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Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to ß-glucocerebrosidase deficiency and glucosylceramide accumulation. Methods: We analyzed short- and long-term dynamics of lyso-glucosylceramide (lyso-Gb1) in a large cohort of GD patients undergoing enzyme replacement therapy (ERT). Results: Eight-years analysis of lyso-Gb1 revealed statistically insignificant variability in the biomarker across the years and relatively high individual variability in patients' results. GD type 1 (GD1) patients exhibited higher variability compared to GD type 3 (GD3) patients (coefficients of variation: 34% and 23%, respectively; p-value = 0.0003). We also investigated the short-term response of the biomarker to enzyme replacement therapy (ERT), measuring lyso-Gb1 right before and 30 min after treatment administration. We tested 20 GD patients (16 GD1, 4 GD3) and observed a rapid and significant reduction in lyso-Gb1 levels (average decrease of 17%; p-value < 0.0001). This immediate response reaffirms the efficacy of ERT in reducing substrate accumulation in GD patients but, on the other hand, suggests the biomarker's instability between the infusions. Conclusions: These findings underscore lyso-Gb1's potential as a reliable biomarker for monitoring efficacy of treatment. However, individual variability and dry blood spot (DBS) testing limitations urge a further refinement in clinical application. Our study contributes valuable insights into GD patient management, emphasizing the evolving role of biomarkers in personalized medicine.
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Terapia de Reemplazo Enzimático , Enfermedad de Gaucher , Glucosilceramidasa , Humanos , Enfermedad de Gaucher/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Glucosilceramidasa/genética , Glucosilceramidasa/uso terapéutico , Adolescente , Adulto Joven , Biomarcadores/sangre , Niño , Psicosina/metabolismo , Psicosina/análogos & derivados , Anciano , PreescolarRESUMEN
BACKGROUND: Liver transplantation (LTx) constitutes a major life-saving routine treatment for children with end-stage liver disease. However, the analysis of LTx registries in children provides much information about changes in the indication profiles in the recent years. METHODS: The article provides a comprehensive review about the successes, hopes, and challenges related to changing indications for LTx in children based on the literature review and our own experience. Retrospective review of the indications for LTx at a tertiary referral pediatric hospital was also presented. RESULTS AND CONCLUSIONS: In the context of the new therapies that have emerged, the need for LTx has decreased in patients with chronic hepatitis B and C infection and tyrosinemia type 1. In primary hyperoxaluria type 1, new RNAi-based therapy has eliminated the requirement for LTx (both isolated or combined). There is a hope that introduction of ileal bile acid transporter (IBAT) blockers reduces the need for LTx in patients with Alagille syndrome or progressive familial intrahepatic cholestasis. The number of children qualified for LTx with urea cycle disorders (UCDs) as a prophylaxis of neurodevelopmental impairment is increasing.
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Trasplante de Hígado , Humanos , Niño , Enfermedad Hepática en Estado Terminal/cirugía , Síndrome de Alagille/cirugía , Preescolar , Tirosinemias/tratamiento farmacológico , Tirosinemias/terapia , Estudios Retrospectivos , Colestasis Intrahepática/cirugía , Adolescente , Hiperoxaluria Primaria/cirugía , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Selección de Paciente , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , LactanteRESUMEN
The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann-Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement.
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Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.
