Initiation Of Enzyme Replacement Therapy Research Articles

Exploring Gaucher disease: A pediatric case of severe dyslipidemia and unique symptoms

Introduction: Gaucher disease is a rare inherited lysosomal storage disorder caused by mutations in the GBA gene, leading to glucocerebrosidase deficiency. This results in the accumulation of glucocerebroside in macrophages, forming "Gaucher cells" that infiltrate various tissues, primarily affecting the liver, spleen, bone marrow, and nervous system. The disease manifests in three types, with Type 1 being the most common and devoid of neurological symptoms. Diagnosis involves enzyme level testing, genetic screening, and imaging, while treatment primarily consists of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Case-Report: A one-year-old girl presented with weakness, irritability, and recurrent fever over six months, previously misdiagnosed with malaria and respiratory infections. Physical examination revealed pallor, hepatosplenomegaly, and cherry-red spots on fundoscopy. Laboratory findings indicated anemia, leukocytosis, and severe dyslipidemia, highlighting atypical features for Gaucher disease. Discussion: This case emphasizes the diagnostic challenges in pediatric Gaucher disease, especially with nonspecific symptoms. The combination of cherry-red spots and dyslipidemia suggests a unique variant or severity of the disease, underlining the necessity for heightened awareness among healthcare providers for prompt diagnosis. Conclusion: Gaucher disease should be considered in pediatric patients with unexplained systemic symptoms. Early detection and ERT initiation can significantly improve clinical outcomes. The case illustrates the variability in clinical presentations, emphasizing the need for comprehensive diagnostic evaluation.

Implementation of newborn screening for mucopolysaccharidosis type IVA and long-term monitoring in Taiwan

PurposeMucopolysaccharidosis IVA (MPS IVA) is a rare lysosomal storage disorder arising from a deficiency in N-acetylgalactosamine-6-sulfatase. MethodsFrom September 2019 to October 2023, a total of 264,843 Taiwanese newborns underwent screening for MPS IVA using dried blood spots and tandem mass spectrometry. ResultsAmong the 95 referred infants, 9 (9%) were confirmed to have MPS IVA (group 1), 18 (19%) were highly suspected to have MPS IVA (group 2), 61 (64%) were identified as heterozygotes of MPS IVA (group 3), and 7 (7%) were determined not to have MPS IVA (group 4). A total of 34 different GALNS (HGNC:4122) gene variants were identified through our MPS IVA newborn screening program. The most prevalent variant was c.857C>T p.(Thr286Met), found in 33 cases (29%), followed by c.953T>G p.(Met318Arg) in 22 cases (19%). Intravenous enzyme replacement therapy was initiated in 5 patients at ages ranging from 0.3 to 1.7 years. The estimated incidence of MPS IVA in this screening program was 3.4 per 100,000 live births. ConclusionBecause of the progressive nature of MPS IVA, an early diagnosis facilitated by newborn screening and prompt initiation of enzyme replacement therapy before irreversible organ damage occurs may result in improved clinical outcomes.

Intravenous Idursulfase for the Treatment of Mucopolysaccharidosis Type II: A Systematic Literature Review.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase. Signs and symptoms typically emerge at 1.5-4 years of age and may include cognitive impairment, depending on whether patients have the neuronopathic or non-neuronopathic form of the disease. Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant iduronate-2-sulfatase (idursulfase). A systematic literature review was conducted to assess the evidence regarding efficacy, effectiveness, and safety of ERT with intravenous idursulfase for MPS II. Electronic databases were searched in January 2023, and 33 eligible articles were found. These were analyzed to evaluate the effects of intravenous idursulfase and the overall benefits and disadvantages in patient subgroups. Studies showed that intravenous idursulfase treatment resulted in improved short- and long-term clinical and patient-centered outcomes, accompanied by a favorable safety profile. Patients with non-neuronopathic MPS II had more pronounced improvements in clinical outcomes than those with neuronopathic MPS II. In addition, the review identified that improvements in clinical outcomes are particularly apparent if intravenous idursulfase is started early in life, strengthening previous recommendations for early ERT initiation to maximally benefit patients. This review provides a comprehensive summary of our current knowledge on the efficacy of ERT in different populations of patients with MPS II and will help to inform the overall management of the disease in an evolving treatment landscape.

