A compound heterozygote case of glutaric aciduria type II in a patient carrying a novel candidate variant in ETFDH gene: A case report and literature review on compound heterozygote cases.

BACKGROUND: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad-spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes. METHODS: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19-year-old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it. RESULTS: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2. CONCLUSION: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies.

Clinico-Biochemical Spectrum of Pakistani Patients with Glutaric Aciduria Type 1 (GA1): Experience from a Specialised Biochemical Genetics Laboratory in Pakistan.

OBJECTIVE: To evaluate the clinical, radiological, and biochemical features of glutaric aciduria Type 1 (GA1) patients identified through urine organic acid testing at a biochemical genetics laboratory (BGL) in Pakistan. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan, from January 2013 to December 2022. METHODOLOGY: Medical charts and urine organic acid (UOA) chromatograms of the patients presenting at the BGL from January 2013 to December 2022 were reviewed. Brain imaging was obtained where available. Variables were noted as per the objective and descriptive statistics were obtained. RESULTS: GA1 was found in 64 (0.4%) patients out of a total of 16,094 UOA requests for high-risk screening cases. The age of diagnosis ranged between one month and three years. The brain MRI findings revealed characteristic abnormalities such as cerebral atrophy, expanded CSF spaces, white matter abnormalities, and a distinct bat wings appearance, in cohesion with the results of biochemical testing. CONCLUSION: Sixty-four cases of GA1 from a single centre indicate a high frequency of the disorder in Pakistan. Late diagnosis emphasises the need for increased clinical awareness and preferably newborn screening to ensure optimal outcomes. KEY WORDS: Glutaric aciduria Type 1 (GA1), Brain imaging, UOA analysis, Glutaryl-CoA dehydrogenase (GCDH), Pakistan.

Evaluation of the first 5 years of a glutaric aciduria type I neonatal screening programme in Asturias.

INTRODUCTION: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community. MATERIAL: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L. RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life. CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.

Late-onset cerebellar ataxia and a new frameshift L2HGDH mutation in a Chinese adult with L-2-hydroxyglutaric aciduria: a case report.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurometabolic disease, which presents with elevated L-2-hydroxyglutarate acid. Generally, L2HGA appear as slowly progressing central nervous system function deterioration during infancy, and a rapid progression in adulthood is uncommon for the syndrome's classic phenotype.

L-2-hydroxyglutaric aciduria: a report of clinical, radiological, and genetic characteristics of two siblings from Egypt.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessive disease characterized by elevated levels of hydroxyglutaric acid in the body fluids and brain with abnormal white matter. We present two siblings with psychomotor retardation and quadriparesis. Their brain imaging showed diffuse bilateral symmetrical involvement of the cerebral cortex, white matter, basal ganglia and cerebellum. The whole exome sequence studies revealed a homozygous likely pathogenic variant on chromosome 14q22.1 (NM_024884.2: c.178G > A; pGly60Arg) in the gene encoding for L-2-hydroxyglutarate dehydrogenase (L2HGDH) (OMIM #236792). Therefore, using the L2HGDH gene study is beneficial for L2HGA diagnosis.

Comprehensive metabolomics analysis reveals novel biomarkers and pathways in falsely suspected glutaric aciduria Type-1 newborns.

BACKGROUND: Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns. METHODOLOGY: DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites. RESULTS: 582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples. CONCLUSIONS: A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.

Compilation of Genotype and Phenotype Data in GCDH-LOVD for Variant Classification and Further Application.

Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease.

¿Encefalopatía o encefalitis por varicela-zóster? Una paciente con una punción lumbar engañosa / ENCEPHALOPATHY OR VARICELLA-ZOSTER ENCEPHALITIS? A PATIENT WITH A TRICKY LUMBAR PUNCTURE

