ABSTRACT
PURPOSE: Several underlying conditions of moyamoya syndrome (MMS) are well established, but so far, D-2-hydroxyglutaric aciduria (D-2-HGA) has not been mentioned. We are the first to describe a case of a patient suffering from D-2-HGA developing MMS. METHODS: The co-occurrence of D-2-HGA and MMS in a patient is reported. Furthermore, we describe the neurosurgical revascularization procedure performed and report on the follow-up. RESULTS: A 7-year-old girl suffering from D-2-HGA developed two transient ischemic attacks (TIAs). Using MRI/MRA and invasive angiography MMS was diagnosed. We performed an encephalo-duro-arterio-myo-synangiosis (EDAMS) as an indirect revascularization procedure first on the right and 2 months later on the left hemisphere. We have followed her up until the age of 10. Since the second surgery, she has not suffered further TIAs and is in a better general medical condition. CONCLUSION: Even though children with D-2-HGA often suffer epileptic attacks, every new (transient) neurological deficit should be followed up by an MRI/MRA so as not to oversee a possible underlying MMS. After diagnosis, EDAMS in combination with acetylsalicylic acid (ASA) is recommended to prevent further ischemic events.
Subject(s)
Moyamoya Disease , Humans , Moyamoya Disease/complications , Moyamoya Disease/diagnostic imaging , Moyamoya Disease/surgery , Female , Child , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/diagnostic imaging , Cerebral Revascularization/methods , Magnetic Resonance ImagingABSTRACT
D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D-2-hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D-2-HGA. Murine models have demonstrated how D-2-hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D-2-HGA type I, who was treated with an anthracycline-free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long-term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D-2-HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.
Subject(s)
Brain Diseases, Metabolic, Inborn , Cardiomyopathies , Cardiomyopathy, Dilated , Leukemia, Myeloid, Acute , Metabolic Diseases , Urogenital Abnormalities , Animals , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/genetics , Cardiomyopathies/complications , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Child , Humans , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mice , Rare DiseasesABSTRACT
INTRODUCTION: Cerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. MATERIALS AND METHODS: This was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. RESULTS: Thirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years. Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients). Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients. Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. CONCLUSION: Intellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.
Subject(s)
Brain Diseases, Metabolic, Inborn/diagnosis , Creatine/deficiency , Guanidinoacetate N-Methyltransferase/deficiency , Language Development Disorders/diagnosis , Mental Retardation, X-Linked/diagnosis , Movement Disorders/congenital , Neurodevelopmental Disorders/diagnosis , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/physiopathology , Child , Child, Preschool , Creatine/genetics , Female , Follow-Up Studies , Guanidinoacetate N-Methyltransferase/genetics , Humans , India , Language Development Disorders/complications , Language Development Disorders/genetics , Language Development Disorders/physiopathology , Male , Mental Retardation, X-Linked/complications , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/physiopathology , Movement Disorders/complications , Movement Disorders/diagnosis , Movement Disorders/genetics , Movement Disorders/physiopathology , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/physiopathology , Plasma Membrane Neurotransmitter Transport Proteins/genetics , Retrospective StudiesABSTRACT
L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder caused by the deficiency of L-2-hydroxyglutarate dehydrogenase (L2HGDH) enzyme. Dystonia, ataxia, pyramidal involvement and seizures are the common clinical manifestations. Coexisting behavioural problems and intellectual disability are also seen, however attention deficit hyperactivity disorder (ADHD) as the presenting clinical feature in L2HGA is rarely described. Here, we report a 5-year-old boy with behavioural problems and mild language delay. On clinical assessment, he fulfilled the diagnostic criteria for ADHD. His MR brain sequences showed classical finding of L2HGA-bilateral symmetrical T2-weighted hyperintensity involving subcortical white matter, basal ganglia and dentate nucleus. Urine analysis showed increased levels of 2-hydroxyglutaric acid and exome sequencing (targeted leukodystrophy panel) revealed homozygous likely pathogenic mutation in L2HGDH He was started on high dose of riboflavin and levocarnitine and rehabilitative measures with which he had improvement in behavioural symptoms. This case illustrates the pivotol role of MR brain imaging in the diagnosis of inborn errors of metabolism.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Brain Diseases, Metabolic, Inborn , Alcohol Oxidoreductases/genetics , Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/drug therapy , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/drug therapy , Child, Preschool , Humans , Magnetic Resonance Imaging , MaleABSTRACT
KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients.