Challenges in Hypophosphatasia: Suspicion, Diagnosis, Genetics, Management, and Follow-Up.

Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum ALP levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges. Diagnosis of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines. Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.

Enzyme replacement therapy and immunotherapy lead to significant functional improvement in two children with Pompe disease: a case report

BackgroundPompe disease, a rare autosomal recessive disorder caused by acid alpha-glucosidase deficiency, results in progressive glycogen accumulation and multisystem dysfunction. Enzyme replacement therapy with recombinant human acid alpha-glucosidase is the standard of care; however, some patients develop anti-recombinant human acid alpha-glucosidase antibodies, leading to reduced efficacy. This case report presents two infants with early-onset Pompe disease who developed IgG antibodies to enzyme replacement therapy and were subsequently treated with methotrexate, highlighting the importance of monitoring antibody development and exploring alternative therapeutic approaches.Case presentationPatient 1, a 10-month-old female from Bogota, Colombia, presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy. Diagnostic tests confirmed early-onset Pompe disease, and enzyme replacement therapy was started at 12 months. Due to a lack of improvement and high anti-recombinant human acid alpha-glucosidase IgG antibody titers (1:1800), methotrexate was started at 18 months. After 8 months of combined therapy, antibody titers were negative and significant improvement in motor function was observed using the Gross Motor Function Measure 88. Patient 2, a 7-year-old female from Bogota, Colombia, was diagnosed with early-onset Pompe disease at 12 months and initiated enzyme replacement therapy. At 5 years of age, she experienced frequent falls and grip strength alterations. Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers (6400). Methotrexate was initiated, leading to a reduction in falls and antibody titers (3200) after 6 months, with no adverse events or complications. Motor function improvement was assessed using the Motor Function Measurement 32.ConclusionsThe presented cases highlight the importance of monitoring patients for anti-recombinant human acid alpha-glucosidase antibody development during enzyme replacement therapy and the potential benefit of methotrexate as an immunomodulatory agent in early-onset Pompe disease. Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic immune tolerance induction, may improve clinical outcomes and reduce the development of anti-recombinant human acid alpha-glucosidase antibodies. The cases also highlight the importance of objective motor function assessment tools, such as Gross Motor Function Measure 88 and Motor Function Measurement 32, in assessing treatment response. Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease.

#636 A phase 4, open label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease

