Microcephaly in Neurometabolic Diseases

Neurometabolic disorders are an important group of diseases that mostly occur in neonates and infants. They are mainly due to the lack or dysfunction of an enzyme or cofactors necessary for a specific biochemical reaction, which leads to a deficiency of essential metabolites in the brain. This, in turn, can cause certain neurometabolic diseases. Disruption of metabolic pathways, and the inhibition at earlier stages, may lead to the storage of reaction intermediates, which are often toxic to the developing brain. Symptoms are caused by the progressive deterioration of mental, motor, and perceptual functions. The authors review the diseases with microcephaly, which may be one of the most visible signs of neurometabolic disorders.

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.

Approach to Neurological Channelopathies and Neurometabolic Disorders in Newborns

Ion channel disorders (channelopathies) can affect any organ system in newborns before 2 months of life, including the skeletal muscle and central nervous system. Channelopathies in newborns can manifest as seizure disorders, which is a critical issue as early onset seizures can mimic the presentation of neurometabolic disorders. Seizures in channelopathies can either be focal or generalized, and range in severity from benign to epileptic encephalopathies that may lead to developmental regression and eventually premature death. The presenting symptoms of channelopathies are challenging for clinicians to decipher, such that an extensive diagnostic survey through a precise step-by-step process is vital. Early diagnosis of a newborn’s disease, either as a channelopathy or neurometabolic disorder, is important for the long-term neurodevelopment of the child.

Neurometabolic Disorders Associated With Disturbances of Small Molecule Metabolism

Inborn errors of metabolism affect approximately 1 in 1,000 to 1 in 3,000 live births. Most of these inherited conditions are autosomal recessive, although a few are autosomal dominant or X-linked. Mitochondrial DNA disorders may be maternally inherited. The clinical symptoms associated with inborn errors of metabolism reflect the disruption of normal biochemical processes required for synthesis, breakdown, or transport of metabolites. This impairment leads to accumulation of metabolites that cause toxic effects, inadequate levels of metabolites required for normal cellular activity, or secondary disruption of essential metabolic pathways. Small molecule disorders involve the metabolism of amino acids, organic acids, carbohydrates, fatty acids, and other biochemical pathways. These disorders may present with acute exacerbations superimposed on long-term neurologic symptoms.

Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency and literature review

Background: Isolated sulfite oxidase deficiency (ISOD) is the rarest types of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. ISOD is extremely rare and till date only 32 mutations have been identified and reported worldwide. Germline mutation in SUOX gene causes ISOD. Methods: Here, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, respiratory failure, cardiac failure, hyperlactatemia, severe metabolic acidosis, hyperglycemia, hyperkalemia, moderate anemia, atrioventricular block and complete right bundle branch block. Results: Whole exome sequencing identified a novel homozygous transition (c.1227G>A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. Hence, it is a loss-of-function variant. Proband’s father and mother is carrying this novel variant in a heterozygous state. This variant was not identified in 200 ethnically matched normal healthy control individuals. Conclusions: Our study not only expand the mutational spectrum of SUOX gene associated ISOD, but also strongly suggested the application of whole exome sequencing for identifying candidate genes and novel disease-causing mutations.

