ABSTRACT
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.
Subject(s)
Alcohol Oxidoreductases , Siblings , Child , Humans , Alcohol Oxidoreductases/genetics , Brain/diagnostic imaging , Brain/pathology , Brain Diseases, Metabolic/genetics , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/diagnostic imaging , Egypt , Magnetic Resonance ImagingABSTRACT
PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.
Subject(s)
Brain Diseases, Metabolic , Leukomalacia, Periventricular , Thalamus , Child , Humans , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/pathology , Diagnosis, Differential , Frontal Lobe , Gestational Age , Infant, Premature , Leukomalacia, Periventricular/diagnostic imaging , Leukomalacia, Periventricular/pathology , Logistic Models , Magnetic Resonance Imaging , Occipital Lobe , Parietal Lobe , Retrospective Studies , Thalamus/diagnostic imaging , Thalamus/injuries , Thalamus/pathology , Biomarkers , Motor Skills , Male , Female , Infant , Child, Preschool , AdolescentABSTRACT
OBJECTIVES: The impact of coronavirus disease-19 (COVID-19) on metabolic outcome in patients with inborn errors of metabolism has rarely been discussed. Herein, we report a case with an acute encephalopathic crisis at the course of COVID-19 disease as the first sign of glutaric aciduria type 1 (GA-1). CASE PRESENTATION: A 9-month-old patient was admitted with encephalopathy and acute loss of acquired motor skills during the course of COVID-19 disease. She had lethargy, hypotonia, and choreoathetoid movements. In terms of COVID-19 encephalopathy, the reverse transcription-polymerase chain reaction assay test for COVID-19 was negative in cerebral spinal fluid. Brain imaging showed frontotemporal atrophy, bilateral subcortical and periventricular white matter, basal ganglia, and thalamic involvement. Elevated glutarylcarnitine in plasma and urinary excretion of glutaric and 3-OH-glutaric acids was noted. A homozygote mutation in the glutaryl-CoA dehydrogenase gene led to the diagnosis of GA-1. CONCLUSIONS: With this report, neurological damage associated with COVID-19 has been reported in GA-1 patients for the first time in literature.
Subject(s)
Amino Acid Metabolism, Inborn Errors/complications , Brain Diseases, Metabolic/complications , Brain Diseases/etiology , COVID-19/complications , Glutaryl-CoA Dehydrogenase/deficiency , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/genetics , Brain/diagnostic imaging , Brain Diseases/complications , Brain Diseases/diagnostic imaging , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/genetics , COVID-19/diagnosis , COVID-19/diagnostic imaging , COVID-19 Testing , Carnitine/analogs & derivatives , Carnitine/blood , Carnitine/urine , Female , Genetic Testing , Glutarates/blood , Glutarates/urine , Glutaryl-CoA Dehydrogenase/genetics , Humans , Infant , Magnetic Resonance Imaging , Motor Skills , Movement Disorders/etiology , Muscle Hypotonia/etiologyABSTRACT
BACKGROUND: Glutaric acidemia type 1 (GA1) is an inherited neurometabolic disease with significant morbidity. However, neuro-radiological correlation is not completely understood. OBJECTIVE: The study aimed to characterize the neuroimaging findings and their association with neurological phenotype in GA1 children. METHODS: Twenty-six Egyptian children (median age = 12 months) diagnosed with GA1 underwent clinical evaluation and brain magnetic resonance imaging (MRI). We objectively assessed the severity of neurological phenotype at the time of MRI using movement disorder (MD) and morbidity scores. Evaluation of brain MRI abnormalities followed a systematic and region-specific scoring approach. Brain MRI findings and scores were correlated with MD and morbidity scores, disease onset, and presence of seizures. RESULTS: Fifteen (57.7%) cases had insidious onset, eight (30.8%) manifested acute onset, whereas three (11.5%) were asymptomatic. Ten (38.5%) cases had seizures, five of which had no acute encephalopathic crisis. Putamen and caudate abnormalities (found in all acute onset, 93.3 and 73.3% of insidious onset, and one of three asymptomatic cases) were significantly related to MD (p = 0.007 and 0.013) and morbidity (p = 0.005 and 0.003) scores. Globus pallidus abnormalities (50% of acute onset, 46.7% of insidious onset, and one of three of asymptomatic cases) were significantly associated with morbidity score (p = 0.023). Other MRI brain abnormalities as well as gray and white matter score showed no significant association with neurological phenotype. Younger age at onset, acute onset, and seizures were significantly associated with worse neurological manifestations. CONCLUSION: Patients with GA1 manifest characteristic and region-specific brain MRI abnormalities, but only striatal affection appears to correlate with neurological phenotype.