Abstract Background and Aims Fabry disease (FD) is a rare inherited lysosomal storage disease caused by pathogenic GLA gene variants which result in a deficiency of the enzymatic activity of α-galactosidase A. Enzyme replacement therapy (ERT) is the mainstay of FD-specific treatment, but there are currently no reported clinical trials of ERT for FD in the Chinese population. This is the first phase 4 study to evaluate the safety and efficacy of ERT for FD in China since the approval of agalsidase beta in China in 2019. Method A 54-week, phase 4, open label, single arm, prospective, post-marketing surveillance (PMS) study of agalsidase beta (NCT05054387) was performed at 6 sites in China. Twenty-two Chinese ERT-naïve FD participants (≥8 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled and received infusions of agalsidase beta (Fabrazyme®, Sanofi) at a dose of 1.0 mg/kg every 2 weeks for up to 48 weeks. The primary endpoint was safety and tolerability of agalsidase beta. The endpoints of clinical efficacy included the changes of plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), FD symptoms (including angiokeratoma, hypohidrosis, anhidrosis, abdominal pain, headache, tinnitus, heat tolerance, and activity tolerance), and eGFR from baseline to week 48. A post-hoc subgroup analysis was conducted to explore the differences in ERT efficacy between two subgroups of different ages (<30 years and ≥30 years). Results All 22 patients completed the study intervention. There were 18 males (81.8%) and the mean age of ERT initiation was 29.0 ± 13.5 years. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%), which was less than ∼60% as previously reported for IARs. Most AEs were mild or moderate and no AE caused permanent treatment discontinuation or death. The mean plasma GL-3 and Lyso-GL-3 levels decreased remarkably at week 6 and remained stable throughout the trial, with the mean percentage reduction from baseline to week 6 through week 48 ranged from −34.6% ± 27.4% to ­41.9% ± 14.9% and −58.8% ± 20.2% to ­64.9% ± 12.7%, respectively (Fig. 1a and b). The reduction was more remarkable for the classic male patients (n = 18; GL-3: 7.99 ± 2.19 ug/mL at baseline and 4.31 ± 1.71 ug/mL at week 48, −46.0% ± 18.4%; Lyso-GL-3: 83.11 ± 25.69 ng/mL at baseline and 25.89 ± 13.43 ng/mL at week 48, −67.8% ± 17.6%). Thirteen (59.1%) participants experienced improved FD symptoms at week 48, with no cases of worsening symptoms. The mean eGFR was 115.6 ± 37.3 mL/min/1.73 m2 at baseline and 118.4 ± 42.9 mL/min/1.73 m2 at week 48, with a change of 0.0 ± 12.4 mL/min/1.73 m2 from baseline to week 48 (Fig. 1c). In the subgroup analysis, participants were divided into the younger group with age <30 years (n = 11) and the older group with age ≥30 years (n = 11) according to their age of ERT initiation. At week 48, the reduction of mean plasma GL-3 (−47.1% ± 23.6% vs −22.0% ± 26.0%) and Lyso-GL-3 levels (−72.4 ± 17.3% vs −48.2% ± 19.8%), the stabilization of renal function (the mean change of eGFR from baseline to week 48: 5.2 ± 7.9 mL/min/1.73 m2 vs −5.2 ± 14.1 mL/min/1.73 m2) and the percentage of symptom improvement (81.8% vs. 36.4%) were generally more remarkable in the younger group than in the older group (Table 1). Conclusion This first phase 4 study of ERT for Fabry disease in China demonstrates that agalsidase beta is safe and well tolerated with a relatively low IAR rate, and effective in reducing plasma GL-3 and Lyso-GL-3, improving symptoms, and stabilizing renal function in Chinese patients with FD. Furthermore, the present study implies that patients who initiate ERT at a younger age benefit more from the therapy. Funding: Commercial support - Sanofi Pharmaceuticals.

THE GLA D313Y MUTATION IN FABRY DISEASE: DIAGNOSTIC DILEMMAS AND THERAPEUTIC CONSIDERATIONS

Abstract Fabry disease is a genetic disorder caused by mutations in the GLA gene, which encodes alpha–galactosidase A, leading to enzyme dysfunction and subsequent accumulation of glycosphingolipids. In the classical form, it occurs in childhood or early adolescence with renal, cardiac, and neurological involvement, resulting in a poor prognosis. The GLA D313Y is a missense mutation resulting in a significant reduction of enzyme activity in plasma, while leukocyte enzyme activity remains within normal limits, leading to a "pseudo–deficiency" of enzyme activity with uncertain pathogenicity. In literature, it has been observed that individuals with this mutation may present predominantly with central neurologic manifestations, characterized by multifocal white matter lesions. Historically they do not receive indications for initiating enzyme replacement or molecular chaperone therapies. We present the case of a man affected by arterial hypertension and history of chronic lower limb pain who experienced a lacunar stroke at the age of 35. The GLA D313Y mutation was identified and enzyme activity assay in plasma was within normal limits, precluding the initiation of enzyme replacement therapy. Over the following years, he suffered two additional ischemic strokes, a progressive decline in renal function to stage 3, and acute coronary syndrome. Transthoracic echocardiography revealed hypertrophic non–obstructive cardiomyopathy (SIVd 20 mm) with normal biventricular ejection fraction. Cardiac magnetic resonance showed late gadolinium enhancement of inferior junctional and inferior wall in middle segment (Fig.1). Considering the patient‘s clinical conditions involving multi–organ impairment, an enzymatic activity test was performed on leukocytes, revealing a reduced activity. This prompted the decision to initiate enzyme replacement therapy. This case report supports the hypothesis that the D313Y mutation may be associated with a later presentation and not only neurological involvement. In our experience, it’s mandatory to proceed with the determination of leukocyte enzyme activity in presence of normal enzyme activity in plasma. As an alternative, the detection of glycosphingolipids’ accumulation could be useful, but myocardial and renal biopsy poses a high bleeding risk, especially in anticoagulated or antiaggregated patients. The authors propose considering the initiation of therapy in patients with the D313Y mutation who exhibit significant organ involvement.