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Fallo Hepático Agudo , Neuroblastoma , Anomalía de Pelger-Huët , Humanos , Fenotipo , Anomalía de Pelger-Huët/complicaciones , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patología , Fallo Hepático Agudo/genética , Mutación Missense , Neuroblastoma/complicacionesRESUMEN
BACKGROUND: Classical homocystinuria (HCU) is an inborn defect of methionine metabolism caused by a deficiency of the enzyme cystathionine ß-synthase (CBS). The main symptoms of classical homocystinuria are lens subluxation, bone lesions, vascular disease and developmental delay/intellectual disability. The treatment method for HCU is a methionine-poor diet supplemented with amino acid preparations. The aim of the study was to examine the relationship of dietary factors, metabolic compensation and selected skeletal parameters in patients with HCU. METHODS: Bone mineral density measurements (DXA) were performed in pediatric patients with HCU, and blood levels of selected amino acids, minerals and vitamins, as well as dietary nutritional value, were analyzed. RESULTS: A total of 11 patients with HCU whose median age was 9.3 years were enrolled in the study. The median DXA total body less head of HCU patients was -0.4 z-score, and the lumbar spine was -1.4 z-score. Despite supplementation, calcium intake was below the age norm. Average vitamin D3 intake was in line with recommendations, but 36% of patients had reduced blood levels. Bone mineral density depended on blood levels of 25-hydroxyvitamin D, homocysteine and methionine, as well as on BMI, age and intake of natural protein (R2 = 98.5%, p = 0.015; R2 = 86.7%, p = 0.0049) and protein from an amino acid preparation (r = 0.69, p = 0.026). CONCLUSION: The results of the study indicate the need for regular densitometry in patients with HCU and also the use of additional calcium and vitamin D3 supplementation. It is also necessary to perform a comprehensive analysis of the diet and metabolic controls.
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Densidad Ósea , Dieta , Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Polonia , Dieta/economía , Índice de Masa Corporal , Fenómenos BiomecánicosRESUMEN
Congenital disorders of glycosylation (CDGs) are a wide group of genetic diseases characterised by a severe clinical spectrum, consisting of developmental delays, dysmorphisms, and neurological deficits. Mutations in the PIGV gene lead to a disorder called hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), distinct from other CDGs in terms of hyperphosphatemia related to abnormal ALP activity and brachytelephalangy. This article discusses the phenotype of six Polish patients with HPMRS1 with a special focus on behavioural and imaging features, which were not addressed in 26 previously reported cases. The medical records of six patients aged 6 to 22 years were collected and analysed. In all cases, the same PIGV homozygotic mutation (c.1022C>A; p.Ala341Glu) was found, although the patients presented a diverse spectrum of neurological and developmental disorders, concerning in most cases the muscular tonus and general developmental delay. The most prevalent dysmorphic features included hypertelorism, high palate, and finger anomalies, whereas other characteristics present in all previously described cases, such as a short, broad nose and brachytelephalangy, were less frequently observed. Similarly to previous reports, the magnetic resonance (MR) and computed tomography (CT) head scans returned varied results, including physiological and pathological brain images in equal measure, the latter of which consisted of cortical atrophy, delayed myelination, hydrocephalus, and hypoplastic corpus callosum. Each patient exhibited symptoms characteristic of autism spectrum disorders, especially in terms of attention deficits, as well as controlling and expressing emotions. The most common type of sensory processing disorder was over-responsivity. Despite the low prevalence of HPMRS1, the patients reported in the literature presented a rather uniform phenotype, which does not correspond with the one found in each individual of the studied group. Behavioural disorders and sensory impairment require additional care and awareness considering the global developmental delay often observed in these patients.
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Anomalías Múltiples , Humanos , Polonia , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Fenotipo , Neuroimagen , Estudios Observacionales como AsuntoRESUMEN
INTRODUCTION: The increasing usage of NGS technology has enabled the discovery of new causal genes in ciliopathies, including the DCDC2 gene. The aim of our study was to present the clinical, pathological and molecular report of six patients (from three unrelated families) with DCDC2 biallelic pathogenic variants. A detailed overview of the reported patients with DCDC2-related disease was provided. MATERIAL AND METHODS: A retrospective chart review of the clinical, biochemical, pathological (liver histology) and molecular features of the study group was performed. The database PubMed (MEDLINE) was searched for relevant studies. RESULTS: All the patients presented with cholestatic jaundice and elevated GGT; the mean age was 2 months. The initial liver biopsy was performed in four children at a mean age of 3 months (age range: 2-5 months). In all of them, features of cholestasis, portal fibrosis and mild portal inflammation were observed; in three of them ductular proliferation was observed. One patient had undergone liver transplantation (LTx) at 8 years of age. At hepatectomy, a biliary-pattern cirrhosis was observed. Only one patient presented with features of renal disease. Whole exome sequencing was performed in all patients at the last follow-up visit (mean age 10 years). Three different variants (one novel) in the DCDC2 gene were identified in the study group. With our six patients, a total of 34 patients with DCDC2-related hepatic ciliopathy were identified. The main clinical presentation of DCDC2-related ciliopathy was liver disease in the form of neonatal sclerosing cholangitis. The predominance of early and severe liver disease associated with no or mildly expressed kidney involvement was observed. CONCLUSIONS: Our findings expand the molecular spectrum of pathogenic DCDC2 variants, provide a more accurate picture of the phenotypic expression associated with molecular changes in this gene and confirm a loss of functional behaviour as the mechanism of disease.