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Brain Diseases, Metabolic , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Brain/diagnostic imaging , Brain/pathology , Brain Diseases, Metabolic/diagnostic imaging , Egypt , Glutaryl-CoA Dehydrogenase/deficiency , Glutaryl-CoA Dehydrogenase/genetics , Humans , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Glutaric Aciduria Type 3 (GA-3) is a rare metabolic disease which is inherited autosomal recessively and characterized by isolated glutaric acid excretion. To date, a limited number of cases have been reported in the literature. We present two patients with GA3 who were diagnosed with the isolated increased level of glutaric acid in urine. CASE: Glutaric aciduria type 1 and type 2 were excluded by genetic analysis and other laboratory and clinical findings. One of our patients had a homozygous mutation p.Arg322Trp (c.964C > T) of SUGCT (NM_001193311) gene. To the best of our knowledge this mutation has not been reported in the literature previously. Symmetrical periventricular and deep cerebral white matter abnormalities were detected on his brain magnetic resonance imaging (MRI). CONCLUSION: We present two patients with GA-3 and a novel mutation in the SUGCT gene. Our findings expand the spectrum of causative mutations and clinical findings in GA-3.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Brain Diseases, Metabolic , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/genetics , Brain/diagnostic imaging , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/genetics , Glutaryl-CoA Dehydrogenase/deficiency , Humans , Magnetic Resonance Imaging , MutationABSTRACT
OBJECTIVE: To evaluate diagnostic capability of brain magnetic resonance imaging (MRI) in detection of inherited neurometabolic disorders. METHODS: This retrospective observational study was performed in Radiology Department at our Hospital in Dhahran, from January 2013 to January 2020. We evaluated brain MRIs of children (under 5) who were referred to pediatric neurology for clinical suspicion of neuro-developmental delay and metabolic disease. Known perinatal ischemia and birth trauma cases were excluded. Imaging criteria included: (i) bilateral symmetric white matter signal abnormality, (ii) diffusion restriction affecting bilateral deep grey nuclei with or without brainstem involvement, (iii) brain atrophy or edema with abnormal white matter signal, (iv) characteristic MR spectroscopic finding. Presence of any one of these findings was considered positive for neurometabolic disease. Two neuroradiologists interpreted MRIs with substantial interobserver agreement. Diagnoses were confirmed on biochemical/ metabolic screening and genetic testing. A 2 x 2 contingency table was used for results. Chi square test was used to determine association. RESULTS: Out of 133 cases, 72 (49 males, 90% AR) were found to have neurometabolic disorders. Sensitivity, specificity, positive and negative predictive values were calculated as 81.94% (CI, 71.11-90.02), 67.21% (CI, 54.00-78.69), 74.68% (CI, 66.96-81.11) and 75.93% (CI, 65.16-84.17) respectively. Findings were found significant (p-value=0.0001). CONCLUSION: Brain MRI can help to predict inherited neurometabolic disorders considering certain findings.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Magnetic Resonance Imaging/methods , Metabolism, Inborn Errors/diagnostic imaging , Neuroimaging/methods , Child, Preschool , Female , Humans , Infant , Male , Retrospective StudiesABSTRACT
Alterations in metabolism during epileptogenesis may be a therapy target. Recently, an increase in amino acid transport into the brain was proposed to play a role in epileptogenesis. We aimed to characterize alterations of substrate utilization during epileptogenesis and in chronic epilepsy. The lithium-pilocarpine post status epilepticus (SE) rat model was used. We performed longitudinal O-(2-[(18)F]fluoroethyl)-l-tyrosine (18F-FET) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and calculated 18F-FET volume of distribution (Vt) and 18F-FDG uptake. Correlation analyses were performed with translocator protein-PET defined neuroinflammation from previously acquired data. We found reduced 18F-FET Vt at 48 h after SE (amygdala: -30.2%, p = 0.014), whereas 18F-FDG showed increased glucose uptake 4 and 24 h after SE (hippocampus: + 43.6% and +42.5%, respectively; p < 0.001) returning to baseline levels thereafter. In chronic epileptic animals, we found a reduction in 18F-FET and 18F-FDG in the hippocampus. No correlation was found for 18F-FET or 18F-FDG to microglial activation at seven days post SE. Whereas metabolic alterations do not reflect higher metabolism associated to activated microglia, they might be partially driven by chronic neuronal loss. However, both metabolisms diverge during early epileptogenesis, pointing to amino acid turnover as a possible biomarker and/or therapeutic target for epileptogenesis.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Brain/metabolism , Epilepsy/metabolism , Positron-Emission Tomography/methods , Amino Acids/pharmacokinetics , Amygdala/diagnostic imaging , Amygdala/metabolism , Animals , Brain Diseases, Metabolic/etiology , Brain Diseases, Metabolic/metabolism , Chronic Disease , Disease Models, Animal , Fluorine Radioisotopes , Fluorodeoxyglucose F18 , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Rats , Substrate SpecificityABSTRACT
