene, poses challenges. Measurement of plasma lyso-Gb3 levels is gaining importance in FN diagnosis, while renal biopsy with electron microscopy remains the gold standard in equivocal cases. Treatment options include Enzyme Replacement Therapy (ERT) and chaperone therapy, demanding careful candidate selection due to high treatment costs. Research has predominantly focused on classical FD, revealing modest treatment benefits. However, evidence for treating patients, especially females, with milder nonclassical or late-onset phenotypes is scarce, emphasizing the necessity for placebo-controlled clinical trials in these subgroups. Meanwhile, participation in global FD registries can improve our understanding of disease management. Case Presentation: A woman in her late sixties presented with moderate chronic kidney disease, mild proteinuria, and microscopic hematuria. Her family history included a prevalence of renal, cardiac and cerebrovascular diseases. Kidney biopsy revealed characteristic myelin figures and zebra bodies in podocytes, strongly suggestive of FN. Genetic analysis identified a VUS in the GLA gene (c.655A > C, p.Ile219Leu), introducing diagnostic uncertainty. Further investigations revealed severe cardiac involvement. Considering the recurring difficulty presented by the finding of a VUS in the GLA gene during FN assessments, along with the uncertainty regarding the need for treatment in nonclassical or late-onset FD phenotypes, especially in women, this case becomes a central focus for a thorough review of the literature. This review aims to propose a practical algorithm that integrates clinical, biochemical, and genetic markers for FN screening and diagnosis. Additionally, it explores treatment benefits in nonclassical or late-onset FD phenotypes, with a focus on female patients.

Atypical infantile-onset Pompe disease with good prognosis from China's Mainland:A case report

BACKGROUND Pompe disease has a broad disease spectrum,including infantile-onset Pompe disease(IOPD)and late-onset Pompe disease(LOPD)forms.It is a type of glycogen storage disorder belonging to autosomal recessive genetic disease,for an estimated incidence of 1/40000 among the neonatal population.In severe cases,the natural course is characterized by death due to cardiopulmonary failure in the first year after birth.However,the clinical outcomes have improved since the emergence of enzyme replacement therapy(ERT)was widely used.CASE SUMMARY The reported female case in China was an atypical IOPD,which demonstrates an unusual presentation of glycogen accumulation syndrome typeⅡwithout obvious skeletal muscle involvement,and reviewed physical examination,biochemical examinations,chest radiograph,and acidα-glucosidase(GAA)mutation analysis.After 4-mo specific ERT,the case received 12-mo follow-up.Moreover,the patient has obtained a very good prognosis under ERT.CONCLUSION For the atypical IOPD patients,early diagnosis and treatment may contribute to good prognosis.

Cardiac Complications in Maroteaux-Lamy Syndrome： Case Report

MLS （Maroteaux-Lamy syndrome） or MPS VI （mucopolysaccharidosis VI） is an autosomal recessive pathology in which there is absence or low activity of the enzyme N-Acetylgalactosamine-4-Sulfatase, which hydrolyzes GAGs （glycosaminoglycans） in the body （mainly dermatan sulfate）. Consequently, there occurs lysosomal deposition of GAGs in connective tissue multisystemic. Myocardium and heart valves are frequently affected structures, presenting a direct correlation with the reports of complications and deaths. Case report： RGS, male, 3 years and 2 months, diagnosed with MPS VI from the first month of life, in weekly ERT （enzyme replacement therapy） since 4 months of age （inconstant）. At physical examination： normotensive, with holosystolic heart murmur 3＋/6＋ in mitral focus. Complementary tests： normal electrocardiogram, echocardiogram with pronounced mitral regurgitation, concentric left ventricular hypertrophy of moderate degree and mild aortic insufficiency. Discussion： Mitral valve disease is common in patients with MLS. Conditions such as cardiomyopathy, fibroelastosis, aneurysm and pulmonary hypertension may occur in these patients, indicative of morbidity and mortality. Early and constant ERT may be useful in slowing a progression of heart disease. Conclusions： follow-up with a cardiologist is important to evaluate the progression of cardiac complications in MPS VI. Constant and early ERT provides better prognosis for these patients.

Impacts of pancreatic exocrine insufficiency on gut microbiota

Pancreatic exocrine insufficiency(PEI)can be induced by various kinds of diseases,including chronic pancreatitis,acute pancreatitis,and post-pancreatectomy.The main pathogenetic mechanism of PEI involves the decline of trypsin synthesis,disorder of pancreatic fluid flow,and imbalance of secretion feedback.Animal studies have shown that PEI could induce gut bacterial overgrowth and dysbiosis,with the abundance of Lactobacillus and Bifidobacterium increasing the most,which could be partially reversed by pancreatic enzyme replacement therapy.Clinical studies have also confirmed the association between PEI and the dysbiosis of gut microbiota.Pancreatic exocrine secretions and changes in duodenal p H as well as bile salt malabsorption brought about by PEI may affect and shape the abundance and composition of gut microbiota.In turn,the gut microbiota may impact the pancreatic exocrine acinus through potential bidirectional crosstalk.Going forward,more and higher-quality studies are needed that focus on the mechanism underlying the impact of PEI on the gut microbiota.