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Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for ß-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.
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Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/patología , alfa-Sinucleína/metabolismo , Terapia de Reemplazo Enzimático , Enfermedad de Parkinson/genética , Heterocigoto , MutaciónRESUMEN
Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload. Gaucher disease (GD) is a recessively inherited disorder resulting in storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. It is directly caused by the deficiency of beta-glucocerebrosidase (GBA) activity. Chitotriosidase has been measured systematically each year in the same group of 49 patients with type 1 and 3 GD for over 20 years. Our analysis showed that chitotriosidase is very sensitive biomarker to enzyme replacement therapy (ERT). The response to treatment introduction is of an almost immediate nature, lowering pathologically high chitotriosidase levels by a factor of 2 in a time scale of 8 months, on average. Long term enzyme replacement therapy (ERT) brings chitotriosidase activity close to reference values. Finally, reducing the dose of ERT quickly boosts chitotriosidase activity, but restoring the initial dose of treatment brings chitotriosidase level of activity back onto the decreasing time trajectory.
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Enfermedad de Gaucher , Humanos , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/metabolismo , Glucosilceramidasa , Estudios Longitudinales , Hexosaminidasas/metabolismo , Hexosaminidasas/uso terapéutico , Glucosilceramidas/metabolismo , Glucosilceramidas/uso terapéuticoRESUMEN
Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
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The article describes the mechanism of molecular and pharmacological chaperones in the treatment of inborn errors of metabolism. The literature review of the usage of ambroxol acting as a pharmacological chaperone for beta-glucocerebrosidase in Gaucher disease and Parkinson's disease associated with GBA variants has been reviewed.
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Ambroxol , Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Mutación , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/tratamiento farmacológico , Ambroxol/farmacología , Ambroxol/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Eleven patients from Yakutia with a new lysosomal disease assumed then as mucopolysaccharidosis-plus syndrome (MPS-PS) were reported by Gurinova et al. in 2014. Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected. Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, and visceral obesity. Functional analyses revealed a slight presence of chondroitin sulphate (only) in urine glycosaminoglycan electrophoresis, presence of sialooligosaccharides in urine by thin-layer chromatography, and normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot. The comparison with other MPS-PS described cases was also provided. The presented description of the natural history of MPS-PS in our patient may broaden the spectrum of phenotypes in this disease.
