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Brain histopathology of patient 1: a section of cerebral cortex and white matter showing subcortical spongiosis ( arrow ) and vascular congestion. No significant myelin loss. HE-LFB 20×. Insert Immunohistochemistry with glial fibrillary acidic protein (GFAP) revealing strong positive reaction of astrogliosis at the subcortical level. GFAP 20×. b Higher power level showing the numerous vacuoles ( arrow ) in the subcortical matter. HE 200×. c Section of cerebellum with marked spongiosis ( arrow ) within the dentate nucleus, no abnormality within the cerebellar folia. HE-LFB 40×. d High power of cerebellar white matter near the dentate nucleus showing marked vacuolation ( arrow ) within the myelin sheaths. HE-LFB 400×. Insert Immunohistochemistry with GFAP revealing the significant astrogliosis surrounding the vacuolated white matter
Source publication
Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older s...
Contexts in source publication
Context 1
... range, 900-950 g). On visual inspection of the central nervous system, the cerebral conformation was normal, and no herniation was seen. On coronal sections, the ventricular system was not enlarged, and there was normal appearance of the gray and white matter. On histology, there was bilateral striking vacuolation in the subcortical white matter (Figs. 1a,b), around and within the putamen, in the dentate nuclei and surrounding in the cerebellum (Fig. 1c). The cerebellar folia were unremarkable. In all involved areas, the spongiosis was accompanied by significant astrogliosis. The vacuoles were mainly seen in the myelin sheaths (Fig. 1d). There was no evidence of neuronal loss, no axonal ...
Context 2
... normal, and no herniation was seen. On coronal sections, the ventricular system was not enlarged, and there was normal appearance of the gray and white matter. On histology, there was bilateral striking vacuolation in the subcortical white matter (Figs. 1a,b), around and within the putamen, in the dentate nuclei and surrounding in the cerebellum (Fig. 1c). The cerebellar folia were unremarkable. In all involved areas, the spongiosis was accompanied by significant astrogliosis. The vacuoles were mainly seen in the myelin sheaths (Fig. 1d). There was no evidence of neuronal loss, no axonal damage, and no significant vascular ...
Context 3
... striking vacuolation in the subcortical white matter (Figs. 1a,b), around and within the putamen, in the dentate nuclei and surrounding in the cerebellum (Fig. 1c). The cerebellar folia were unremarkable. In all involved areas, the spongiosis was accompanied by significant astrogliosis. The vacuoles were mainly seen in the myelin sheaths (Fig. 1d). There was no evidence of neuronal loss, no axonal damage, and no significant vascular ...
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Citations
... A case report on SIDS victim two female infants who were sisters as well, revealed a homozygous L2HGDH gene mutation. This gene is known to be associated with inherited metabolic disorders if mutated but it was first time reported in SIDS victims in this report published in 2009 (157). ...
Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches.
Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis.
Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, “hsa-miR-133a-3p” was found to be prevalent in the targeted genes.
Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.
... Even so, there are reported cases of metabolic conditions that evaded diagnosis during life yet led to sudden unexpected deaths even when newborn screening had been performed. [24][25][26] Cardiac Arrhythmia and Cardiomyopathy Cardiac disorders have been extensively investigated as potential causes of SIDS, yet there is still much that is unknown in this area. In 1976, it was first formally postulated that cardiac arrhythmias, in particular Long QT syndrome (LQTS), was a plausible mechanism contributing to SIDS deaths. ...
Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions. Here we review genetic studies that address each of these areas in SIDS cases and cohorts, providing a broad view of the genetic underpinnings of this devastating phenomenon. The current literature has established a role for monogenic genetic causes of SIDS mortality in a subset of cases. To expand upon our current knowledge of disease-causing genetic variants in SIDS cohorts and their mechanisms, future genetic studies may employ functional assessments of implicated variants, broader genetic tests, and the inclusion of parental genetic data and family history information.
... While the largest case series does not describe an acute presentation, there are several case reports of L2HGA with severe neonatal encephalopathy, sudden death in infancy, encephalopathy with rapid functional decline following seizures, and trauma. [17][18][19][20] Our series had two children (20%) with acute presentation and documented metabolic acidosis, which was not described in any of the aforementioned cases. Both the children had features of acute HHE syndrome, though they did not improve with time as reported by Lee et al.; [16] while one succumbed to the illness, the other had a rapid functional decline in our series. ...
... [26][27][28] ere are autopsy reports revealing spongiosis and cystic cavitations in subcortical white matter, with minimal abnormalities of the basal ganglia and dentate nucleus without abnormal storage in neurons and glial cells. [20,29,30] Neonatal autopsy had also revealed gliosis in the pontine and inferior olivary nuclei. [17] Correlation Although the clinical phenotype appears homogenous, correlation between phenotype, biochemical parameters, radiological and genotypic features in this disorder has been difficult to establish with the available literature. ...
Context:
Neurometabolic disorders form an important group of potentially treatable diseases. It is important to recognize the clinical phenotype and characteristic imaging patterns to make an early diagnosis and initiate appropriate treatment. L-2-hydroxy glutaric aciduria (L2HGA) is a rare organic aciduria with a consistent and highly characteristic imaging pattern, which clinches the diagnosis in most cases.