Subject(s)
Abnormalities, Multiple/genetics , Lysine-tRNA Ligase/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Adolescent , Alleles , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/pathology , Child , Child, Preschool , Cohort Studies , Cytosol/metabolism , Disease Progression , Female , Homozygote , Humans , Infant , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Microcephaly/complications , Microcephaly/genetics , Microcephaly/pathology , Mitochondria/genetics , Mitochondria/metabolism , Organisms, Genetically Modified , Pedigree , Phenotype , Saccharomyces cerevisiaeABSTRACT
L-2-hydroxiglutaric aciduria (L2HGA) is a rare, childhood-onset, organic aciduria, with characteristic clinical (cerebellar ataxia) and neuroimaging (subcortical leukodystrophy) features. Movement disorders in this condition are usually of hyperkinetic type. Herein is reported the case of two adult siblings with recent L2HGA diagnosis, presenting with dopa-responsive parkinsonism and MRI iron deposition.
Subject(s)
Brain Diseases, Metabolic, Inborn/complications , Brain/pathology , Iron Metabolism Disorders/genetics , Parkinsonian Disorders/genetics , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , PedigreeABSTRACT
Inborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors. Neurotransmitter dysfunctions could also result from the impairment of neuronal receptors, intracellular signaling, vesicle release or other synaptic abnormalities. Epilepsy is the main clinical hallmark in some of these diseases (e.g. disorders of GABA metabolism, glycine encephalopathy) while it is infrequent in others (e.g. all the disorders of monoamine metabolism in exception for dihydropteridine reductase deficiency). This review analyzes the epileptogenic mechanisms, the epilepsy phenotypes and the principle for the clinical management of epilepsy in primary and secondary inherited disorders of neurotransmitter metabolism (disorders of GABA, serine and glycine metabolism, disorders of neurotransmitter receptors and secondary neurotransmitter diseases).
Subject(s)
Brain Diseases, Metabolic, Inborn/complications , Epilepsy/therapy , Brain Diseases, Metabolic, Inborn/metabolism , Epilepsy/etiology , Epilepsy/metabolism , HumansABSTRACT
X-linked creatine transporter deficiency is caused by the deficiency of the creatine transporter encoded by the SLC6A8 gene on Xq28. We here report a 3-year-old boy with global developmental delay, autism and epilepsy. He had a normal MRI of the brain. Brain magnetic resonance spectroscopy (MRS) subsequently showed an abnormally small creatine peak. His high urine creatine/creatinine ratio further suggested the diagnosis, later confirmed by hemizygous mutation detected in the SLC6A8 gene. His mother was also heterozygous for the same mutation. Supplementation with creatine monohydrate, arginine, and glycine (precursors of creatine) and supportive therapies, resulted in modest clinical improvement after 12 months. This case highlights the importance of doing MRS for boys with global delay/intellectual disability, autism and epilepsy even with a normal MRI of the brain, to pick up a potentially treatable cause.
Subject(s)
Autistic Disorder/genetics , Brain Diseases, Metabolic, Inborn/diagnosis , Creatine/deficiency , Epilepsy/genetics , Intellectual Disability/genetics , Mental Retardation, X-Linked/diagnosis , Nerve Tissue Proteins/genetics , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/genetics , Child, Preschool , Creatine/analysis , Creatine/genetics , Creatine/metabolism , Hemizygote , Humans , Magnetic Resonance Spectroscopy , Male , Mental Retardation, X-Linked/complications , Mental Retardation, X-Linked/genetics , Mutation , Nerve Tissue Proteins/deficiency , Plasma Membrane Neurotransmitter Transport Proteins/geneticsABSTRACT
Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr.
Subject(s)
Autistic Disorder/etiology , Brain Diseases, Metabolic, Inborn/drug therapy , Cognition Disorders/etiology , Creatine/deficiency , Creatinine/analogs & derivatives , Epilepsy/etiology , Mental Retardation, X-Linked/drug therapy , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Animals , Autistic Disorder/drug therapy , Blood-Brain Barrier , Brain Diseases, Metabolic, Inborn/complications , Cerebrovascular Circulation/drug effects , Cognition Disorders/drug therapy , Creatinine/therapeutic use , Disease Models, Animal , Electroencephalography , Epilepsy/drug therapy , Hemodynamics/drug effects , Male , Mental Retardation, X-Linked/complications , Mice , Mice, Inbred C57BL , Phenotype , Seizures/drug therapy , Seizures/etiology , Stereotyped Behavior/drug effectsSubject(s)
Aspartate Carbamoyltransferase/deficiency , Brain Diseases, Metabolic, Inborn , Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/deficiency , Dihydroorotase/deficiency , Drug Resistant Epilepsy , Anticonvulsants/administration & dosage , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/drug therapy , Brain Diseases, Metabolic, Inborn/enzymology , Consanguinity , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/drug therapy , Drug Resistant Epilepsy/enzymology , Drug Resistant Epilepsy/etiology , Humans , Infant , Phenytoin/administration & dosage , Uridine/administration & dosageABSTRACT
D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.