Patrones de seguimiento y manejo clínico multidisciplinario en pacientes con Mucopolisacaridosis tipo IVA en Colombia

Background: There is limited data on the follow-up and management of patients with mucopolysaccharidosis IVA (MPS-IVA) undergoing enzyme replacement therapy (ERT) in Colombia. Objective: We aim to assess the real-world data of patients with MPS-IVA undergoing ERT in Colombia to understand patient profiles, follow-up patterns, and treatment dynamics. Methods: A convenience sample of geneticists and pediatric neurologists were recruited from November-2020 to January-2021. The physicians responded to a questionnaire-based report for each patient under their care regarding the patient profiles, follow-up patterns, and treatment dynamics. Results: A total of 24 physicians (geneticists [92%] and pediatric neurologists [8%]) provided data on 107 patients with MPS-IVA. Patients were diagnosed through molecular (36%) and/or enzymatic assays (97%). The mean age of patients was 19.5 years and 51% were male. The average time from first symptom to diagnosis was 7.1 years. The mean age at first symptoms was 4 years and at diagnosis was 11 years, further, the mean age at first ERT was 15 years. There was an increase in assessments after ERT initiation; parameters most frequently evaluated were weight, height, and echocardiography; quality of life, 6MWT, and 3-minute stair-climb test were the least frequent. ERT interruptions >2 months were observed in 63% patients. Conclusions: Monitoring of MPS-IVA patients receiving ERT remains suboptimal in Colombia. Establishing national management guidelines and implementing centralized reference centers, where patients can receive comprehensive care are warranted for ensuring appropriate systems, services, and support as a priority, with a potential positive effect in the course of the disease.

Modern Approach to Fabry Disease Diagnosis and Management in Children

Fabry disease (FD), or Andersen-Fabry disease, is a rare hereditary lysosomal disease (sphingolipids storage disease) characterized by progressive multisystem involvement. The major symptoms among children are neuropathic pain / acroparesthesia, angiokeratomas, hypo- or anhidrosis, vortex keratopathy. Biochemical tests, molecular genetic testing, and family screening play crucial role in the diagnosis of the disease. Specific pathogenetic treatment of FD includes enzyme replacement therapy (ERT) with recombinant medications of the lysosomal enzyme -galactosidase A. ERT initiation before the development of severe organs and systems’ damage contributes to its higher efficacy. This article covers various aspects of pathogenesis, clinical picture features in childhood, modern methods of diagnosis and management of FD according to literature data.

Idursulfase Beta (Hunterase) Therapeutic Experience in a Patient with Mucopolysaccharidosis Type II

Background. Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive disease caused by lysosomal enzyme iduronate-2-sulfatase deficiency resulting in progressive glycosaminoglycans (GAG) accumulation in tissues (dermatan sulfate and heparan sulfate). GAG accumulation in cells leads to the development of progressive pathological disorders, malfunction of various organs and systems, early disability, and decrease in life expectancy. Enzyme replacement therapy (ERT) reduces the rate of life-threatening conditions development in patient. ERT would be more effective if it is prescribed early, especially at preclinical stage. This is the time when there are no severe irreversible changes in the cell, thus, pathogenetic therapy will decrease GAG accumulation in lysosomes, slow down the pathological process, and improve patient's condition. Clinical case description. Male patient diagnosed with MPS II was administrated with ERT idursulfase beta at the age of 6 months. It led to milder disease course compared to proband uncle who had similar mutation in the IDS gene, severe disease phenotype, and later initiation of ERT (at the age of 2.5 years). Conclusion. Early ERT initiation in patients with MPS II significantly slows down development of severe and life-threatening complications, increases the duration and improves the quality of life.

Multidisciplinary treatment in the long-term management of Fabry disease

Fabry disease is a rare X-linked hereditary condition caused by mutations in the α-galactosidase A (GLA) gene, resulting in decreased α-GAL A enzyme activity. The clinical manifestations of Fabry disease are diverse, which leads to delays in diagnosis and treatment, thereby increasing the disease burden for patients and their families. Given its characteristics, multidisciplinary treatment (MDT) is critical for the long-term management of Fabry disease, and should include nephrology departments, cardiovascular departments, neurology departments, and pediatric department, among others. This study focuses on early screening for Fabry disease, the indication for initiating enzyme replacement therapy, pre-treatment evaluation, and monitoring to provide practical guidance for Chinese clinicians.