Aims:
The study aims to describe the clinical profile, magnetic resonance imaging (MRI) patterns, and outcome in a cohort of children with L2HGA and to assess the clinicoradiological correlation.
Materials and methods:
This is a retrospective descriptive study done at the Department of Radiodiagnosis and Neurological Sciences of our institution. Clinical and radiological findings of children diagnosed with L2HGA over an 8-year period (2010-2017) were collected and analyzed. Descriptive statistical analysis of clinical and imaging data was performed.
Results:
There were six girls and four boys. A total of 14 MRI brain studies in 10 patients with the diagnosis were analyzed. MRI of all patients showed a similar pattern with extensive confluent subcortical white-matter signal changes with symmetrical involvement of dentate nuclei and basal ganglia. In two children who presented with acute decompensation, there was asymmetric cortical involvement and restricted diffusion, which are previously unreported. There was no significant correlation between the radiological pattern with the disease duration, clinical features, or course of the disease.
Conclusion:
MRI findings in L2HGA are highly consistent and diagnostic, which helps in early diagnosis, particularly in resource-constraint settings, where detailed metabolic workup is not possible. The article also describes novel clinical radiological profile of acute encephalopathic clinical presentation.
... 19 In contrast, a report also showed that riboflavin treatment to a 9-year-old patient was unsuccessful without significant reduction in L-2hydroxyglutaric acid, neurological assessment and MRI readings remain unchanged. 20 These trials show that riboflavin and FAD treatment may only be effective in cases of mild missense mutations in L2HGDH. 13 Our patient did not receive any medical therapy for L2HGA but continued to receive supportive management for the control of her seizures. ...
L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare, autosomal recessive organic aciduria with increased levels of L-2-hydroxyglutaric acid in the urine and other body fluids. Clinical presentation includes developmental delay, epilepsy, and typical neuroimaging findings. This is a report of the clinical, neuroimaging, and biochemical findings of the first diagnosed case of L-2-hydroxyglutaric aciduria in the Philippines. This paper likewise reaffirms the importance of locally available biochemical tests in diagnosing inborn error of metabolism.
... There is one report of a neonate with L-2-HGA and a rapidly fatal outcome [18]. An 11-month-old girl, born to consanguineous parents of Tamil origin suddenly died at 11 months of age, during an intercurrent illness [22]. There was no correlation between the severity of clinical symptoms and the amount of L-2-OHG acid in urine or CSF [12]. ...
... Nevertheless, it appears that this approach is only effective in "mild" missense mutations of L2HGDH (supplementation with FAD 30 mg/day) and levocarnitine chloride (900 mg/day)), whereas truncated enzymes (presumed null mu-tations) are not responsive [1]. Therapeutic trials with oral coenzyme Q10 (400 mg/day) during 6 months and with oral riboflavin (200 mg/day) during 2 months showed no biochemical and clinical effects [22]. We could confirm this observation in our patient. ...
Introduction:
L-2-Hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disease with a slowly progressive course and characterized by increased levels of hydroxyglutaric acid in urine, cerebrospinal fluid and plasma. In this condition clinical features mainly consist of mental deterioration, ataxia and motor deficits.
Case outline:
The patient is a 16-year-old girl, the first and only child of healthy, non-consanguineous parents of Serbian origin. At the age of 4 years her walk became unsteady and ataxic. Other signs of cerebellar involvement were soon observed. Head circumference was above two standard deviations (55 cm). Mild mental retardation was revealed by formal intelligence testing (IQ 60). MR examination of the brain showed confluent subcortical white matter lesions spread centripetally, and atrophy of the cerebellar vermis with involvement of dentate nuclei, without deep white matter abnormalities. Laboratory investigation revealed increased amounts and a very large peak of HGA in urine and plasma. Enantiomeric analysis confirmed the L-configuration (> 90%) establishing the diagnosis of L-2-HGA. The first epileptic seizure, partial with secondary generalization, occurred at age of 8 years. Favorable seizure control was achieved. A slow progression of neurological impairment was noted. Therapeutic trials with oral coenzyme Q10 and with oral riboflavin showed no biochemical and clinical effects. Recently, the diagnosis was proven by the presence of a mutation in the L-2-HGA gene.
Conclusion:
To our knowledge, this is the first report of L-2-HGA in Serbia. L-2-HGA must be considered in the differential diagnosis based on specific findings in cranial MRI.
... In contrast to these two patients, a two month therapeutical trial with riboflavin (200 mg/day) was unsuccessful in a 9-year-old female with L-2-HGA (Jequier et al 2008). She developed a progressive action tremor, light gait ataxia, dysarthria and moderate mental retardation associated with a homozygous splice site mutation in L2HGDH. ...
The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.
... To date, 35 mutations throughout the L2HGDH gene have been published [Haliloglu et al., 2008;Jequier Gygax et al., 2009;Larnaout et al., 2008;O'Conner et al., 2009;Rzem et al., 2004;Samuraki et al., 2008;Sass et al., 2008;Topcu et al., 2004;Vilarinho et al., 2005;Zafeiriou et al., 2008]. In this article these mutations will be reviewed and we will report 35 novel mutations, detected by either direct sequence analysis, polymerase chain reaction (PCR), or multiplex ligation dependent probe amplification (MLPA). ...
