Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

PTPN4 germline variants result in aberrant neurodevelopment and growth.

Protein-tyrosine phosphatases (PTPs) are pleomorphic regulators of eukaryotic cellular responses to extracellular signals that function by modulating the phosphotyrosine of specific proteins. A handful of PTPs have been implicated in germline and somatic human disease. Using exome sequencing, we identified missense and truncating variants in PTPN4 in six unrelated individuals with varying degrees of intellectual disability or developmental delay. The variants occurred de novo in all five subjects in whom segregation analysis was possible. Recurring features include postnatal growth deficiency or excess, seizures, and, less commonly, structural CNS, heart, or skeletal anomalies. PTPN4 is a widely expressed protein tyrosine phosphatase that regulates neuronal cell homeostasis by protecting neurons against apoptosis. We suggest that pathogenic variants in PTPN4 confer risk for growth and cognitive abnormalities in humans.

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

Levetiracetam for the treatment of neonatal seizures.

Seizures are a common occurrence in the neonatal intensive care unit, especially among low-birth-weight infants. The efficacy and safety of standard anticonvulsants have not been evaluated extensively in the neonate. In addition, there is concern for the adverse effects of phenobarbital on long-term development. Levetiracetam has been a commonly prescribed oral anticonvulsant for the use of adjunctive therapy for partial seizures in adults with favorable tolerability, and it has been recently approved for children older than age 4 years. There are no published studies regarding the safety and efficacy of this medication in the infant population. This report describes the initiation of levetiracetam in 3 infants, aged 2 days to 3 months, for refractory seizures or intolerance to other anticonvulsants. Each patient was without seizure on levetiracetam monotherapy, and there were no adverse effects.

Successful treatment of recalcitrant restless legs syndrome with botulinum toxin type-A.

STUDY OBJECTIVE: We report the effective use of injected BTX-A to treat refractory restless legs syndrome (RLS). METHODS: This is an observational case series of 3 patients meeting the essential diagnostic criteria for RLS whose symptoms were refractory to or who refused oral medication. Areas of maximal discomfort were injected as described below. RESULTS: Patient #1, a 58-year-old man with refractory RLS, received injections in both legs. The effect persisted for 12 weeks after injections. He temporarily stopped taking gabapentin. He experienced a mild increase in a timed run. Patient #2, a 38-year-old man with refractory RLS, received BTX-A injections in both legs and his lumbar paraspinal muscles. Three days after injection, he reported great improvement. Within 1 month, his Epworth Sleepiness Scale score had decreased from 19 to 5. He stopped oral therapy during the peak therapeutic period. There were no untoward effects. Patient #3, a 38-year-old woman had a prolonged sleep latency due to RLS. BTX-A was administered in the legs. In 2 days, her discomfort and her subjective sleep latency improved. Both the urge to move and nocturnal restlessness resolved for 10 weeks. There were no untoward effects in all patients, and the response was repeated in successive injection cycles. CONCLUSIONS: Intramuscular BTX-A alleviated symptoms, reduced medication use, and/or reduced daytime sleepiness with minimal, if any, untoward effects. BTX-A should be further investigated in controlled studies as a treatment of RLS.

Rash, fever, and neck pain in the office: is this a neurologic emergency?

Anticonvulsants, neuroleptics, and antispasticity agents are used with increasing frequency in the pediatric population. Each of the drugs discussed in this article has serious but potentially reversible adverse effects. Pediatric primary care providers must be aware of the potential emergencies associated with the use of these neurologic medications to provide prompt and effective treatment.

Neurodevelopmental toxicology.

The fields of neurotoxicology and developmental toxicology are exploding in research and interest. Much of the data currently known are from epidemiologic human studies or studies of animal models. Each of these modes is difficult to translate to individual clinical encounters. It is often difficult to state with certainty which of the numerous chemical or physical agents in our environment are neurotoxic. Basic scientists will help with advances in molecular biology and toxicology. Improved clinical understanding of these issues may help patients to understand the medical issues; allay feelings of anxiety, guilt, or fear; and avoid unnecessary testing. For exposures that manifest as threshold phenomena, such as lead, the risk to society is even greater than to an individual. Individual risk may be less of a concern than the population's risk because small elevations in the average BLL can cause profound shifts in the normative curve of intelligence, increasing the burden on our institutions and bankrupting the brain trust. Good scholarship and interpersonal judgement are vital when counseling patients on the potential consequences of chemical exposures and are no less important when making policy. The challenge for the clinician reading the research is to remain aware of the limitations and biases of our science.

Nerve agent attacks on children: diagnosis and management.

Nerve agents (NAs) are the most lethal chemical weapons. We review the pathophysiology and management of NA poisoning of children. NAs cause cholinergic crisis. Children may manifest signs of cholinergic poisoning differently than adults. Children may be less likely to manifest miosis and glandular secretions. They may present with neurologic derangements alone. The goals of treatment should be to limit additional exposure, to provide respiratory support, and to prevent neurologic morbidity. Autoinjectors are optimal delivery vehicles for intramuscular antidotes and are likely to be used in civilian prehospital care. Antidotes include anticholinergics, oximes, and benzodiazepines. Several medications may be available within each class of antidotes. Clinicians will select an antidote based on the status of the individual victim, the accessibility of supportive care, and the availability of the drug. Atropine is well-tolerated and high doses may be required. The oxime pralidoxime chloride has a longer half-life in children. Currently, diazepam is the standard NA anticonvulsant. Midazolam may be the most effective intramuscular anticonvulsant after NA exposure, but, despite its efficacy, it is not an approved agent for seizures. Supportive care and long-term complications are summarized.