Resumo em Inglês:

Abstract Fabry disease is a metabolic alteration linked to an enzymatic deficiency of Alpha-Galactosidase A, this disorder compromises the sphingolipid metabolism, leading to an accumulation of lysosomal globotriaosylceramide and is inherited in an X-linked recessive way. The diagnostic of this disease, in general, requires the confirmation of below-normal levels of Alpha-Galactosidase A obtained from dried blood spot (DBS) samples, followed by an assessment of the enzyme in leukocytes. We aimed to report the Alpha-Galactosidase A values obtained in Colombian males with end-stage renal disease (ESRD) screened using dried blood spot samples during ten years. This screening was performed with samples sent to the analysis center from 6156 patients between 2006- 2016. All patients with low levels in enzyme activity (compared to the control population) were sent to confirmation through enzyme analysis in isolated leukocytes. 26 males (0.42%) with low levels of Alpha-Galactosidase A were identified (Range 0.0 - 1.14 nmol/ml/hour, cut-off: 1.15), 22 patients were subsequently measured in isolated leukocytes having a confirmation of Fabry disease in 5 patients (0.08% of total male population) (Range: 0.3 -4.7 nmol/mg prot/h). These results are similar to those reported in studies with comparable characteristics being this the first reporting frequency of Fabry disease among Colombian males with end-stage renal disease.

Resumo em Inglês:

Abstract Mucopolysaccharidoses (MPS) are lysosomal diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Sensorineural hearing impairment is a common feature in MPS patients, but there is no consensus on its etiology. For this reason, we aimed to identify genes and pathways related to hearing loss and to correlate them with gene expression data in MPS. We used HPO and Disgenet to identify candidate genes. We constructed the network with string and Cytoscape, and hub genes were identified in Cytohubba. Expression data were obtained from the MPSBase website. We found the NDUFA gene family as the major hub genes and 114 enriched pathways related to hearing loss. These genes and biological pathways may serve as potential candidates for clinical studies to better understand hearing impairment mechanisms in lysosomal storage diseases like mucopolysaccharidosis.

Resumo em Inglês:

Abstract Gaucher disease (GD) is one of the most common lysosomal disorders, occurring in approximately 1 in 40,000 live births worldwide. Since 2014 enzyme replacement therapy (ERT) with taliglucerase alfa has been the treatment of choice for adult patients with GD in Brazil. The aim of this study was to evaluate the long-term efficacy and safety of taliglucerase alfa in a cohort of Brazilian patients treated at a referral center for inborn errors of metabolism. All patients who received at least one infusion of the enzyme at the study center were considered eligible to participate. Patients were followed for adverse reactions and events throughout the study period. Platelets, hemoglobin, chitotriosidase activity, bone marrow burden (BMB) score, bone mineral density, and the severity score index (SSI) were analyzed. For patients who were switched to taliglucerase alfa from imiglucerase, the same variables were compared before and after the switch. At 9-year follow-up, all parameters of interest had remained stable or improved. The overall rate of adverse events was lower than in other studies that evaluated long-term ERT with taliglucerase, and no serious adverse events were considered related to treatment. Based on our findings, ERT with taliglucerase alfa is an effective and safe approach for treatment of patients with GD.

Resumo em Inglês:

Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CLN2/TPP1 gene, leading to a deficiency in tripeptidyl peptidase 1 activity. Enzyme replacement therapy with cerliponase alfa (recombinant human TPP1 [rhTPP1]; Brineura®) was approved in the United States and Europe for the treatment of CLN2 disease in 2017. We retrospectively report a cohort of 19 patients with CLN2 assisted in a specialized center in Argentina, including 8 newly diagnosed cases. Speech disorders and white matter changes/ventricular system enlargement were the most frequent clinical and imaging findings at CLN2 disease onset, respectively. Patients treated with cerliponase alfa presented a stable or improved course of the disease in this Latin American real world setting, as described in clinical trials.

Resumo em Inglês:

Abstract The mainstay of management of phenylketonuria (PKU) is restriction of dietary phenylalanine (Phe) intake. The present study sought to assess the perception and understanding of health care providers and lay users (patients/family members/caregivers) regarding the national reference database for checking the Phe content of foods, provided by the Brazilian Health Regulatory Agency (Anvisa), whose data are presented in the Table of Phenylalanine Content of Foods (TCFA-Anvisa) and recently in the Phenylalanine Content of Foods Dashboard (PCCFA-Anvisa); and to identify factors which interfere with the usability of these resources. Two online questionnaires, one for providers (n=33) and another for lay users (n=194), were used to collect sociodemographic information, knowledge about dietary management of PKU, sources of information about the Phe content of foods, and perception and understanding of the Anvisa tools. TCFA-Anvisa and PCCFA-Anvisa were not used as main sources of information by either group. Among the participants who had used these tools (15 providers;35 lay users), most considered the PCCFA-Anvisa to be superior or partially superior to the TCFA-Anvisa. The main limitations reported were related to layout and limited variety of foods. We suggest that the limitations identified in this study be considered for future improvement of these resources.