... This type of mutation predicts alternative splicing, and is therefore to be considered pathogenic. In the literature six variants altering splice site sequences of acceptor or donor sites have been described [Jequier Gygax et al., 2009;Sass et al., 2008;Topcu et al., 2004;Vilarinho et al., 2005]. ...
L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.
... Consecutive patients, diagnosed with L2HGA in our laboratory on the basis of both biochemical analysis of urine and mutational analysis of L2HGDH between August 2000 and August 2007, were initially included in our study. This included 89 patients, 10 of whom have been included in previously published studies (4,7,13,16,17,(19)(20)(21)(22). We excluded patients with any of the following: (a) no MR images available (n ϭ 26); (b) incomplete or poor-quality transverse T2-weighted MR images, preventing a detailed evaluation of the WM abnormalities (n ϭ 5); (c) age younger than 12 months at MR imaging, preventing the evaluation of the WM abnormalities owing to incomplete myelination (n ϭ 1; age, 2.5 months); and (d) presence of important other neurologic diseases or syndromes (n ϭ 1). ...
To describe the pattern of magnetic resonance (MR) imaging abnormalities in l-2-hydroxyglutaric aciduria (L2HGA) and to evaluate the correlation between imaging abnormalities and disease duration.
MR images in 56 patients (30 male, 26 female; mean age +/- standard deviation, 11.9 years +/- 8.5) with genetically confirmed L2HGA were retrospectively reviewed, with institutional review board approval and waiver of informed consent. At least one complete series of transverse T2-weighted images was available for all patients. The images were evaluated by using a previously established scoring list. The correlation between MR imaging abnormalities and disease duration was assessed (Mann-Whitney or Kruskal-Wallis test).
The cerebral white matter (WM) abnormalities preferentially affected the frontal and subcortical regions. The abnormal subcortical WM often had a mildly swollen appearance (37 patients). Initially, the WM abnormalities were at least partially multifocal (32 patients). In patients with longer disease duration, the WM abnormalities became more confluent and spread centripetally, but the periventricular rim remained relatively spared (41 patients). The mean disease duration in patients with WM atrophy (14.8 years) was significantly longer (P = .001) than that in patients without atrophy (6.7 years). Bilateral involvement of the globus pallidus (55 patients), caudate nucleus (56 patients), and putamen (56 patients) was seen at all stages. The cerebellar WM was never affected. The dentate nucleus was involved bilaterally in 55 of 56 patients.
L2HGA has a distinct highly characteristic pattern of MR imaging abnormalities: a combination of predominantly subcortical cerebral WM abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus. With increasing disease duration, WM abnormalities and basal ganglia signal intensity abnormalities become more diffuse and cerebral WM atrophy ensues.
Mixing or regrouping of calves from different pens is a common animal management practice on the farm, which frequently occurs after weaning and has a negative effect on calve welfare. Social integration before regrouping may relieve stresses, but more evidences are needed to verify this hypothesis. The present study aimed to investigate acute physiological and behavioral variations of individually- or group-housed calves after being introduced into a mixed group. A total of 132 postnatal calves were randomly divided into groups of 1, 3, 6 and 12 animals (S, G3, G6, and G12; 6 replicates in each group) until 59 days of age. At 60 days of age, every two replicates from different groups (S, G3, G6 and G12) were introduced in a larger pen which containing 44 of the aboved experimental calves. Before and after regrouping, physiological parameters of stress, including heart rate (HR), saliva cortisol (S-CORT), saliva secretory immunoglobulin A (SIgA), interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and behavioral responses were recorded. After regrouping, HR and S-CORT increased immediately (P
Objective
In this study, we performed analysis of brainstem reflexes and movement disorders using surface polymyogram in L-2-hydroxyglutaric aciduria (L2HGA). We also reviewed all cases in the literature with detailed clinical and radiological description to analyze the anatomical correlates of involuntary movements.Patients and methodWe performed surface electromyography of appropriate muscles, long-loop reflexes, and somatosensory evoked potentials and analyzed the neuroimaging findings in patients with L2HGA and recorded blink reflex (BR), auditory startle response (ASR), and startle response after somatosensory stimuli (SSS) in patients and healthy subjects. We also performed a systematic literature search to identify the association of neuroimaging findings and movements disorders in previous patients with L2HGA.ResultsThirteen patients were enrolled in the study. Among them, ten had low-amplitude postural tremor with a frequency between 4 and 7 Hz. The tremor was predominant on distal parts of the upper extremities. Postural tremor was accompanied by negative myoclonus in one-third. The BR, ASR, and SSS, all, were hypoactive. There was a close association of postural tremor with cerebellar atrophy in patients who participated in this study and by the analysis of the previously reported patients.Conclusions
Low-amplitude postural tremor is common in L2HGA. It is related with cerebellar atrophy. Although the neuroimaging shows no overt lesions at the brainstem, there is a functional inhibition at this level.