La encefalopatía es un cuadro clínico característico de múltiples procesos neurológicos y sistémicos que no hay que confundir con la encefalitis, que es una inflamación cerebral, normalmente causadas por infecciones virales. Se presenta el caso de una mujer de 58 años con enfermedad renal crónica en diálisis peritoneal, que ingresa por sepsis de origen peritoneal con clínica de encefalopatía y crisis epilépticas parciales. La paciente presenta lesiones de herpes zóster en zona lumbar y se practica punción lumbar, con resultado del líquido cefalorraquídeo positivo para virus varicela-zóster, por lo que completa tratamiento con aciclovir. En la resonancia magnética no presenta ninguna alteración, y una segunda punción lumbar tras mejoría de las lesiones cutáneas es negativa. El curso de la paciente es fluctuante durante el ingreso, con mejoría significativa tras antibióticos, hemodiálisis y tratamiento antiepiléptico, y no respondiendo al aciclovir. La etiología sospechada es la debida al contexto infeccioso y metabólico de la paciente. Probablemente el resultado del líquido fue contaminado por la proximidad de las lesiones herpéticas, ya que además no es frecuente encontrar encefalitis infecciosas agudas sin alteraciones en las pruebas de imagen. La mejoría final fue debida tanto a la medicación antiepiléptica como al inicio de hemodiálisis

Encefalopathy is a clinical syndrome ocurring in multiple neurologic and systemic diseases which must not be mistaken with encephalitis, that is a cerebral inflammatory process, often caused by viral infections. We present the case of a 58-year-old woman with chronic renal failure receiving peritoneal dyalisis, who was admitted into hospital for sepsis secondary to infectious peritonitis, with encefalopathy and epileptic partial seizures. The patient presented lumbar herpetic cutaneous lesions and a lumbar punction is practiced, with a positive result in the cerebrospinal fluid for varicella-zoster virus. Treatment with aciclovir was completed. Her cerebral magnetic resonance was absolutely normal, and a second lumbar puncture when herpetic lesions got better was negative. The course is fluctuating during the stay, and a significant clinical improvement occurs after antibiotics, hemodyalisis and antiepileptic treatment. The patient did not respond to aciclovir. The suspected ethiology is the infectious and metabolic context. Positivity for the virus is thought to be a contamination from the nearby herpetic lesions. Also, it is rare for an infectious acute encephalitis to present with normal radiologic imaging. The final clinical improvement was probably due to hemodyalisis initiation and the antiepileptic treatment.

Encefalopatias: etiologia, fisiopatologia e manuseio clínico de algumas das principais formas de apresentação da doença / Encephalopathies: etiology, pathophysiology, and clinical management of some major forms of disease presentation

JUSTIFICATIVA E OBJETIVOS: As encefalopatias compõem um grupo heterogêneo de etiologias, onde a pronta e correta atuação médica direcionada à causa da doença, pode modificar o prognóstico do paciente. O objetivo deste estudo foi rever os aspectos fisiopatológicos das diferentes encefalopatias bem como seus principais fatores desencadeantes e manuseio clínico.CONTEÚDO: Foram selecionadas as mais frequentes encefalopatias observadas na prática clínica e discutir sua fisiopatologia, bem como sua abordagem terapêutica, destacando: encefalopatia hipertensiva, hipóxico-isquêmica, metabólica, Wernicke-Korsakoff, traumática e tóxica.CONCLUSÃO: Trata-se de uma complexa condição clínica que exige rápida identificação e preciso manuseio clínico com o intuito de reduzir sua elevada taxa de morbimortalidade. O atraso no reconhecimento dessa condição clínica poderá ser extremamente prejudicial ao paciente que estará sofrendo lesão cerebral muitas vezes irreversível.

BACKGROUND AND OBJECTIVES: Encephalopathies comprise a heterogeneous group of clinical conditions, in which the prompt and adequate medical intervention can modify patient prognosis. This paper aims to discuss the pathophysiological aspects of different encephalopathies, their etiology, and clinical management.CONTENTS: We selected the main encephalopathies observed in clinical practice, such as hypertensive, hypoxic-ischemic, metabolic, Wernicke-Korsakoff, traumatic, and toxic encephalopathies, and to discuss their therapeutic approaches.CONCLUSION: This is a complex clinical condition that requires rapid identification and accurate clinical management with the aim of reducing its high morbidity and mortality rates. Delay in recognizing this condition can be extremely harmful to the patient who is suffering from often irreversible brain injury.