Impact of kidney biopsy on deciding when to initiate enzyme replacement therapy in children with Fabry disease

BackgroundRecommendations on when to start enzyme replacement therapy (ERT) in children with Fabry disease (FD) differ between guidelines. In this study, kidney biopsies of a cohort of 14 untreated children and one treated child were analyzed for their morphologic changes to determine whether early initiation of ERT is indicated.MethodsAll pediatric FD patients (< 18 years old) diagnosed between 2003 and 2021 in our department who received a kidney biopsy were enrolled. Clinical symptoms; laboratory parameters regarding kidney function, such as eGFR, plasma urea, protein-creatinine, and albumin/creatinine ratio; and 14 kidney biopsies prior to ERT and one under treatment were retrospectively analyzed.ResultsA total of 14 patients were enrolled, including 9 male and 5 female children, aged 3–18 years (median age 11). Seven of the enrolled children were 10 years old or younger. Histological analysis of kidney biopsy samples revealed severe vacuolization and accumulation of inclusions in podocytes and renal tubules. The majority of cases had no FD-specific clinical or laboratory features independent of age, gender, or genotype. The youngest FD patient presenting with isolated abnormal kidney biopsy was 3 years old.ConclusionsWe demonstrate that histological lesions, typical for FD, can be observed in kidney biopsies at a very young age in patients without classical clinical symptoms or laboratory abnormalities. Thus, we recommend kidney biopsies as a possible tool for early diagnosis of renal involvement in FD. As a consequence of these early biopsy findings without a clinical correlate, an early initiation of ERT should be considered.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Clinical Profiles of Children with Hypophosphatasia prior to Treatment with Enzyme Replacement Therapy: An Observational Analysis from the Global HPP Registry

Introduction: The objective of this study was to better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT). Methods: Pretreatment demographics and medical histories of ERT-treated children (aged <18 years) enrolled in the Global HPP Registry (2015–2020) were analyzed overall, by age at first HPP manifestation (<6 months vs. 6 months to 18 years), and by geographic region (USA/Canada, Europe, and Japan). Results: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost types being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at <6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Those from Japan were reported to have a younger median age overall, the highest proportion of skeletal manifestations (80.4%) and growth impairment, while European data reported the highest proportion of muscular manifestations (70.7%). In the USA/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%). Conclusion: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation.

Effects of enzyme replacement therapy on bone density in late onset Pompe disease

Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.

Outcome of BCG Vaccination in ADA-SCID Patients: A 12-Patient Series.

Vaccination with Bacillus Calmette-Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.

Clinical features and enzyme replacement therapy in 10 children with Fabry disease.

To summarize the clinical features, diagnosis and enzyme replacement therapy(ERT) of Fabry disease (FD) in children. The clinical data, laboratory tests, genetic variations and treatment of 10 FD children diagnosed in Shandong Provincial Hospital from September 2020 to June 2022 were retrospectively analyzed. Among the 10 cases from 6 families, 7 patients were boys of 4 to 13 years of age, and 3 were girls of 12 to 15 years of age. There were 7 symptomatic patients, including 6 boys and 1 girl. All 7 patients presented with acral neuralgia. Five patients had little or no sweating. Five patients presented with cutaneous angiokeratoma. Two patients had abdominal pain. One patient developed joint symptoms. Four patients had corneal opacity. One patient had hearing loss; one patient had short stature. One patient had mild proteinuria and 1 patient had dysplasia of the right kidney with decreased eGFR (55.28 ml/min.1.73 m2). The left ventricular mass index was slightly elevated in 1 patient. Three patients had mild obstructive ventilatory dysfunction; a small amount of effusion in the intestinal space of the lower abdomen or mild fatty liver was found in 2 patients. Partial empty sella turcica in 1 patient. A total of 6 GLA gene variants were detected in 10 children, among which C.1059_1061delGAT (p.met353del) was a newly discovered mutation. Five children received ERT, of which 4 were treated with agalsidase beta and 1 was treated with agalsidase alpha. Only 1 patient had anaphylaxis. Lyso-GL-3 levels decreased significantly in the first 3 months of ERT initiation and remained relatively stable thereafter in 3 patients. The Lyso-GL-3 level was decreased, but renal impairment continued to progress in 1 patient treated with agalsidase alpha. The clinical manifestations of FD in childhood are diverse, and it is necessary to make a definite diagnosis by combining family history, enzyme activity, biomarkers, gene testing and other indicators. Pedigree screening and high-risk population screening are helpful for early identification, early diagnosis and early treatment. No serious adverse reactions were found during the short-term treatment with agalsidase alpha and beta.