Inherited neurotransmitter disorders are rare neurometabolic conditions which encompass genetic disorders of neurotransmitter metabolism or transport. The clinical manifestations of these rare disorders are often nonspecific, ranging from encephalopathies and seizures to movement disorders. As a consequence, neurotransmitter disorders are underrecognized and often misdiagnosed. Accurate and timely diagnosis is, however, of utmost importance, given the availability of therapeutic strategies. A high index of clinical suspicion and familiarity with the neuroimaging phenotypes is therefore crucial. While the imaging features of various neurotransmitter disorders often overlap and are nonspecific, imaging can be helpful in providing useful clues to guide the diagnostic algorithm for uncommon conditions in a neonate presenting with nonspecific neurological symptoms. In this review paper, we aim to bring together current knowledge of neuroimaging phenotypes associated with inherited (primary) disorders of neurotransmitter biosynthesis. Magnetic resonance imaging phenotypes of disorders of monoamine biosynthesis, primary cerebral folate deficiency, disorders of pyridoxine metabolism, disorders of gamma-aminobutyric acid metabolism, nonketotic hyperglycinemia (glycine encephalopathy), disorders of serine biosynthesis, and cerebral creatine deficiency syndrome will be discussed and illustrated with case examples.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Biogenic Monoamines , Brain Diseases, Metabolic , Neuroimaging , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/metabolism , Amino Acid Metabolism, Inborn Errors/pathology , Amino Acid Metabolism, Inborn Errors/physiopathology , Biogenic Monoamines/metabolism , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/metabolism , Brain Diseases, Metabolic/pathology , Brain Diseases, Metabolic/physiopathology , HumansABSTRACT
Toxic and metabolic brain disorders are relatively uncommon diseases that affect the central nervous system, but they are important to recognize as they can lead to catastrophic outcomes if not rapidly and properly managed. Imaging plays a key role in determining the most probable diagnosis, pointing to the next steps of investigation, and providing prognostic information. The majority of cases demonstrate bilateral and symmetric involvement of structures at imaging, affecting the deep gray nuclei, cortical gray matter, and/or periventricular white matter, and some cases show specific imaging manifestations. When an appropriate clinical situation suggests exogenous or endogenous toxic effects, the associated imaging pattern usually indicates a restricted group of diagnostic possibilities. Nonetheless, toxic and metabolic brain disorders in the literature are usually approached in the literature by starting with common causal agents and then reaching imaging abnormalities, frequently mixing many different possible manifestations. Conversely, this article proposes a systematic approach to address this group of diseases based on the most important imaging patterns encountered in clinical practice. Each pattern is suggestive of a most likely differential diagnosis, which more closely resembles real-world scenarios faced by radiologists. Basic pathophysiologic concepts regarding cerebral edemas and their relation to imaging are introduced-an important topic for overall understanding. The most important imaging patterns are presented, and the main differential diagnosis for each pattern is discussed. Online supplemental material is available for this article. ©RSNA, 2019.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Magnetic Resonance Imaging , Neuroimaging , Neurotoxicity Syndromes/diagnostic imaging , Tomography, X-Ray Computed , Brain Edema/diagnostic imaging , Humans , Magnetic Resonance Imaging/methods , Neuroimaging/methods , Tomography, X-Ray Computed/methodsABSTRACT
