Women with Gaucher Disease.

Gaucher disease is an inherited disorder in which there is a deficiency of the enzyme glucocerebrosidase, which leads to the accumulation of glucosylceramide. Although much scientific evidence is now available, there is still limited data on the impact on the different life stages of women with this disease. Among other alterations, a delay in menarche has been described, although it has not been related to fertility problems. Menorrhagia is relatively frequent, being related to the presence of thrombocytopenia, thrombocytopathies or coagulation disorders. On the other hand, pregnancy planning is an increasingly frequent concern. All patients should undergo genetic counseling, and it is important to monitor the appearance or worsening of organomegaly, bone and hematologic abnormalities to establish clinical and therapeutic recommendations. Management during the puerperium will depend on the evolution of gestation, and, during the lactation period, the potential appearance of bone complications should be assessed. An early onset of menopause, compared to the general population, has also been described, which may accelerate the development of osteopenia. Finally, although the usual screening protocols for neoplasms are currently being performed, it is recommended to watch for early signs of liver or renal neoplasms when examining the results of imaging tests performed during evaluations for this disease.

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study / Carga de la enfermedad y calidad de vida en pacientes con porfiria hepática aguda: estudio COPHASE

Background: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. Results: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. Conclusions: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.(AU)

Antecedentes: La porfiria hepática aguda (PHA) comprende un grupo de enfermedades genéticas raras caracterizadas por crisis neuroviscerales que se manifiestan por dolor abdominal y síntomas neurológicos y/o psicológicos que interfieren en la capacidad de llevar una vida normal. Nuestro objetivo fue determinar la carga de la enfermedad en un año y la calidad de vida relacionada con la salud (CVRS) en pacientes con PHA. Resultados: Se analizaron 28 pacientes. La edad media fue de 36,6±10,2 años, el 89,3% eran mujeres y la media de crisis fue de 1,9±1,5. El coste medio anual por paciente fue de 38.255,40€. El 80,2% de los costes fueron costes médicos directos, el 17,5% estuvieron asociados a pérdida de productividad y el 2,3% fueron costes directos no médicos. El 85,9% del coste total correspondió a las crisis. El período entre crisis representó el 14,1% restante. El índice global del EQ-5D-5L (HRQoL) fue de 0,751±0,24. Las dimensiones de dolor/malestar, ansiedad/depresión y actividades cotidianas fueron las más afectadas. Ocio, viajes/vacaciones y actividades del hogar fueron las actividades diarias más afectadas. El 53,6% de los pacientes requirieron un cuidador debido a la PHA. El 92,9% no presentaron sobrecarga y el 7,1% presentaron sobrecarga extrema. Conclusiones: Los pacientes con PHA se asocian con un alto impacto económico y una CVRS afectada en la dimensión dolor/malestar, con impacto negativo en el desempeño de las actividades diarias y riesgo de enfermedades psiquiátricas.(AU)

The burden of disease and quality of life in patients with acute hepatic porphyria: COPHASE study.

BACKGROUND: Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP. RESULTS: 28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload. CONCLUSIONS: Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.

Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation.

PURPOSE: MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (1H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare 1H-MRS of MELAS patients with controls, the 1H-MRS after glutamine supplementation in the MELAS group, and investigate the association between 1H-MRS and CSF lactate, glutamate, and glutamine levels. METHODS: We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software. RESULTS: Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003). CONCLUSION: No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and 1H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome.

Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.

High-dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

BACKGROUND AND PURPOSE: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There are no disease-modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate-glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high-dose oral glutamine supplementation could reduce the increase in glutamate levels. METHOD: This open-label, single-cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation. RESULTS: Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 µmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 µmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke-like episode. DISCUSSION: This study demonstrates that high-dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

Efectividad y seguridad del tratamiento de las enfermedades de depósito lisosomal: análisis de 22 pacientes / Effectiveness and safety of the treatment of lysosomal deposit diseases: Analysis of 22 patients