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Mucopolisacaridosis , Proteínas de Transporte Vesicular , Sulfatos de Condroitina/orina , Glicosaminoglicanos/orina , Humanos , Mucopolisacaridosis/sangre , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis/genética , Mucopolisacaridosis/orina , Mutación , Polonia , Esfingolípidos/sangre , Proteínas de Transporte Vesicular/genéticaRESUMEN
INTRODUCTION: Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study was to present the long-term follow-up of 12 Polish patients with AM, evaluate the clinical, biochemical, and molecular findings and progression of the disease. MATERIAL AND METHODS: The article presents a long-term (over 30 years) observational, retrospective, single-center study of patients with AM. RESULTS: The hearing loss, as one of the first symptoms, was detected in childhood (mean age of 2 years and 6 months) in 10 patients. The other symptoms include: recurrent infections (all patients), inguinal hernias (6 patients), craniosynostosis (1 patient). The mean age at AM diagnosis was 6 years while median was 4 years (age range: 1 year and 8 months - 12 years). The most commonly identified variant in the MAN2B1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14 years (range: 1 year - 26 years). Following birth, children with AM grow slowly, finally reaching the 3rd percentile (or values below the 3rd percentile). Hearing loss was not progressive while a gradual exacerbation of intellectual disability with no developmental regression was observed in all patients. Ataxia was diagnosed in 6 patients in the second decade of life (age range 15-20 years). CONCLUSIONS: Our study revealed the sensorineural hearing loss as one of the first noted symptom in AM which was congenital and non-progressive during the natural course of disease. A detailed anthropometric phenotype of AM patients was provided with observation of the growth decline during the long-term follow-up. Our study confirmed the existence of two distinguished clinical phenotypes of AM (mild and moderate), and also the lack of clear genotype-phenotype correlation.
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BACKGROUND: Enzyme replacement therapy (ERT) with idursulfase is available for patients with mucopolysaccharidosis (MPS) type II, and improvements in certain somatic signs and symptoms have been reported. The aim of the study was to assess the effectiveness of ERT with idursulfase (Elaprase®) on the passive joint range of motion (JROM) in the upper and lower extremities of patients with MPS II. METHODS: The study included 16 Polish patients diagnosed with MPS II and followed in our Institute in the years 2009-2016. The study group was divided for groups of neuronopathic (group 1, n=12) and non-neuronopathic (group 2, n=4) patients. A passive JROM was measured with a goniometer by one physiotherapist, while in group 1 it was assessed at baseline and after both short-term (52 weeks) and long-term (mean 230 weeks, range: 108-332 weeks) ERT. In group 2, it was assessed at baseline and after short-term ERT (68-85 weeks, no data for long-term ERT). RESULTS: In group 1, after 52 weeks of ERT, we observed some improvement of passive ROM in wrist flexion (5/12 patients), shoulder abduction and wrist extension (3/12 patients), shoulder flexion, elbow and knee extension (2/12 patients). After long-term ERT (mean 230 weeks), the improvement in JROM was observed only in 2 patients. There was no improvement in the shoulder abduction, elbow flexion and extension, hip and knee extension. In group 2, the improvement in passive ROM was observed in several joints: shoulder flexion, wrist flexion and extension improved (2/4 patients) and shoulder abduction (1/4 patients). CONCLUSION: ERT is of low efficacy on correcting the range of motion of joints in MPS II patients.
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Terapia de Reemplazo Enzimático/métodos , Iduronato Sulfatasa/uso terapéutico , Extremidad Inferior/fisiopatología , Mucopolisacaridosis II/tratamiento farmacológico , Rango del Movimiento Articular , Extremidad Superior/fisiopatología , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Artropatías/tratamiento farmacológico , Artropatías/fisiopatología , Masculino , Mucopolisacaridosis II/fisiopatología , PoloniaRESUMEN
Adenosine kinase (ADK) deficiency is a rare inborn error of methionine and adenosine metabolism. So far, a total of 27 patients with ADK deficiency have been reported. Here, we describe the first Polish patient diagnosed with ADK deficiency, aiming to highlight the clinical presentation of disease, emphasize diagnostic difficulties, and report the long-term follow-up. Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine. A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy. The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency. Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine.
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Lysosomal acid lipase (LAL) plays a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes. LAL deficiency is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. In the case of LAL deficiency, cholesteryl esters and triglycerides accumulate within the lysosomes. The up-regulation of endogenous cholesterol production, increased synthesis of apolipoprotein B (ApoB) and increased production of very-low-density lipoprotein cholesterol (VLDL-C) is observed. The diagnosis is easy due to the currently available method of testing the enzyme activity in a dry blood spot. Molecular analysis is necessary to verify the clinical and biochemical diagnosis and to analyze the genotype-phenotype correlation. Sebelipase alfa is a recombinant human lysosomal lipase intended for use in enzyme replacement therapy in patients with LAL deficiency.