Resumo em Inglês:

Abstract Introduction Mucopolysaccharidoses (MPS) can lead to cervical spinal cord compression (SCC). Diagnostic scores for SCC in MPS use the obliteration of the passage of cerebrospinal fluid in the anterior and posterior spinal cord in the sagittal section of magnetic resonance imaging (MRI). The spinal cord occupation ratio (SCOR) published, by Nouri et al (2018), establishes the spinal cord filling index for the spinal cord, identifying disproportionate spinal cord occupation in the canal. When evaluating congenital canal stenosis, the risk of spinal cord injury has been considered increased when the SCOR is ≥70% in the median sagittal plane or ≥ 80% in the axial plane. Although these values ​​have not been validated for MPS populations, they could be useful. Objective To verify the SCOR in MPS patients with diagnosis of cervical SCC comparing the SCOR with other markers proposed in the existing MPS SCC scores, such as the extent of gliosis, clinical impact and the SCC assessment as represented by the obliteration of CSF flow. Methods We reviewed imaging tests of the cervical spine from MPS patients with previously confirmed SCC, using the SCOR measure in the median sagittal plane, evaluation of the presence and extent of spinal gliosis on MRI, evaluation of the clinical impact using a clinical score and evaluation of the images for the obliteration of cerebral spinal fluid (CSF) flow. Results Thirty-one MRI of 24 different patients were included. The average SCOR was 87.1%. This was lower (81.6%) in patients without gliosis, when compared to those with focal (90.5%) and extensive (97%) gliosis. The only patient with gliosis associated with a lacunar lesion, resulting from an acute compressive injury, had a 68% SCOR, due to the atrophic spinal cord injury. As expected, SCOR was higher in patients with total or partial CSF obliteration, but one among the 3 patients without CSF flow obliteration, with a 76% SCOR, had already developed focal gliosis and mild clinical abnormalities. Patients with more extensive gliosis had higher clinical scores. Four patients had more than one imaging scan evaluated. SCOR upward trend showed an annual average increase of 3.8%. Discussion & Conclusions The use of SCOR allows the diagnosis of cervical spinal canal stenosis in an objective way. It is possible that the cut-off values used by Nouri et al in patients with congenital stenosis could be useful to diagnose cervical stenosis in MPS patients, preceding the finding of CSF flow obstruction, presence of gliosis or clinical abnormalities. Furthermore, the use of SCOR may assist in the longitudinal evaluation of disease progression. Better follow-up and timely diagnosis allows for scheduling of surgery at the best clinical moment, minimizing complications.

Resumo em Inglês:

Abstract Mucopolysaccharidoses (MPS) are rare inborn errors of metabolism, leading to the accumulation of glycosaminoglycans (GAG) in distinct tissues. We investigated oropharyngeal dysphagia using the videofluoroscopic swallowing study (VFSS) in patients with different MPS types. Since there is a lack of studies systematically evaluating this disorder in this population, the use of a standard technique should contribute to better evaluate individuals with MPS. A cross-sectional and observational study enrolling patients followed by an outpatient service for lysosomal diseases at the Genetics Service of the Hospital de Clínicas de Porto Alegre (SGM/HCPA) was conducted. Patients underwent semi-structured interviews, clinical evaluation and VFSS. Nineteen patients were evaluated, including patients with MPS types I (16%), II (42%), IIIb (10%) and IVa (32%). Nearly all patients (95%) presented with oropharyngeal dysphagia in the VFSS. The most frequent findings were impaired chewing during oral phase (94%) and reduced laryngeal elevation in the pharyngeal phase (72%). Oropharyngeal dysphagia constituted a prevalent symptom in the studied cohort regardless of MPS type. Our data reinforces the notion that this disorder should be objectively assessed since it can significantly compromise the nutrition and the hydration of these patients as well as lead to tracheobronchial aspiration, thus resulting in aspiration pneumonia and even death eventually.

