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.
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.
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.
Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. ...However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%,
= 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP.
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.
Patient-reported outcome measures (PROMs) and patient-reported experiences measures (PREMs) are crucial for understanding the impact of GD on quality of life and patient's perceptions on care, but ...also to guide decision-making processes. Nevertheless, no specific PREMs in GD have been published, neither PROMs for Spanish GD patients have been developed.
Two project coordinators selected key-points to be included in a PROMs/PREMs questionnaire, and the scientific committee and a group of expert patients contributed to the initial draft. Then, 9 meetings with experts were held to discuss controversial points. After, a questionnaire with 103 items regarding symptomatology, aspects of daily life and care experience was developed. Finally, it was conducted a Delphi survey among a multidisciplinary group of experts in GD.
Consensus was reached on 85 out of the 103 items. Recommendations on PROMs and PREMs regarding symptomatology, aspects of daily life and care experience were obtained. Consensus was reached on the importance of considering fatigue, concentration problems, and communication issues in GD patients using 5-step analog scales. Panelists recommended asking GD patients about the impact on social functioning and work/school performance. Finally, consensus was reached on considering care experiences, such as treatment satisfaction, treatment interruptions or transitions and healthcare professionals involved in patient's management to perceive patient's perceptions.
This expert consensus may help developing GD-specific PROMs/PREMs for improving GD management. Properly developed and validated PROMs/PREMs may help decision-making, establishing patient-tailored therapeutic and follow-up goals.
Las medidas de resultados informadas por los pacientes (PROM) y las medidas de experiencias informadas por los pacientes (PREM) son cruciales para comprender el impacto de la enfermedad de Gaucher (EG) en la calidad de vida y las percepciones sobre la atención, pero también para guiar los procesos de toma de decisiones. Sin embargo, no se han publicado PREM específicas en la EG, ni se han desarrollado PROM para pacientes españoles con EG.
Dos coordinadores del proyecto seleccionaron los puntos clave a incluir en un cuestionario de PROM/PREM, y el comité científico y un grupo de pacientes expertos contribuyeron al borrador inicial. A continuación, se celebraron 9 reuniones con expertos para debatir los puntos controvertidos. Después, se elaboró un cuestionario con 103 ítems sobre sintomatología, aspectos de la vida diaria y experiencia asistencial. Por último, se realizó una encuesta Delphi entre un grupo multidisciplinar de expertos en la EG.
Se alcanzó consenso en 85 de los 103 ítems. Se obtuvieron recomendaciones sobre PROM y PREM relativas a sintomatología, aspectos de la vida diaria y experiencia asistencial. Se alcanzó un consenso sobre la importancia de tener en cuenta la fatiga, los problemas de concentración y los problemas de comunicación en los pacientes con EG. Los panelistas recomendaron preguntar a los pacientes con EG sobre el impacto en el funcionamiento social y el rendimiento laboral/escolar. Por último, se llegó a un consenso sobre la importancia de tener en cuenta las experiencias asistenciales, como la satisfacción con el tratamiento, las interrupciones o transiciones del tratamiento y los profesionales sanitarios implicados en el tratamiento del paciente para percibir los efectos de la enfermedad.
Este consenso de expertos puede ayudar a desarrollar PROM/PREM específicos de la EG para mejorar el manejo de la misma. Unas PROM/PREM adecuadamente desarrolladas y validadas pueden ayudar a la toma de decisiones, y a establecer objetivos terapéuticos y de seguimiento adaptados al paciente.
Delayed leukoencephalopathy (DL) is a rare entity associated with cerebral hypoxia and heroin consumption. We describe the clinical course of three cases of DL due to non-heroin drug use.
We describe ...the cases of three DL patients admitted to our hospital in 2012.
These cases contribute to the aetiological spectrum of DL since multifactorial causes could account for the clinical symptoms.
Substances toxic to the CNS can damage the CNS directly (direct toxicity) or by depressing the respiratory centre (cerebral hypoxia).As clinical manifestations can appear after a time lag, we recommend a period of initial monitoring.Histological and radiological findings can contribute to better understanding of the pathophysiological mechanisms and causes involved.
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.
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 (
1
H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare
1
H-MRS of MELAS patients with controls, the
1
H-MRS after glutamine supplementation in the MELAS group, and investigate the association between
1
H-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
1
H-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
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