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Enfermedad de Wolman , Homeostasis , Humanos , Lipasa , Lípidos , Lisosomas , Enfermedad de Wolman/diagnóstico , Enfermedad de Wolman/genética , Enfermedad de Wolman/terapiaRESUMEN
BACKGROUND: Growth failure is commonly reported in children with PMM2-CDG. The aim of the study was to delineate the longitudinal anthropometric phenotype of patients with PMM2-CDG and attempt to find some correlations between the genotype and anthropometric phenotype. MATERIALS AND METHODS: Retrospective chart review of PMM2-CDG patients' medical records was performed regarding the anthropometric measurements (head circumference, body length/height, body weight, body mass index) and PMM2 variants. RESULTS: A negative tendency of growth evolution was observed. Patients found to be heterozygous for R141H grew slower than other patients. Body weight was correlated with body height. A negative tendency of the growth rate of head circumference was observed. Patients found to be heterozygous for R141H experienced slower growth than other patients. CONCLUSIONS: Long-term observational studies are essential to characterize the anthropometric phenotype. The body growth failure, as well as head circumference growth failure, were more severe in patients found to be heterozygous for R141H.
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BACKGROUND: Several transferrin gene polymorphisms are known to result in a shifted IEF pattern. The aim of this study was to characterize the transferrin gene polymorphisms observed in patients from one referral center. MATERIALS AND METHODS: Patients with solely increased pentasialo-Tf were selected. The whole exome sequencing was done from probands (patients) and from DNA available from their parents. RESULTS: Two various polymorphisms in the transferrin gene: c.2012G>A, p.Gly671Glu and c.1027C>T, p.Arg343Trp, were found. CONCLUSIONS: Two transferrin gene polymorphisms: c.2012G>A, p.(Gly671Glu) and c.1027C>T, p.(Arg343Trp) solely correspond to an elevated pentasialo-Tf.
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Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Polimorfismo Genético , Transferrina/genética , Trastornos Congénitos de Glicosilación/sangre , Humanos , Focalización Isoeléctrica , Tamizaje Masivo/métodos , Secuenciación del Exoma/métodosRESUMEN
Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. This manuscript aims to provide a classification of the clinical presentation, diagnostic methods, and treatment of CDG based on the literature review and our own experience (referral center in Poland). A diagnostic algorithm for CDG was also proposed. Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosing N-glycosylation disorders associated with sialic acid deficiency. Nowadays, high-performance liquid chromatography, capillary zone electrophoresis, and mass spectrometry techniques are used, although they are not routinely available. Since next-generation sequencing became more widely available, an improvement in diagnostics has been observed, with more patients and novel CDG subtypes being reported. Early and accurate diagnosis of CDG is crucial for timely implementation of appropriate therapies and improving clinical outcomes. However, causative treatment is available only for few CDG types.
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Congenital disorders of glycosylation (CDGs) are a heterogeneous group of disorders with impaired glycosylation of proteins and lipids. These conditions have multisystemic clinical manifestations, resulting in gradually progressive complications including skeletal involvement and reduced bone mineral density. Contrary to PMM2-CDG, all remaining CDG, including ALG12-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, PGM3-CDG, CSGALNACT1-CDG, SLC35D1-CDG and TMEM-165, are characterized by well-defined skeletal dysplasia. In some of them, prenatal-onset severe skeletal dysplasia is observed associated with early death. Osteoporosis or osteopenia are frequently observed in all CDG types and are more pronounced in adults. Hormonal dysfunction, limited mobility and inadequate diet are common risk factors for reduced bone mineral density. Skeletal involvement in CDGs is underestimated and, thus, should always be carefully investigated and managed to prevent fractures and chronic pain. With the advent of new therapeutic developments for CDGs, the severity of skeletal complications may be reduced. This review focuses on possible mechanisms of skeletal manifestations, risk factors for osteoporosis, and bone markers in reported paediatric and adult CDG patients.