Hyponatremia and brain injury: absence of alterations of serum brain natriuretic peptide and vasopressin / Hiponatremia e traumatismo cranioencefálico: ausência de alteração sanguínea do peptídeo natriurético cerebral e hormônio antidiurético

OBJECTIVE: To study any possible relation between hyponatremia following brain injury and the presence of cerebral salt-wasting syndrome (CSWS) or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and if vasopressin, brain natriuretic peptide (BNP) and aldosterone have a role in its mechanism. METHOD: Patients with brain injury admitted to the intensive care unit were included and had their BNP, aldosterone and vasopressin levels dosed on day 7. RESULTS: Twenty six adult patients were included in the study. Nine (34.6 percent) had hyponatremia and presented with a negative water balance and higher values of urinary sodium, serum potassium and diuresis than patients with normonatremia. The serum levels of BNP, aldosterone, and vasopressin were normal and no relation was observed between plasma sodium and BNP, aldosterone or vasopressin. CONCLUSION: The most likely cause of hyponatremia was CSWS and there was no correlation between BNP, aldosterone and vasopressin with serum sodium level.

OBJETIVO: Estudar a possível relação entre a hiponatremia seguindo traumatismo cranioencefálico e a presença da síndrome cerebral perdedora de sal (SCPS) ou a síndrome da secreção inapropriada do hormônio antidiurético (SSIHAD), e se a vasopressina, peptídeo natriurético cerebral (BNP) e aldosterona têm um papel nesse mecanismo. MÉTODO: Foram incluídos pacientes com traumatismo cranioencefálico admitidos na unidade de terapia intensiva e foram dosados no sétimo dia seguindo o trauma, BNP, aldosterona e vasopressina. RESULTADOS: Vinte e seis pacientes foram incluídos no estudo. Nove (34,6 por cento) tiveram hiponatremia e apresentaram um balanço hídrico mais negativo e altos valores de sódio urinário, potássio sérico e diurese quando comparados com o grupo que apresentou normonatremia. Os níveis séricos de BNP, aldosterona e vasopressina foram normais e não foi observada relação entre o sódio sérico e BNP, aldosterona e vasopressina. CONCLUSÃO: A causa mais provável da hiponatremia foi a SCPS e não houve correlação entre BNP, aldosterona e vasopressina com o nível sérico de sódio.

Encefalopatía inducida por ácido valproico / Encephalopathy induced by valproico acid

El ácido valproico es una droga de creciente uso para el tratamiento de las convulsiones, desórdenes conductales, enfermedades psiquiátricas y migrañas. Como efecto adverso poco frecuente puede desarrollar encefalopatía debido a hiperamoniemia.Esta reacción es frecuentemente observada en niños y en pacientes con factores de riesgo. Casos de encefalopatía hiperamoniémica sin disfunción hepática debido a ácido valproico se han descripto en adultos luego de tomas adecuadas o excesicas de la droga. Este trastorno es más común cuando se asocia a fenobarbital, fenitoína o carbamecepina, siendo infrecuente cuando el valproato es usado como monoterapia. Las complicaciones a nivel del SNC tiene la desventaja de no estar relacionads con la dosis, lo que hace dificil su predicción. La naturaleza y severidad de dicha disfunción depende de la causa, el grado de hiperamoniemia, su forma de inicio y la edad del paciente. Los signos típicos son el comienzo agudo del deterioro de la conciencia con confusión y letargia. Este es un trastorno reversible pero sin tratamiento puede ocasionar daño cerebral permanente y deterioro congnitivo severo. Por ello es necesario monitorear cercanamente el tratamiento con el anticonvulsivante y detectar individuos con alto riesgo de desarrollar como por valproato. Hay medidas preventivas y en pacientes gravemente enfermos la terapéutica incluye depuración dialítica.

Lentidão cognitiva e psicomotora em hemodialisados crônicos / Cognitive and psychomotor slowing in chronic hemodialysis patients

