Biallelic Variants in LIPT2 as a Cause of Infantile-Onset Dystonia: Expanding the Clinical and Molecular Spectrum.

Background: Lipoyl transferase 2 is involved in the biosynthesis of lipoate. Lipoate is the cofactor for the glycine cleavage system and four dehydrogenase enzymes. Biallelic variants in LIPT2 causing severe neonatal encephalopathy was first described in 2017.

Seizure Characteristics and EEG Features in Intoxication Type and Energy Deficiency Neurometabolic Disorders in the Pediatric Intensive Care Unit: Single-Center Experience Over 10 Years.

Background: Acute metabolic crises in inborn errors of metabolism (such as urea cycle disorders, organic acidemia, maple syrup urine disease, and mitochondrial disorders) are neurological emergencies requiring management in the pediatric intensive care unit (PICU). There is a paucity of data pertaining to electroencephalograms (EEG) characteristics in this cohort. We hypothesized that the incidence of background abnormalities and seizures in this cohort would be high.

COL4A1-related disorder as a mimic of congenital TORCHES infection-Expanding the clinical, neuroimaging and genotype spectrum.

Pseudo-TORCH Syndrome (PTS) encompasses a heterogeneous group of genetic disorders that may clinically and radiologically resemble congenital TORCH infections. These mimickers present with overlapping features manifested as intracranial and systemic abnormalities. Collagen type IV alpha 1 chain (COL4A1)-related diseases, characterized by autosomal dominant inheritance, exhibit a diverse phenotypic spectrum involving cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities.

Expedited Exome Reanalysis Following Deep Phenotyping and Muscle Biopsy in Suspected Mitochondrial Disorder.

Background: Exome sequencing (ES) is a useful tool in diagnosing suspected mitochondrial disease but can miss pathogenic variants for several reasons. Additional testing, such as muscle biopsy or biochemical testing, can be helpful in exome-negative cases.

Methods: We report a patient who presented with repeated episodes of lactic acidosis and failure to thrive.

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.

Background: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex.

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by , , , ) sharing a neurological/epileptic phenotype, as well as citrin deficiency () with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects.

Gaps in Neurogenetics Education During Child Neurology Residency: Results of a National Survey.

The practice of child neurology has changed significantly in the past two decades as we have integrated genetic testing into our standard of care to achieve precise diagnoses and to guide management of many childhood neurological conditions. Despite this paradigm shift, there appears to be a gap in both clinical exposure to neurogenetic disorders and education provided to residents in ordering and interpreting genetic testing. We therefore conducted a national survey for child neurology trainees in all programs across the United States to delineate their perception of the adequacy of current training and didactics in genetic/neurogenetic disorders.

Haploinsufficiency of PRRT2 Leading to Familial Hemiplegic Migraine in Chromosome 16p11.2 Deletion Syndrome.

Microdeletion in the 16p11.2 loci lead to a distinct neurodevelopmental disorder with intellectual disability and autism spectrum disorder in addition to dysmorphia, macrocephaly, and increased body mass index. One of the deleted genes in this region is which codes for proline-rich transmembrane protein 2.

Global Regulatory and Public Health Initiatives to Advance Pediatric Drug Development for Rare Diseases.

The literature thoroughly describes the challenges of pediatric drug development for rare diseases. This includes (1) generating interest from sponsors, (2) small numbers of children affected by a particular disease, (3) difficulties with study design, (4) lack of definitive outcome measures and assessment tools, (5) the need for additional safeguards for children as a vulnerable population, and (6) logistical hurdles to completing trials, especially with the need for longer term follow-up to establish safety and efficacy. There has also been an increasing awareness of the need to engage patients and their families in drug development processes and to address inequities in access to pediatric clinical trials.

Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.

In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology.

Neuromonitoring in Rare Disorders of Metabolism.

Inborn errors of metabolism (IEM) are a unique class of genetic diseases due to mutations in genes involved in key metabolic pathways. The combined incidence of IEM has been estimated to be as high as 1:1000. Urea Cycle disorders (UCD), one class of IEM, can present with cerebral edema and represent a possible target to explore the utility of different neuromonitoring techniques during an hyperammonemic crisis.

Select Ethical Aspects of Next-Generation Sequencing Tests for Newborn Screening and Diagnostic Evaluation of Critically Ill Newborns.

In this review, we analyze medical and select ethical aspects of the increasing use of next-generation sequencing (NGS) based tests in newborn medicine. In the last five years, there have been several studies exploring the role of rapid exome sequencing (ES) and genome sequencing (GS) in critically ill newborns. While the advantages include a high diagnostic yield with potential changes in interventions, there have been ethical dilemmas surrounding consent, information about adult-onset diseases and resolution of variants of uncertain significance.

Fifteen years of urea cycle disorders brain research: Looking back, looking forward.

Urea cycle disorders (UCD) are inherited diseases resulting from deficiency in one of six enzymes or two carriers that are required to remove ammonia from the body. UCD may be associated with neurological damage encompassing a spectrum from asymptomatic/mild to severe encephalopathy, which results in most cases from Hyperammonemia (HA) and elevation of other neurotoxic intermediates of metabolism. Electroencephalography (EEG), Magnetic resonance imaging (MRI) and Proton Magnetic resonance spectroscopy (MRS) are noninvasive measures of brain function and structure that can be used during HA to guide management and provide prognostic information, in addition to being research tools to understand the pathophysiology of UCD associated brain injury.

Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue.

The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked.

Management considerations for stroke-like episodes in MELAS with concurrent COVID-19 infection.

There have been considerations since the beginning of the Coronavirus pandemic that COVID-19 infection, like any other viral illness, can trigger neurological and metabolic decompensation in patients with mitochondrial diseases. At the time of writing, there were no published reports reviewing experiences and guidelines about management of COVID-19 infection in this patient population. We present a challenging case of an adult patient with a known diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS) complicated by COVID-19 infection.

Novel presentations associated with a PDHA1 variant - Alternating hemiplegia in Hemizygote proband and Guillain Barre Syndrome in Heterozygote mother.

We report a 5-year-old male with a PDHA1 variant who presented with alternating hemiplegia of childhood and later developed developmental regression, basal ganglia injury and episodic lactic acidosis. Enzyme assay in lymphocytes confirmed a diagnosis of Pyruvate Dehydrogenase Complex (PDC) deficiency. His mother who was heterozygous for the same variant suffered from ophthalmoplegia, chronic migraine and developed flaccid paralysis at 36 years of age.