Mucopolysaccharidosis type 4 (Morquio syndrome): A case report

Abstract Introduction Mucopolysaccharidosis (MPS) IVA (Morquio syndrome) is a rare lysosomal storage disease, that is caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to an autosomal recessive mutation in the GALNS gene. Herein, we present a MPS IVA case without regular follow-up, whose enzyme replacement was planned to start at age 30 for the first time, so as to attract attention to this rare disease. Clinical Case A 30-year-old female patient diagnosed with MPS IVA, that was evaluated due to corneal clouding referred to the Marmara University endocrinology outpatient clinic for enzyme replacement. On admission, she complains of impaired vision, hearing loss, hypoglycemic symptoms and numbness of hands and feet. While she was normal for about 2 years after birth, she was noticed for delays in crawling and walking from 2–3 year of age. However, she had definitive diagnosis of MPS-IVA at the age of 9 years, with low enzymatic analysis and genetic mutation in the GALNS gene located on chromosome 16q24.3. She operated on for bilateral glaucoma and cerebellar mass when she was 17. Her parents were third degree consanguineous, and she had one healthy younger brother. On physical examination, blood pressure: 99/67 mmHg, pulse: 72/min, temperature: 36°C, SpO2:99. She was in a wheelchair. Her height was 92 cm, weight was 30 kg, BMI: 25.6 kg/m2. Disproportionate short stature, coarse facial features, hypertelorism, genu valgum, pectus carinatum, kyphoscoliosis, were detected. Her neuromotor development was normal. Laboratory findings were unremarkable except for vitamin D hypovitaminosis. Radiographic findings were dysostosis multiplex, include abnormally shaped vertebral bodies with anterior beaking, posterior scalloping, platyspondyly and dens hypoplasia, thoracolumbar kyphosis, short, broad metacarpals, acetabular dysplasia, genu valgum, pectus carinatum, paddle-shaped ribs and short, and thick clavicles (Fig 1). Bone densitometry results were in osteoporotic range BMD at the femoral neck was 0.491 g/cm2, Z score was -2.8 and at the lumbar spine was 0.707 g/cm2, Z score was -3.6. She continued the 6-min walk test with the help of a walker and knee pad for 2.37 minutes and walked 3.4 meters. Echocardiography demonstrated that ejection fraction was 65%, normal left ventricular systolic function, no ventricular segmental wall motion defect, aortic 3 cusps, mild to moderate aortic valvular regurgitation, mild mitral valvular regurgitation. Pectus carinatum was detected on thorax CT imaging, whereas a restrictive disease pattern was not observed in PFT and DLCO. Bilateral severe mixed hearing loss was detected. Recombinant human GALNS (elosulfase alfa), 2.0 mg/kg/week, was planned to administer IV in 4 hr. Conclusion Because of the progressive nature of MPS- IVA, early diagnosis and early initiation of enzyme replacement therapy are critical to prevent cumulative systemic manifestations of the patient, especially the skeletal system.