Advances in genetics has revolutionised the way we understand, diagnose and manage neurological disorders. Notwithstanding the fact that genetic confirmation has already become standard of care in routine clinical practice, radiological and clinical phenotyping has not diminished in value; in fact it has found an enhanced role in guiding and interpreting genetic test results. Inherited neurometabolic disorders are a prominent group of disorders which are seen commonly in clinical practice and many are potentially treatable. The concept of Radiogenomics is the bridge from phenotype to genotype and the strength of association varies widely across different inherited metabolic diseases. Understanding the strengths and limitations of these correlations forms the basis of success of multidisciplinary approach to diagnose these disorders. In this article authors give a brief overview of the genetic basis of a disease, available genetic tests and the prominent role of radiology in contemplating a diagnostic suspicion and guiding further confirmatory tests.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Genomics/methods , Metabolic Diseases/diagnostic imaging , Nervous System Diseases/diagnostic imaging , Pediatricians , Radiology/methods , ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics , Adult , Algorithms , Brain Diseases, Metabolic/genetics , Child , Child, Preschool , Diagnostic Imaging/methods , Female , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Testing/methods , Genotype , Humans , Male , Membrane Proteins/genetics , Metabolic Diseases/genetics , Mitochondrial Proteins/genetics , Nervous System Diseases/genetics , Phenotype , Young AdultABSTRACT
Glutaric acidemia type 1 (GA1) is an inherited metabolic autosomal recessive disorder that is caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Untreated patients suffer primarily from severe striatal damage. More than 250 variants in the GCDH gene have been reported with a variable frequency among different ethnic groups. In this study, we aimed to characterize 89 Egyptian patients with GA1 and identify the variants in the 41 patients who were available for genotyping. All of our patients demonstrated clinical, neuroradiological, and biochemical characteristics that are consistent with a diagnosis of GA1. All patients presented with variable degrees of developmental delay ranging from mild to severe. Most of the 89 patients presented with acute onset type (71.9%), followed by insidious (19%) and asymptomatic (9%). A delay in diagnosis was inversely associated with macrocephaly. The prevalence rate ratio (PR) for macrocephaly that was associated with each 6-month delay was 0.95 (95%CI 0.91-0.99). However, high body weight was associated with a higher likelihood of having macrocephaly (PR 1.16, 95%CI 1.06-1.26 per 1 SD increment of Z score weight). However, body weight was inversely associated with the morbidity score. Consanguinity level was 64% among our patient's cohort and was positively associated with the C5DC level (ß (95%CI) 1.06 (0.12-1.99)). Forty-one patients were available for genotyping and were sequenced for the GCDH gene. We identified a total of 25 variants, of which the following six novel variants were identified: three missense variants, c.320G > T (p.Gly107Val), c.481C > T (p.Arg161Trp) and c.572 T > G (p.Met191Arg); two deletions, c.78delG (p.Ala27Argfs34) and c.1035delG (p.Gly346Alafs*11); and one indel, c.272_331del (p.Val91_Lys111delinsGlu). All of the novel variants were absent in the 300 normal chromosomes. The most common variant, c.*165A > G, was detected in 42 alleles, and the most commonly detected missense variant, c.1204C > T (p.Arg402Trp), was identified in 29 mutated alleles in 15/41 (34.2%) of patients. Our findings suggest that GA1 is not uncommon organic acidemia disease in Egypt; therefore, there is a need for supporting neonatal screening programs in Egypt.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diagnosis , Brain Diseases, Metabolic/diagnosis , Glutaryl-CoA Dehydrogenase/deficiency , Glutaryl-CoA Dehydrogenase/genetics , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/metabolism , Body Weight/physiology , Brain/diagnostic imaging , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/genetics , Brain Diseases, Metabolic/metabolism , Child , Child, Preschool , Egypt , Female , Genotype , Glutaryl-CoA Dehydrogenase/metabolism , Humans , Magnetic Resonance Imaging , Male , Mutation, Missense , Severity of Illness Index , Symptom AssessmentSubject(s)
Brain Diseases, Metabolic/complications , Seizures/etiology , Uremia/complications , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/therapy , Diffusion Magnetic Resonance Imaging , Humans , Male , Obesity/complications , Renal Replacement Therapy , Uremia/diagnosis , Young AdultABSTRACT