Objetivos: Los objetivos son: identificar variables de eficacia empleadas en fármacos para enfermedades de depósito lisosomal (EDL), evaluar la calidad de esta evidencia, y conocer la efectividad y seguridad de estos tratamientos.Material y métodosEstudio observacional retrospectivo que incluyó pacientes con EDL tratados con terapia de sustitución enzimática (TSE) o de reducción de sustrato (TRS). Se revisaron los ensayos clínicos (EC) publicados y guías de tratamiento de EDL para seleccionar las variables de eficacia. Se obtuvieron los datos para medirlas (y efectos adversos) de la historia clínica.ResultadosNo se encontraron EC en los que se evalúe la eficacia con variables finales, todas fueron subrogadas. Se incluyeron 22 pacientes: 8 con enfermedad de Gaucher, 6 con enfermedad de Niemann-Pick tipo C, 2 con enfermedad de Hunter, uno con enfermedad de Morquio-A y 5 con enfermedad de Pompe. Ocho pacientes respondieron a TSE y uno a TRS. La TSE no se relacionó con efectos adversos. Miglustat produjo problemas de tolerancia que requirieron cambio de tratamiento en un paciente.ConclusionesLa efectividad fue variable según la enfermedad. Respecto a seguridad, se asociaron reacciones adversas a TRS manejables con ajustes posológicos. (AU)

Objectives: Identify the efficacy variables collected in the literature for therapies used in lysosomal storage diseases (LDS), evaluate the quality of this evidence, and know the effectiveness and safety of these treatments.Material and methodsRetrospective observational study that included patients with LDS treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Published clinical trials (CT) and LDS treatment guidelines were reviewed to select efficacy variables. Data to measure them (and adverse effects) were obtained from the medical history.ResultsNo CTs have been found in which efficacy is evaluated with final variables, all have been surrogated. Twenty-two patients were included: eight with Gaucher disease, six with Niemann–PickC disease, two with Hunter disease, one with Morquio-A disease, and five with Pompe disease. Eight patients have responded to ERT and one to SRT with eliglustat. ERT has not been associated with adverse effects. Miglustat has produced tolerance problems, requiring a change in a patient.ConclusionsThe effectiveness was variable according to the pathology. Regarding safety, manageable adverse reactions to SRT were associated with dosage adjustments. (AU)

Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review.

Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5' UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism.

Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain.

Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 µmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 µmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.

Recommendations for the Diagnosis and Therapeutic Management of Hyperammonaemia in Paediatric and Adult Patients.

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200−350 µmol/L in children up to 18 months of age and >150−200 µmol/L after that age.

Effectiveness and safety of the treatment of lysosomal deposit diseases: Analysis of 22 patients. / Efectividad y seguridad del tratamiento de las enfermedades de depósito lisosomal: análisis de 22 pacientes.

OBJECTIVES: Identify the efficacy variables collected in the literature for therapies used in lysosomal storage diseases (LDS), evaluate the quality of this evidence, and know the effectiveness and safety of these treatments. MATERIAL AND METHODS: Retrospective observational study that included patients with LDS treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Published clinical trials (CT) and LDS treatment guidelines were reviewed to select efficacy variables. Data to measure them (and adverse effects) were obtained from the medical history. RESULTS: No CTs have been found in which efficacy is evaluated with final variables, all have been surrogated. Twenty-two patients were included: eight with Gaucher disease, six with Niemann-PickC disease, two with Hunter disease, one with Morquio-A disease, and five with Pompe disease. Eight patients have responded to ERT and one to SRT with eliglustat. ERT has not been associated with adverse effects. Miglustat has produced tolerance problems, requiring a change in a patient. CONCLUSIONS: The effectiveness was variable according to the pathology. Regarding safety, manageable adverse reactions to SRT were associated with dosage adjustments.

Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients. METHODS: This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined. RESULTS: Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 µmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 µmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS. CONCLUSIONS: Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.

Understanding the ecosystem of patients with lysosomal storage diseases in Spain: a qualitative research with patients and health care professionals.

BACKGROUND: Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients' quality of life. METHODS: Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people's views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. RESULTS: In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. CONCLUSIONS: Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.

Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.

Diagnosis and Management of Inborn Errors of Metabolism in Adult Patients in the Emergency Department.

Inborn errors of metabolism (IEM) constitute an important group of conditions characterized by an altered metabolic pathway. There are numerous guidelines for the diagnosis and management of IEMs in the pediatric population but not for adults. Given the increasing frequency of this group of conditions in adulthood, other clinicians in addition to pediatricians should be aware of them and learn to identify their characteristic manifestations. Early recognition and implementation of an appropriate therapeutic approach would improve the clinical outcome of many of these patients. This review presents when and how to investigate a metabolic disorder with the aim of encouraging physicians not to overlook a treatable disorder.

Clinical features and health-related quality of life in adult patients with mucopolysaccharidosis IVA: the Spanish experience.

BACKGROUND: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). RESULTS: Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5-40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106-136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03-2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68-3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25-2.34) versus 2.25 (1.62-3.00) in patients not treated with ERT. CONCLUSIONS: The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.

First female with Allan-Herndon-Dudley syndrome and partial deletion of X-inactivation center.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.