Subject(s)
Brain Diseases, Metabolic, Inborn/genetics , Chondromatosis/genetics , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Diseases, Metabolic, Inborn/complications , Child, Preschool , Chondromatosis/complications , Chondromatosis/drug therapy , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy , Male , Mutation , Treatment OutcomeABSTRACT
INTRODUCTION: Stroke-like episodes (SLEs) are typical cerebral manifestations of certain mitochondrial disorders (MIDs). They are characterised by a vasogenic edema in a non-vascular distribution. PATIENTS CONCERNS:: none DIAGNOSIS:: SLEs show up on cerebral MRI as stroke-like lesions (SLLs), characterised by vasogenic edema in a non-vascular distribution. SLLs expand in the acute stage and regress during the chronic stage. They show hyperperfusion in the acute stage and hypoperfusion in the chronic stage. INTERVENTIONS: SLLs respond favorably to antiseizure drugs, to No-precursors, steroids, the ketogenic diet, and antioxidants. OUTCOME: SLLs end up as normal tissue, white matter lesion, grey matter lesion, cyst, laminar cortical necrosis, or the toenail sign. CONCLUSIONS: SLLs are a frequent manifestation of MIDs. They undergo dynamic changes in the acute and chronic stage. They need to be differentiated from ischemic stroke as they are differentially treated.
Subject(s)
Brain Diseases, Metabolic, Inborn/drug therapy , Encephalitis/drug therapy , MELAS Syndrome/diagnostic imaging , MELAS Syndrome/genetics , Mitochondrial Diseases/complications , Stroke/drug therapy , Acidosis, Lactic/diagnosis , Anticonvulsants/therapeutic use , Antioxidants/therapeutic use , Asian People/ethnology , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Edema/diagnostic imaging , Child , DNA, Mitochondrial/genetics , Diagnosis, Differential , Diet, Ketogenic/adverse effects , Diet, Ketogenic/methods , Encephalitis/diagnosis , Humans , MELAS Syndrome/drug therapy , MELAS Syndrome/pathology , Magnetic Resonance Imaging , Male , Mitochondrial Encephalomyopathies/diagnosis , Oxidative Phosphorylation/drug effects , Stroke/classification , Stroke/pathologyABSTRACT
BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder characterized by a slowly progressive clinical course, psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings. The diagnosis depends on the presentation of increased levels of L-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluids. Patients with L2HGA have an increased risk for the development of cerebral neoplasms which, though rarely, can be the initial presentation of the disease. Moreover, patients with L2HGA have an increased risk for the development of cerebral neoplasms. CASES PRESENTATION: Although psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings are the most common characteristics of the disease, we present two rare cases admitted with tumoral symptoms. CONCLUSION: Patients with L2HGA have an increased risk for the development of cerebral neoplasms.
Subject(s)
Brain Diseases, Metabolic, Inborn , Intellectual Disability , Megalencephaly , Neoplasms , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnostic imaging , Humans , Magnetic Resonance ImagingABSTRACT
Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism.
Subject(s)
Basal Ganglia Diseases , Brain Diseases, Metabolic, Inborn , Glutathione/metabolism , Adult , Basal Ganglia Diseases/etiology , Basal Ganglia Diseases/genetics , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/pathology , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/metabolism , Brain Diseases, Metabolic, Inborn/pathology , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients.
Subject(s)
Amino Acid Metabolism, Inborn Errors/complications , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Liver/pathology , Acidosis, Lactic/complications , Adult , Age of Onset , Amino Acid Metabolism, Inborn Errors/diagnosis , Brain Diseases, Metabolic, Inborn/complications , Child , Female , Humans , Infant , Infant, Newborn , Liver/diagnostic imaging , Male , Metabolism, Inborn Errors/complications , Methylmalonyl-CoA Mutase/deficiency , Tomography, X-Ray Computed , Ultrasonography , Young AdultABSTRACT
Hyperammonaemia is a metabolic disturbance characterized by accumulation of ammonia in the blood. Entry of ammonia into the brain via the blood-brain barrier leads to hyperammonaemic encephalopathy. The causes of hyperammonaemia in paediatric patients vary. We present 3 cases of hyperammonaemia in critically ill children in whom an inborn metabolic disorder was identified and provide insights into the phenotypes, diagnostic approaches and management. In children with acute overwhelming illness and progressive neurological deterioration plasma ammonia measurement should be included in the urgent diagnostic work-up. We here raise the awareness that hyperammonaemia is a metabolic emergency requiring prompt recognition and treatment to avoid subsequent complications.