FUNDAMENTOS: A encefalopatia urêmica subclínica pode levar a comprometimento ocupacional de difícil diagnóstico por requerer o emprego de medidas sensíveis. PROPOSITO: Testar as hipóteses de que (1) pacientes em hemodiálise crônica (HDC) se saem pior do que controles normais em uma bateria de desempenho, (2) um dia extra de uremia comprometeria ainda mais o comprometimento neuropsicológico desses pacientes, e (3) a uremia dificultaria a melhora do desempenho em uma segunda sessão de testes. MÉTODO: A agilidade cognitiva e motora de 28 pacientes em HDC foi avaliada com os testes de Trilhas (A e B), Algarismos e Símbolos, e Stroop. RESULTADOS: (1a) o desempenho cognitivo e motor se encontravam mais lento nos pacientes, (2a) um dia a mais de uremia comprometeu o desempenho na Parte B do Teste de Trilhas, e (3a) pacientes em HDC apresentaram redução da capacidade de aprender novos procedimentos. CONCLUSÃO: Pacientes em HDC podem apresentar uma "encefalopatia subclínica" cuja detecção pode requerer a aplicação de testes sensíveis. A agilidade mental e motora, e a capacidade de aprender novas rotinas estão comprometidas em, pelo menos, alguns pacientes em HDC com cognição global normal.

BACKGROUND: The diagnosis of "subclinical uremic encephalopathy" may need the administration of sensitive tests. PURPOSE: To test the hypotheses that (1) patients on chronic hemodialysis (CHD) fare worse than normal controls on a brief performance battery, (2) one extra-day of uremia further jeopardizes the neuropsychological performance of CHD patients, and (3) uremia impairs improvement on a second testing session. METHOD: The cognitive and motor agility of 28 patients on CHD were assessed with the Trails A and B, Digit Symbol, and Stroop tests. RESULTS: (1a) cognitive and psychomotor performance were slowed in patients, (2a) one extra-day of uremia impaired performance further on Trail Making B, and (3a) CHD patients had a decreased ability to learn novel procedures even in the short-term. CONCLUSION: CHD patients may present with a "subclinical encephalopathy" whose detection may require the administration of sensible tests. Mental and motor agility, and the ability to learn new routines are impaired in at least some CHD patients with a normal global cognitive state.

Programa de rehabilitación basada en la comunidad para el diagnostico y tratamiento de las alteraciones motoras cerebrales infantiles / Community-based rehabilitation program for the diagnosis and treatment of the child cerebral motor alterations

El proyecto consiste en una propuesta de intervencion, orientada a dar solución a uno de los principales problemas de salud en nuestro medio que no ha sido encarado aún en forma apropiada: las alteraciones cerebrales infantiles. Se pretende beneficiar a una población seleccionada que pueda acceder a un programa de Rehabilitación Basada en la Comunidad (RBC). Se busca trabajar con mayor énfasis a nivel comunitario mediante la capacitación de madres lideres, que son para este proyecto el respaldo y nexo entre el personal de salud y la población beneficiaria, a través de la participación comprometida de los Centros de Atención Primaria en Salud...

Hallazgos neurorradiológicos en aminoaciduria glutárica tipo I: informe de dos casos / Neuroradiologic findings in glutaric aminoaciduria type I

Se informan los hallazgos neurradiológicos de dos pacientes pediátricos con aminoaciduria glutárica tipo I (AG-I), a quienes se les realizó tomografía de cabeza y, sólo a uno, estudio de imagen de resonancia magnética. El diagnóstico bioquímico se llevo a cabo mediante la medición de ácido glutártico libre en orina, así como por cromatografía de gas para determinar la actividad enzimática del glutaril Co-A deshidrogenasa en los leucocitos. El retardo en la mielinización, con su consecuente disminución generalizada de la sustancia blanca, es característico de varias enfermedades metabólicas; las evidencias de las alteraciones de disgénesis cerebral se obtienen básicamente mediante estudios de neuroimagen. Se debe sospechar una probable enfermedad hereditaria del metabolismo como AG-I cuando se tenga un paciente pediátrico con retraso psicomotor, alteraciones motoras extrapiramidales o macrocrania, en el cual se obtengan los siguientes hallazgos neurorradiológicos: atrofia bilateral de la fosa temporal asociada con áreas hipodensas difusas en la sustancia blanca, ligera atrofia o pérdida del volumen de los ganglios basales, hipoplasia del vermis del cerebelo y ocasionalmente colección subdural de líquido.

Encefalopatia mitocondrial / Mitochondrial encephapathy

Os autores relatam o caso de um paciente de 13 anos com sinais de comprometimento do sistema extrapiramidal e da musculatura estriada. O exame histopatológico muscular com histoquímica (DHS) e a microscopia eletrônica comprovaram a existência de alteraçöes mitocondrias quantitativas e qualitativas