Resumo em Inglês:

Abstract Classical galactosemia is caused by the genetic deficiency of galactose-1-phosphate-urydyl-transferase resulting in clinical symptoms development during the first weeks of life including jaundice, hypotonia, lethargy, emesis, hepatomegaly, among others. Currently, dietary restriction of galactose is considered the standard for classical galactosemia management. For several years, severe dietary galactose restriction was considered necessary, implying restriction not only of dairy products, but also fruits, vegetables, legumes, and viscera. Such management failed to improve or prevent the appearance of long-term complications, by contrast, such restrictive approach may lead to nutritional deficiencies development. Thus, the last consensus suggests guidelines that are more flexible. In addition, the lack of knowledge regarding the physiopathology of the disease, and the toxicity threshold of the metabolites accumulated, make even more difficult to propose novel and more effective therapeutic approaches. This review summarizes the current state of knowledge regarding classical galactosemia in terms of physiopathology, long-term complications, newborn screening and genetic variants and their implications on galactosemia treatment, summed to the challenges that researchers working on this disease must address in future studies including the analysis of galactose content in foods, galactose tolerance threshold and search for novel therapeutic targets.

Resumo em Inglês:

Abstract Phenylketonuria (PKU) is a correctable inborn error of metabolism which causes lethal intellectual delay and neurobehavioral anomalies. A screening package, especially for early recognition can support to regulate the PKU process of most patients. New-born screening program in any country focuses at the earliest detection of inheritance deficiency disorders in order to avoid the most severe repercussion by appropriate medication. This screening program needs a concomitant diagnosis and involves additional clinical research. Strategies from developed countries recommend that new-born screening should be done as soon as possible after birth before hospital/clinic discharge because if detected later, it conveys to significantly increase in disability as well as morbidity. Although exact protocol differs among different countries, testing procedures for PKU should be followed universally recognized in the developed world. Unfortunately, new-born screening program in Bangladesh is in lying-in room or possibly in pilot study in particular hospital, because the health-care system is classically targeted mortality (like childbirth complications) and transmittable morbidities (such as COVID-19) but not inborn frailties. Although policies and management of childbirth complications have been successfully lowered infant and mother mortality rates, the number of disabled babies increased tremendously. The study aims to investigate the current status of new-born screening (NBS) program of PKU in the Rajshahi Division Bangladesh, and focus on future plans to manage with life-long treatment. The primary challenges such as financial support for newborn screening, publicity, should be identified and implemented for national PKU-NBS policy as a role model of Bangladesh for developing countries.

Resumo em Inglês:

ABSTRACT Research on the genetics, epidemiology, and clinical manifestations of Fabry disease (FD) has increased significantly in recent years. However, some relevant clinical questions still need to be answered to develop better approaches to patient management. This review focuses on answering specific questions raised by Brazilian experts based on their experience in diagnosing and managing patients with FD. The questions are as follows: What is the role of globotriaosylsphingosine in diagnosis? How does one proceed with the diagnosis if there is a variant of unknown significance? What are the earliest and most reliable markers of renal, cardiac, and neurological impairment? What is the prevalence of FD in patients with cryptogenic stroke? What is the average delay in diagnosis in patients with FD? Based on these questions, our objective was to highlight epidemiological, diagnostic, and clinical aspects relating to the literature in the FD field.

Resumo em Inglês:

Abstract Introduction: Neuronal ceroid lipofuscinosis (NCLs) is an autosomal recessive neurodegenerative disorders group. We report the first case in Colombia involving a new genetically confirmed variant of a homozygous CLN6 mutation. Case report: 12-year-old male, history of blood parents and average growth until 5 years of age. At this age began focal crises, progressive regression of neurodevelopment, severe cognitive deficit, and swallowing disorder that led to gastrostomy. Clinical exome + CNVs + mitochondrial DNA genetic study identified variant NM_017882.3 (CLN6): c. 22C>T, p. (Gln8*) in homozygous, deleterious. Late-onset infantile neuronal ceroid lipofuscinosis was diagnosed. Discussion: Mutations in the CLN6 gene are associated with late-onset infantile lipofuscinosis of autosomal recessive inheritance. This variant has not been previously described in the medical literature nor is it listed in the population databases, which indicates that it is extremely rare. The treatment focuses on the control of seizures, sleep disturbances, extrapyramidal symptoms, behavioral disorders, anxiety, and psychosis. Conclusion: To date, this variant of the CLN6 gene has not been reported in the world. There are currently no etiological or disease-specific therapeutic approaches. The use of exome/whole genome sequencing can be very useful for etiological diagnosis and differential diagnosis. An early diagnosis opens the door to future care and treatment.