Subject(s)
Hyperammonemia/diagnosis , Hyperammonemia/therapy , Ammonia/blood , Arginine/administration & dosage , Biomarkers/blood , Brain Diseases, Metabolic, Inborn/complications , Carnitine/administration & dosage , Critical Illness , Diet, Protein-Restricted , Early Diagnosis , Emergencies , Female , Humans , Hyperammonemia/etiology , Infant , Infant, Newborn , Male , Phenylbutyrates/administration & dosage , Sodium Benzoate/administration & dosage , Treatment OutcomeABSTRACT
Early identification is a goal for creatine transporter deficiency and will be critical for future treatment. Before their first birthday, one-half of this sample showed both a significant feeding/weight gain issue and delayed sitting or crawling. Combined, these early indicators could have alerted providers to conduct a urine screen.
Subject(s)
Brain Diseases, Metabolic, Inborn/diagnosis , Creatine/deficiency , Mental Retardation, X-Linked/diagnosis , Plasma Membrane Neurotransmitter Transport Proteins/deficiency , Adolescent , Age Factors , Brain Diseases, Metabolic, Inborn/complications , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Mental Retardation, X-Linked/complications , Retrospective Studies , Risk Factors , Symptom Assessment , Urinalysis , Young AdultABSTRACT
The enantiomers of 2-hydroxyglutarate (2HG) are potent regulators of metabolism, chromatin modifications and cell fate decisions. Although these compounds are associated with tumor metabolism and commonly referred to as oncometabolites, both D- and L-2HG are also synthesized by healthy cells and likely serve endogenous functions. The metabolic mechanisms that control 2HG metabolism in vivo are poorly understood. One clue towards how cells regulate 2HG levels has emerged from an inborn error of metabolism known as combined D- and L-2HG aciduria (D-/L-2HGA), which results in elevated D- and L-2HG accumulation. Because this disorder is caused by mutations in the mitochondrial citrate transporter (CIC), citrate must somehow govern 2HG metabolism in healthy cells. The mechanism linking citrate and 2HG, however, remains unknown. Here, we use the fruit fly Drosophila melanogaster to elucidate a metabolic link between citrate transport and L-2HG accumulation. Our study reveals that the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, dampens glycolytic flux and restricts L-2HG accumulation. Moreover, we find that sea mutants accumulate excess L-2HG owing to elevated lactate production, which inhibits L-2HG degradation by interfering with L-2HG dehydrogenase activity. This unexpected result demonstrates that citrate indirectly regulates L-2HG stability and reveals a feedback mechanism that coordinates L-2HG metabolism with glycolysis and the tricarboxylic acid cycle. Finally, our study also suggests a potential strategy for preventing L-2HG accumulation in human patients with CIC deficiency.This article has an associated First Person interview with the first author of the paper.
Subject(s)
Brain Diseases, Metabolic, Inborn/complications , Citrates/metabolism , Drosophila melanogaster/metabolism , Metabolome , Mitochondria/metabolism , Neoplasms/metabolism , Animals , Biological Transport , Citric Acid Cycle , Disease Models, Animal , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Glutarates/metabolism , Glycolysis , Larva/metabolism , Models, Biological , Mutation/geneticsABSTRACT
The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis-endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biological processes disturbed by genetic mutations and the clinical presentation of these disorders. The great majority of diseases may present as epileptic encephalopathies, intellectual disability (syndromic or nonsyndromic) with/without autism spectrum disorder (and other neuropsychiatric symptoms), and movement disorders. These symptoms may overlap and present in patients as a combination of clinical signs that results in the spectrum of the synaptopathies. A small number of diseases may also exhibit neuromuscular signs. In general, SV disorders tend to be severe, early encephalopathies that interfere with neurodevelopment. As a consequence, developmental delay and intellectual disability are constant in almost all the defects described. Considering that some of these diseases might mimic other neurometabolic conditions (and in particular treatable disorders), an initial extensive metabolic workup should always be considered. Further knowledge into pathophysiological mechanisms and biomarkers, as well as descriptions of new presynaptic disorders, will probably take place in the near future.
Subject(s)
Brain Diseases, Metabolic, Inborn/complications , Presynaptic Terminals/pathology , Synaptic Transmission , Synaptic Vesicles/pathology , Autism Spectrum Disorder/etiology , Endocytosis , Epilepsy/etiology , Exocytosis , Humans , Intellectual Disability/etiology , Movement Disorders/etiology , Neurodegenerative Diseases , Neuromuscular Diseases/etiologyABSTRACT
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals. These multiple and debilitating hemangiomas have never been previously reported in patients with MC-HGA. Mutation analyses including Sanger sequencing of genes involving in enchondromatosis and the metabolic pathway of D-2-hydroxyglutarate including PTHR1, D2HGDH, HOT, and IDH1, as well as whole-exome sequencing for proband-parent trio analysis and paired blood versus hemangioma studies showed no pathogenic variants. In summary, we reported the tenth patient with MC-HGA who manifested widespread and debilitating hemangiomas in several organs, expanding the clinical spectrum of MC-HGA.