New in pediatric neurodietology

Современная нейродиетология детского возраста затрагивает столь многочисленные неврологические и соматоневрологические состояния, что было бы не вполне правильно сосредоточиться на некоторых из них, проигнорировав остальные. Эпилепсия, мигрень и головная боль, нейрометаболические болезни, наследственная нейромышечная патология, демиелинизирующие и аутоиммунные заболевания центральной нервной системы, расстройства сна, а также нарушения поведения – все они составляют далеко не полный список условных «мишеней» нейродиетологии. Важна и ее роль в формировании адекватного когнитивного и эмоционального развития индивида, которой принадлежит особое значение в детском возрасте. Следует отметить, что нейродиетология и подходы к выбору лечебного питания с каждым годом занимают все более прочное положение в мировой клинической медицине. В данном обзоре литературы рассматриваются основные отечественные и зарубежные публикации последних лет, посвященные нейродиетологии и нутритивной терапии неврологических болезней и патологических состояний у пациентов педиатрического возраста. В числе вышеупомянутых нозологических форм фигурируют синдром дефицита внимания с гиперактивностью, инсульт, мигрень, головная боль, нарушения сна, эпилепсия, гликогеноз VII типа (фруктокиназная недостаточность), рассеянный склероз, вариабельная нейромышечная патология (спинальная мышечная атрофия и др.), а также различные нейрометаболические заболевания (метилмалоновая ацидемия, пропионовая ацидемия, изовалериановая ацидемия, митохондриальная патология) и т. д. Особо подчеркивается роль нейродиетологии в стимуляции нейрокогнитивного развития у детей различного возраста. Вариабельность нутритивных подходов к практическому лечению неврологической патологии у пациентов педиатрического возраста отражает многогранность современной нейродиетологии. Modern childhood neurodietology affects so many neurological and somatoneurological conditions that it would not be entirely correct to focus on some of them and ignore the rest. Epilepsy, migraine and headache, neurometabolic diseases, hereditary neuromuscular pathology, demyelinating and autoimmune diseases of the central nervous system, sleep disorders, as well as behavioral disorders – all of them are not a complete list of conditional «targets» of neurodietology. Its role in the formation of an adequate cognitive and emotional development of the individual is also important, which is of particular importance in childhood. It should be noted that neurodietology and approaches to the choice of therapeutic nutrition every year occupy an increasingly strong position in the world of clinical medicine. Russian and foreign basic publications of recent years are considered in the review of literature, dedicated to neurodietological and nutritional therapy issues for neurological diseases and pathological disorders in patients of pediatric age. Attention deficit/hyperactivity disorder, stroke, migraine, headaches, sleep disorders, epilepsy, glycogen storage disease type VII (fructokinase deficiency), multiple sclerosis, variable neuromuscular pathologies (spinal muscular atrophy – SMA and others), as well as various neurometabolic disorders (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, mitochondrial cythopathies) etc. can be listed among above-mentioned nosological forms of pathology. The role of neurodietology is stressed in particular for stimulation of neurocognition development in infants and children of various age groups. Variability of nutritional approaches to practical management of neurological disorders in patients of pediatric age reflects the versatility of contemporary neurodietology.

Clinico-Metabolic Profile of Neurometabolic Disorders of Children in a Tertiary Care Hospital of Bangladesh

Background: Neurometabolic disorders are inborn errors of metabolism with neurological manifestations. They are individually rare but as a group have a significant burden. They constitute 4.9% of genetic cause of moderate and severe mental retardation. Aims and objective: To explore clinical & metabolic profile of various forms of childhood Neurometabolic disorders. Methods: A hospital based retrospective study was conducted at Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University, and Dhaka from January 2016 to December 2020. Total 59 suspected children of Neurometabolic disorders (NMD), who admitted in hospital during the study period, were included. Among them 41 cases of NMD were diagnoses confirmed on the basis of clinical suspicion, biochemical test, and neuroimaging study and in few cases molecular genetics investigations. Results: Among 59 suspected cases, total 41 patients were diagnosed as Neurometabolic disorders. Most of the (63.2%) patients were within 0-3 years age. Male patients (70.73%) were outnumbered than female (29.26%). Male: Female ratio were 2.4:1. More than half of patients 25(60.90%) had parental consanguinity followed by Sib death 7 (17.07%), Prematurity 11 (26.82%). Common Neurometabolic disorders were aminoacidopathy 14 (34.14%) and lysosomal storage disorders 15 (36.58%) followed by mitochondrial disorders 5(12.19%), Urea cycle disorders 3(7.31%), CHO metabolism disorders 5(2.43%), Peroxisomal disorders 3(7.31%). Among aminoacidopathy, Organic acidamia 4(9.72%), MSUD 3(7.31%), PKU 2(4.86%), Gluteric Aciduria 3(7.31%), and Biotinidase deficiency disorder 1(2.43%) were common disorders. Among lysosomal storage disorders, mucopolysaccaridosis 4(9.72%) and metachromatic leukodystrophy 8(19.44%) were most common disorders. Common presentations were developmental delay 37(90.24%), developmental regression 21(51.21%), hypotonia 29(70.73) and seizures 26(63.41%). Neuroimaging changes found in about three fourth (80.49%) of cases. About 26.82% cases presented with white matter hyper intensity followed by basal ganglia hyper intensity (19.51%) and cerebral atrophy (14.63%). Abnormally high ammonia and lactate found in 6(14.63%) and 10(24.40%) cases respectively followed by Positive urinary ketones 8 (19.51%). Conclusions: Neurometabolic disorders are not uncommon. The commonest neurometabolic disorders were aminoaciduria and lysosomal storage disease in our study. Among aminoacid disorders, Organic acidamia, MSUD, Glutaric aciduria and in lysosomal storage disorders metachromatic leukodystrophy & Mucopolysaccharoidosis were common disorders. Neuroimaging changes were found in about three- forth cases in this study.