Electroencephalogram and phenotype patterns in neuronopathic Gaucher disease patients-ten years of experience in a single center

Background This study aimed to investigate the unique electroencephalography(EEG)patterns in neuronopathic Gaucher disease(GD)patients and explore the correlations between EEG findings and neurological phenotypes so as to optimize clinical outcomes.Methods A retrospective analysis was conducted on 74 EEG recordings from 50 GD patients between January 2012 and July 2022.Results Twenty-three patients exhibited abnormal EEG recordings,including 11 of the GD1 type(the transitional type)and 12 with neuronopathic GD.Of the 12 neuronopathic GD patients,9 patients with epilepsy were analysed specifically in terms of the clinical course.The primary waveform observed in the neuronopathic EEG recordings was the spike-and-wave complex(SWC)during both awake and sleep states.This was significantly different from sharp waves observed only during sleep in the patients of the transitional type(P=0.0230).The abnormal discharges in the neuronopathic patients were most commonly located in the bilateral Rolandic areas,while the transitional type commonly involved the bilateral frontal regions.Three patients with an epileptic EEG pattern reported their initial seizures years later.Seizures in the neuronopathic patients were effectively controlled with anti-seizure medications(ASMs),despite the ongoing presence of abnormal EEG patterns.The EEG patterns during ocular symptoms were characterized by sporadic or continuous unilateral SWC during sleep.Conclusions Patients with neuronopathic GD exhibit distinct EEG patterns that can help differentiate them from GD1 patients.Early treatment with ASMs can effectively control seizures.EEG plays a crucial role in monitoring seizures and can facilitate prompt intervention for GD patients.

The Hong Kong consensus recommendations on the diagnosis and management of pancreatic cystic lesions

Background:The finding of pancreatic cystic lesions(PCL)on incidental imaging is becoming increasingly common.International studies report a prevalence of 2.2-44.7%depending on the population,imaging modality and indication for imaging,and the prevalence increases with age.Patients with PCL are at risk of developing pancreatic cancer,a disease with a poor prognosis.This publication summarizes recommendations for the diagnosis and management of PCL and post-operative pancreatic exocrine insufficiency(PEI)from a group of local specialists.Methods:Clinical evidence was consolidated from narrative reviews and consensus statements formulated during two online meetings in March 2022.The expert panel included gastroenterologists,hepatobiliary surgeons,oncologists,radiologists,and endocrinologists.Results:Patients with PCL require careful investigation and follow-up due to the risk of malignant transformation of these lesions.They should undergo clinical investigation and pancreas-specific imaging to classify lesions and understand the risk profile of the patient.Where indicated,patients should undergo pancreatectomy to excise PCL.Following pancreatectomy,patients are at risk of PEI,leading to gastrointestinal dysfunction and malnutrition.Therefore,such patients should be monitored for symptoms of PEI,and promptly treated with pancreatic enzyme replacement therapy(PERT).Patients with poor response to PERT may require increases in dose,addition of a proton pump inhibitor,and/or further investigation,including tests for pancreatic function.Patients are also at risk of new-onset diabetes mellitus after pancreatectomy;they should be screened and treated with insulin if indicated.Conclusions:These statements are an accurate summary of our approach to the diagnosis and management of patients with PCL and will be of assistance to clinicians treating these patients in a similar clinical landscape.

From cradle to grave:seamless management of chronic pancreatitis but consider the special requests for children

We have read the position paper by A.Jay Freeman and the members of the Pancreas Nutrition Committee of the North American and the European Societies for Pediatric Gastroenterology,Hepatology,and Nutrition(NASPGHAN and ESPGHAN)(1).That paper focused on chronic pancreatitis(CP)in children and endoscopic procedures about which NASPGHAN published a second position paper(2).There are clinical practice guidelines for the management of CP in adults but not for CP in children(3).

Pancreatic exocrine insufficiency guidelines:more questions than answers!

Pancreatic exocrine insufficiency(PEI)has classically been described as a maldigestive disorder resulting from decreased secretion or altered function of pancreatic digestive enzymes(1).As a result of this maldigestion and ensuing malabsorption,patients can experience symptoms such as steatorrhea and weight loss as well as complications related to the loss of fat-soluble vitamins and micronutrients.PEI has been most extensively studied in cystic fibrosis,but other causes include acute and chronic pancreatitis(CP),pancreatic adenocarcinoma(PDAC),and rarely,congenital syndromes such as Shwachman-Diamond and Johnson-Blizzard(2).

Neurological manifestations in Fabry disease

Fabry disease(FD)is a rare,progressive,multisystem and highly debilitating disease.FD is an X-linked lysosome storage disorder that results inα-galactosidase A deficiency.The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells.The resulting effect of the deposition is generalized inflammation and vasculopathy,which can also affect the central and peripheral nervous system.FD progresses with kidney dysfunction,angiokeratoma of the skin,cardiomyopathy,cerebrovascular events and neurological disorders.In the present review,the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy,cochlear nerve dysfunction,psychiatric and cognitive symptoms,autonomic dysfunction and peripheral neuropathy.Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life,which make it essential to diagnose FD as soon as possible.

Current strategies for the treatment of inborn errors of metabolism

Inborn errors of metabolism（IEMs） are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.

Exocrine pancreatic insufficiency: more compromise than precision

Exocrine pancreatic insufficiency(EPI)can be defined as a reduction in the secretion or intraluminal activity of pancreatic enzymes at a level that does not allow the normal digestion of nutrients contained in food.This condition is difficult to diagnose and treat and has long been misunderstood,underestimated,and overlooked to some extent.