Clinical Characteristics of a Patient with Mucopolysaccharidosis Type IVA (Morquio Syndrome)

Mucopolysaccharidosis (MPS) type IVA (Morquio syndrome) is a hereditary lysosomal storage disease caused by deficiency of N-acetylglucosamine-6-sulfate sulfatase. This enzyme deficiency leads to specific glycosaminoglycans (keratan sulfate and chondroitin-6sulfate) accumulation mainly in the bone and cartilage tissues, as well as in the cardiovascular, respiratory systems, and visual systems. Patients with MPS IVA look healthy at birth, however, they develop typical spine deformities (kyphoscoliosis), pectus carinatum, wrists hypermobility with decreased muscle strength and loss of fine motor skills, valgus deformation of lower limbs during the first years of life. Pathological changes in cardiovascular and respiratory systems, visual and acoustic analyzers can be revealed. Early diagnosis of the disease is crucial for timely initiation of enzyme replacement therapy. Thus, low incidence of the disease and its heterogeneous clinical picture complicates diagnosis. Consequently, patients with MAS IVA often become severely disabled as early as adolescence. Patients with severe form and without treatment die before the age of 30 due to complications of respiratory system diseases, valvular heart apparatus involvement, and cervical myelopathy.

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase.

People with Hunter syndrome are known to be affected by a variety of airway pathologies. Treatment of Hunter syndrome with the enzyme replacement therapy (ERT) idursulfase is now the standard of care. However, it is not known how ERT changes the progression of airway involvement. To evaluate this, we performed a retrospective analysis of bronchoscopies performed on children with Hunter syndrome who were part of intrathecal ERT trials. Findings for airway pathology were extracted from bronchoscopy reports and analyses were performed for cross-sectional and longitudinal changes in airway disease. One-hundred and thirty bronchoscopies from 23 subjects were analyzed. Upper airway disease (adenoid hypertrophy and/or pharyngomalacia) was reported in 93% and 87% of bronchoscopies, respectively. Laryngeal abnormalities were recognized in 46% of cases. There were lower airway (tracheal and or bronchial) findings in 64% of all bronchoscopies and prevalence increased with age. Evaluations over time adjusted for repeat evaluations showed that increasing airway involvement was associated with older age (p = 0.0007) despite ongoing ERT. No association was discovered between age of intravenous ERT initiation and progression of airway disease. Individuals with Hunter syndrome who are receiving intravenous enzyme replacement therapy showed the progression of airways disease supporting the need for regular airway monitoring and intervention.

Left atrial strain correlates with severity of cardiac involvement in Anderson-Fabry disease

ObjectivesCardiac involvement in Anderson-Fabry disease (AFD) results in myocardial lipid depositions. An early diagnosis can maximize therapeutic benefit. Thus, this study aims to investigate the potential of cardiac MRI (CMR) based parameters of left atrial (LA) function and strain to detect early stages of AFD.MethodsPatients (n = 58, age 40 (29–51) years, 31 female) with genetically proven AFD had undergone CMR including left ventricular (LV) volumetry, mass index (LVMi), T1, and late gadolinium enhancement, complemented by LA and LV strain measurements and atrial emptying fractions. Patients were stratified into three disease phases and compared to age and sex-matched healthy controls (HC, n = 58, age 41 [26–56] years, 31 female).ResultsA total of 19 early-, 20 intermediate-, and 19 advanced-phase patients were included. LV and LA reservoir strain was significantly impaired in all AFD phases, including early disease (both p < 0.001). In contrast, LA volumetry, T1, and LVMi showed no significant differences between the early phase and HC (p > 0.05). In the intermediate phase, LVMi and T1 demonstrated significant differences. In advanced phase, all parameters except active emptying fractions differed significantly from HC. ROC curve analyses of early disease phases revealed superior diagnostic confidence for the LA reservoir strain (AUC 0.88, sensitivity 89%, specificity 75%) over the LV strain (AUC 0.82).ConclusionsLA reservoir strain showed impairment in early AFD and significantly correlated with disease severity. The novel approach performed better in identifying early disease than the established approach using LVMi and T1. Further studies are needed to evaluate whether these results justify earlier initiation of therapy and help minimize cardiac complications.Key Points• Parameters of left atrial function and deformation showed impairments in the early stages of Anderson-Fabry disease and correlated significantly with the severity of Anderson-Fabry disease.• Left atrial reservoir strain performed superior to ventricular strain in detecting early myocardial involvement in Anderson-Fabry disease and improved diagnostic accuracies of approaches already using ventricular strain.• Further studies are needed to evaluate whether earlier initiation of enzyme replacement therapy based on these results can help minimize cardiac complications from Anderson-Fabry disease.