Three young patients with glutaric aciduria type I (age 6-23â¯years) of different ethnic origins, treated for their metabolic disease since early childhood, presented with malignant central nervous system tumors. We recommend continuing clinical follow-up, including monitoring of neurological manifestations and neuroradiological findings, in all patients with glutaric aciduria type I beyond early childhood, especially if adherence to diet is poor or the treatment was not started neonatally.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Brain Diseases, Metabolic/genetics , Brain Neoplasms/genetics , Brain/metabolism , Glioblastoma/genetics , Glutaryl-CoA Dehydrogenase/deficiency , Adult , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/diagnostic imaging , Amino Acid Metabolism, Inborn Errors/physiopathology , Brain/diagnostic imaging , Brain/pathology , Brain Diseases, Metabolic/complications , Brain Diseases, Metabolic/diagnostic imaging , Brain Diseases, Metabolic/physiopathology , Brain Neoplasms/complications , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/physiopathology , Child , Child, Preschool , Female , Glioblastoma/complications , Glioblastoma/diagnostic imaging , Glioblastoma/pathology , Glutarates/metabolism , Glutaryl-CoA Dehydrogenase/genetics , Humans , Male , Young AdultABSTRACT
Our purpose is to describe typical computed tomography and magnetic resonance imaging findings in encephalopathies in the emergency. The focus of this article are the most frequent toxic and acquired metabolic diseases and their preferential sites of involvement, such as hepatic encephalopathy, hypoglicemia, nonketotic hyperglycemia, osmotic demyelination, posterior reversible encephalopathy syndrome, uremia, illegal drug abuse, carbon monoxide poisoning, and hypoxic-ischemic encephalopathy. The radiologist must be able to identify the most usual patterns of lesion in computed tomography and magnetic resonance imaging in these settings.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Emergency Service, Hospital , Hypoxia-Ischemia, Brain/diagnostic imaging , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Brain/pathology , Brain Diseases, Metabolic/pathology , Humans , Hypoxia-Ischemia, Brain/pathology , Tomography, X-Ray Computed/methodsABSTRACT
No disponible
Subject(s)
Humans , Male , Infant, Newborn , Sulfite Oxidase/deficiency , Brain Diseases, Metabolic/diagnostic imaging , Sulfite Oxidase/urine , Neuroimaging/methods , Magnetic Resonance Spectroscopy/methodsABSTRACT
OBJECTIVE: To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. METHODS: A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." RESULTS: MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. INTERPRETATION: Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829.
Subject(s)
Aspartic Acid/analogs & derivatives , Brain Diseases, Metabolic/etiology , Brain/metabolism , Spinocerebellar Ataxias/pathology , Activities of Daily Living , Adult , Aged , Aspartic Acid/metabolism , Ataxins/genetics , Brain/diagnostic imaging , Brain Diseases, Metabolic/diagnostic imaging , Case-Control Studies , Cohort Studies , Cross-Sectional Studies , Disease Progression , Female , Glutamic Acid/metabolism , Humans , Inositol/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Middle Aged , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/genetics , Young Adult , gamma-Aminobutyric Acid/metabolismABSTRACT
RATIONALE: Hypoglycemic encephalopathy is a metabolic encephalopathy. Clinical risk is mixed with acute cerebrovascular disease, so it is critical to identify and make the correct diagnosis of the disease as early as possible. PATIENT CONCERNS: Here, we report a case of a 51-year-old male patient with hypoglycemic encephalopathy, who presented confusion and unconsciousness for 1 day. DIAGNOSES: In addition to blood-related indicators and medical histories, magnetic resonance imaging (MRI), especially diffusion-weighted imaging (DWI), can be valuable to the diagnosis of hypoglycemic encephalopathy, which showed diffuse high-signal intensity in the cerebral cortex, and also the hippocampus, head of the caudate nucleus, the lentiform nucleus, and corpus callosum. INTERVENTIONS: Intravenous glucose injection and drip was performed repeatedly. The blood glucose levels were gradually corrected, and the resulting blood glucose was 6.5âmmol/L. OUTCOMES: The prognosis depends on the degree of hypoglycemia, duration, and condition of the organism. Due to the long duration of hypoglycemia, unfortunately, the patient died. LESSONS: It is critical to diagnose hypoglycemic encephalopathy as early as possible. MRI reveals diffuse abnormal intensity in the cortex and basal ganglia region. DWI using high b values provides important information for diagnosis.
Subject(s)
Brain Diseases, Metabolic/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , Hypoglycemia/complications , Brain Diseases, Metabolic/drug therapy , Brain Diseases, Metabolic/etiology , Cerebral Cortex/diagnostic imaging , Fatal Outcome , Hippocampus/diagnostic imaging , Humans , Hypoglycemia/drug therapy , Hypoglycemic Agents/therapeutic use , Male , Middle AgedABSTRACT
OBJECTIVE: Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency. METHODS: A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. RESULTS: Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). CONCLUSION: In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy.