Phenomenology and clinical relevance of minor neurological signs in child neurology

Magostini F, Paris G, Capuano A. Phenomenology and clinical relevance of minor neurological signs in child neurology and psychiatry. Front Neurol. 2026 May 8;17:1761780. doi: 10.3389/fneur.2026.1761780. PMID: 42180220; PMCID: PMC13193831.

Abstract

Minor Neurological Signs, also referred to as neurological soft signs, are subtle abnormalities detected during neurological examination that do not meet criteria for major focal deficits. They are increasingly considered indicators of variability in neurodevelopment, likely reflecting differences in sensorimotor integration and maturation of cortico–subcortical networks. This mini review summarizes current evidence on the phenomenology, neurobiological correlates, and clinical relevance of MNS in child neurology and psychiatry. MNS include motor features such as overflow movements, dysmetria, dysrhythmia, and mild alterations in coordination, tone, and balance. Their assessment relies on standardized, developmentally appropriate tools that support identification of distinct patterns of dysfunction. MNS are frequently reported in neurodevelopmental and psychiatric conditions. While not diagnostically specific, they have been associated with symptom severity and functional outcomes. Further longitudinal and integrative studies are needed to clarify their developmental trajectories, neurobiological mechanisms, and potential clinical utility.

From the article:

In line with the movement disorders classification and subsequent classification efforts in the field of minor neurological signs, we can identify the following phenomenological categories:

1) Hyperkinetic movement disorders: these are characterized by involuntary movements, primarily manifesting as tremors, choreiform movements, and dystonic postures.

a) Tremor: defined as a rhythmic, oscillatory movement of a body part, resulting from alternating or synchronous contractions of antagonist muscles, and may occur at rest, during posture, or during action.

b) Choreiform movements: frequently described as “dance-like” or “piano playing movements”, consist of brief, irregular, non-rhythmic, and unpredictable movements that flow randomly from one body part to another, predominantly affecting the distal extremities. These movements are not suppressible and are characterized by variability in timing, amplitude, and distribution.

c) Dystonia: characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. These movements are typically patterned, twisting, and may be triggered or worsened by voluntary action.

2) Overflow movements: these refer to involuntary movements of body parts that are not necessary to perform a motor task effectively. Notable examples include contralateral motor overflow and mirror movements.

3) Dysmetria: this is identified as an inability to control the trajectory of purposeful movements, particularly concerning coordination of the extremities.

4) Miscellaneous disturbances: this category includes mild alterations in muscle tone, abnormalities in balance and gait (e.g., tandem gait), lateralization and dysrhythmia (an impairment of motor timing and of the ability to generate, maintain, or synchronize temporal sequences of movement, resulting in irregularity in rhythmic execution and coordination).

Although individually non-specific, these signs reflect variations in the organization and integration of distributed sensorimotor networks and are commonly observed within the spectrum of minor neurological signs...

The systematic observation of MNS provides clinically relevant information on the functional organization of developing neural systems involved in motor control and sensory integration. Rather than directly informing etiology, MNS can be understood as observable markers of variability in the organization and functioning of subcortical and cortico–subcortical systems. However, their clinical relevance is often underestimated and not always fully recognized during assessment, despite their potential to support early identification of risk in children who do not yet meet full diagnostic criteria but present emerging signs of neurodevelopmental vulnerability.

In the clinical context, MNS should be conceptualized as structured, domain-specific configurations of signs that support the identification of neurodevelopmental subgroups. MNS can be interpreted as intermediate phenotypes along a spectrum that includes, on one end, transient maturational variations and, on the other, conditions characterized by structural and persistent deficits, such as cerebral palsy.

The systematic assessment of MNS using standardized and specific tools is essential to clinical practice. Recognizing MNS as central components of neurodevelopmental assessment may improve early diagnosis, refine phenotypic stratification, and support the implementation of earlier and more tailored interventions in neurodevelopmental disorders.

Multiple genetic etiologies causing Dandy-Walker variant with microcephaly, epilepsy, and global developmental delay.

Zhang LB, Wu YY, Qiu DJ, Li WB, Ye ZL. Child Neurology: Multiple Genetic Etiologies Causing Dandy-Walker Variant With Microcephaly, Epilepsy, and Global Developmental Delay. Neurology. 2026 Apr 14;106(7):e214793. doi: 10.1212/WNL.0000000000214793. Epub 2026 Mar 6. PMID: 41791021.

Abstract

Dandy-Walker syndrome is typically characterized by near-complete cerebellar vermis agenesis, enlarged posterior fossa, and dilated fourth ventricle. By contrast, Dandy-Walker variant (DWv) shows milder features, typically characterized by partial agenesis of the cerebellar vermis, mild enlargement of the posterior fossa, and variable dilation of the fourth ventricle. Both conditions are usually associated with normal or enlarged head circumference. We report a 16-month-old girl presenting with congenital microcephaly, frequent seizures, and severe global developmental delay. Brain MRI revealed findings consistent with DWv, which did not explain the severity of her clinical symptoms or her microcephaly. Chromosomal microarray analysis revealed multiple regions of homozygosity on chromosome 11, indicating potential recessive inheritance; karyotype analysis and mitochondrial testing showed no clear etiology. Trio-based whole-exome sequencing identified a heterozygous variant (NM_021096.4:c.4891T>A/p.Phe1631Ile) in CACNA1I and a homozygous variant (NM_002335.4:c.1310C>T/p.Thr437Met) in LRP5. Variants in CACNA1I are associated with neurodevelopmental disorders, including epilepsy and developmental delay, while variants in LRP5 are linked to osteoporosis and microcephaly. Based on the clinical presentation and molecular findings, we hypothesize that both variants contributed to the patient's complex phenotype. This case highlights that in patients with unusually severe or atypical manifestations, the possibility of multiple genetic pathogenic contributions should be considered, and comprehensive genomic evaluation is essential for accurate diagnosis and management.

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

Cellucci T, Van Mater H, Graus F, Muscal E, Gallentine W, Klein-Gitelman MS, Benseler SM, Frankovich J, Gorman MP, Van Haren K, Dalmau J, Dale RC. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2020 Jan 17;7(2):e663. doi: 10.1212/NXI.0000000000000663. Erratum in: Neurol Neuroimmunol Neuroinflamm. 2020 Apr 15;7(4):e730. doi: 10.1212/NXI.0000000000000730. PMID: 31953309; PMCID: PMC7051207.

Abstract

Objective: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.

Methods: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.

Results: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.

Conclusions: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

Last American to use an iron lung dies

A 78-year-old Oklahoma woman who was diagnosed with polio as a child and was the last American to rely on an iron lung to live has died.

Martha Lillard found out she had the once-feared disease when she was 5 years old, which left her paralyzed from the neck down, and required her to use the machine to help her breathe while she slept.

Lillard contracted COVID-19 twice during the pandemic, which left her in the machine nearly 24 hours a day.

"They told her she wasn't supposed to live past 20 years old," her younger sister, Cindy McVey, told The Associated Press on Friday. "She had the enthusiasm and the drive to continue living and make the best of her life."

Despite having polio, Lillard was able to go to school two hours a day as a child, and she had tutors the rest of the time. She also used an intercom phone system that allowed her to interact with her teachers and classmates from home.

Lillard was even able to take road trips as a child because of a custom trailer that could accommodate the iron lung and her father making sure their hotels had wide enough doors for the machine.

An iron lung is a negative-pressure ventilator that helps a patient with paralyzed lung muscles breathe.

The disease once caused thousands of cases of paralysis in children during outbreaks each year in the first part of the 20th century before a vaccine became available in 1955.

By 1979, polio was considered eliminated in the U.S.

Later, Lillard was able to regain the use of her left arm and legs through therapy and was even able to drive for a time.

She lived independently for many years, even getting married earlier this year to a man from Egypt she corresponded with for two decades after he was able to obtain a visa.

"They were really soul mates," McVey said. "He's extremely brokenhearted."

Lillard, who wrote poetry and volunteered with the Humane Society, according to her sister, had just 25% lung capacity before she was diagnosed with COVID.

https://www.foxnews.com/health/last-american-use-iron-lung-dies-78-years-old-childhood-polio-diagnosis

Riboflavin transporter deficiency and energy dysmetabolism

Colasuonno F, Marioli C, Tartaglia M, Bertini E, Compagnucci C, Moreno S. New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement. Biomedicines. 2022 Jun 6;10(6):1329. doi: 10.3390/biomedicines10061329. PMID: 35740351; PMCID: PMC9219947.

Abstract

Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments.

Marioli C, Magliocca V, Petrini S, Niceforo A, Borghi R, Petrillo S, La Rosa P, Colasuonno F, Persichini T, Piemonte F, Massey K, Tartaglia M, Moreno S, Bertini E, Compagnucci C. Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells. Int J Mol Sci. 2020 Oct 7;21(19):7402. doi: 10.3390/ijms21197402. PMID: 33036493; PMCID: PMC7582490.

Abstract

Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.

Colasuonno F, Niceforo A, Marioli C, Fracassi A, Stregapede F, Massey K, Tartaglia M, Bertini E, Compagnucci C, Moreno S. Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency. Oxid Med Cell Longev. 2020 Aug 12;2020:6821247. doi: 10.1155/2020/6821247. PMID: 32855765; PMCID: PMC7443020.

Abstract

Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl β-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.

Shades of Questcor 8

I hold my nose and prescribe.

How much money does the manufacturer of Valtoco make?

The manufacturer of Valtoco, Neurelis, Inc., generated an estimated $295 million to $300 million in net sales for the full year of 2025. Because Valtoco is their flagship commercial product, it drives the vast majority of this revenue.

A breakdown of Neurelis' financial performance highlights their latest earnings structure:

Net Sales Growth: The $295–$300 million figure for 2025 represents an immense jump, more than doubling their 2024 net sales figures.

Profitability: The company reported an EBITDA margin of 30%+, meaning their core operating profitability is roughly $90 million or more before accounting for interest, taxes, depreciation, and amortization.Cash Reserves: As of December 31, 2025, Neurelis held $175+ million in cash with zero bank debt.

Growth Catalysts: Sales spiked dramatically following the FDA indication expansion allowing children ages 2 to 5 to be prescribed the nasal spray.

Google AI

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Why is Valtoco so expensive?

AI Overview

Valtoco is expensive because it is a brand-name medication with no generic alternative. Its high cost reflects the years of research and clinical trials required to develop its specialized, needle-free nasal delivery system, alongside the proprietary Intravail absorption technology. 

Because it is a patented pharmaceutical manufactured by Neurelis, there are no competitors to drive down the retail price, which can easily exceed $380 to $1,000+ depending on the prescribed dosage. However, according to discussion on the r/Epilepsy Reddit Forum, users agree that the prohibitive retail prices can be bypassed using manufacturer savings programs and patient assistance programs, often bringing costs down significantly. 

Patients prescribed Valtoco can utilize several tools to reduce their out-of-pocket costs: 

Manufacturer Co-Pay Cards: Patients with commercial insurance can often pay as little as $20 through the VALTOCO Co-Pay Card Program.

Patient Assistance Programs: Uninsured or underinsured patients may qualify to receive the medication at no cost through the myNEURELIS Support Program.

Discount Cards: Using tools like the GoodRx Valtoco Page can also provide pharmacy coupons that drop the cash price well below retail. 

Google AI

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https://www.goodrx.com/compare/valtoco-vs-nayzilam?srsltid=AfmBOoqX1pJPJOst4uJ4rSnKKPZYn5bM43xB8ft4cw03pqGiX3lfJmio

ZNF292 neurodevelopmental disorder

Inspired by a patient

Kaushik K, Chapman G, Prakasam R, Batool F, Saleh M, Determan J, Huettner JE, Kroll KL. Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function. Cell Rep. 2025 May 27;44(5):115597. doi: 10.1016/j.celrep.2025.115597. Epub 2025 Apr 20. PMID: 40257863; PMCID: PMC12283078.

Abstract

Pathogenic mutation of the zinc-finger transcription factor ZNF292 is a recently defined contributor to human neurodevelopmental disorders (NDDs). However, the gene's roles in cortical development and regulatory networks under its control were previously undefined. Here, human stem cell models of ZNF292 deficiency, resembling pathogenic haploinsufficiency, are used to derive cortical inhibitory neuron progenitors and neurons. ZNF292-deficient progenitors undergo precocious differentiation but subsequently exhibit compromised interneuron maturation and function. In progenitors, genome-wide occupancy and transcriptomic analyses identify direct target genes controlling neuronal differentiation and synapse formation that are upregulated upon ZNF292 deficiency. By contrast, deficiency in interneurons compromises ZNF292 genome-wide association with and causes downregulation of direct target genes promoting interneuron maturation and function, including other NDD genes. ZNF292-deficient interneurons also exhibit altered channel activities, elevated GABA responsiveness, and hallmarks of neuronal hyperactivity. Together, the results of this work define neurodevelopmental requirements for ZNF292, some of which may contribute to pathogenic ZNF292 mutation-related NDDs.

Mirzaa GM, Chong JX, Piton A, Popp B, Foss K, Guo H, Harripaul R, Xia K, Scheck J, Aldinger KA, Sajan SA, Tang S, Bonneau D, Beck A, White J, Mahida S, Harris J, Smith-Hicks C, Hoyer J, Zweier C, Reis A, Thiel CT, Jamra RA, Zeid N, Yang A, Farach LS, Walsh L, Payne K, Rohena L, Velinov M, Ziegler A, Schaefer E, Gatinois V, Geneviève D, Simon MEH, Kohler J, Rotenberg J, Wheeler P, Larson A, Ernst ME, Akman CI, Westman R, Blanchet P, Schillaci LA, Vincent-Delorme C, Gripp KW, Mattioli F, Guyader GL, Gerard B, Mathieu-Dramard M, Morin G, Sasanfar R, Ayub M, Vasli N, Yang S, Person R, Monaghan KG, Nickerson DA, van Binsbergen E, Enns GM, Dries AM, Rowe LJ, Tsai ACH, Svihovec S, Friedman J, Agha Z, Qamar R, Rodan LH, Martinez-Agosto J, Ockeloen CW, Vincent M, Sunderland WJ, Bernstein JA; Undiagnosed Diseases Network,; Eichler EE, Vincent JB; University of Washington Center for Mendelian Genomics (UW-CMG),; Bamshad MJ. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet Med. 2020 Mar;22(3):538-546. doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14. PMID: 31723249; PMCID: PMC7060121.

Abstract

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.

Dongxue L, Ruen Y, Ying Y, Liting C, Jie W, Chunjiao L, Wei L, Rikun C, Cuiyun L. Short Stature and Developmental Delay Associated With a Novel Frame-Shift Mutation in ZNF292: Case Report and Literature Review. Clin Case Rep. 2025 Aug 7;13(8):e70747. doi: 10.1002/ccr3.70747. PMID: 40777882; PMCID: PMC12329236.

Abstract

Pathogenic mutations in the ZNF292 gene are a significant genetic cause of Intellectual Developmental Disorder (IDD) in individuals, manifesting with a spectrum of clinical features including mild to severe intellectual impairment, speech delay, and co-occurring autism spectrum disorder (ASD). In this study, we present a novel clinical phenotype associated with a newly identified variant of ZNF292 and conduct a thorough review of relevant literature. A 4-year-old female patient displayed language developmental delays, short stature, and skeletal abnormalities. Trio whole-exome sequencing revealed a novel de novo heterozygous frameshift variant in exon 8 of the ZNF292 gene, c.5977_5978del, p.Gln1993fs. According to the ACMG guidelines, this variant is expected to be pathogenic. Our research unveils a novel variant in ZNF292-related disorders and expands the associated phenotypic spectrum. This study highlights the significance of employing next-generation sequencing for timely patient diagnosis, while further clinical phenotypic and genotypic investigations could improve the understanding of ZNF292-linked conditions.

Wang F, Qi N, Gao Y, Wu D, Zhang M, Zhang Q, Yang K, Peng H, Lei X, Liao S. [Genetic analysis of two children with developmental delay and intellectual disability]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Jul 10;40(7):876-880. Chinese. doi: 10.3760/cma.j.cn511374-20220318-00181. PMID: 37368394.

Abstract

Objective: To explore the genetic etiology of two patients with developmental delay and intellectual disability.

Methods: Two children who were respectively admitted to Henan Provincial People's Hospital on August 29, 2021 and August 5, 2019 were selected as the study subjects. Clinical data were collected, and array comparative genomic hybridization (aCGH) was carried out on the children and their parents for the detection of chromosomal microduplication/microdeletions.

Results: Patient 1 was a 2-year-and-10-month female and patient 2 was a 3-year-old female. Both children had featured developmental delay, intellectual disability, and abnormal findings on cranial MRI. aCGH revealed that patient 1 has harbored arr[hg19] 6q14.2q15(84621837_90815662)×1, a 6.19 Mb deletion at 6q14.2q15, which encompassed ZNF292, the pathogenic gene for Autosomal dominant intellectual developmental disorder 64. Patient 2 has harbored arr[hg19] 22q13.31q13.33(46294326_51178264)×1, a 4.88 Mb deletion at 22q13.31q13.33 encompassing the SHANK3 gene, haploinsufficiency of which can lead to Phelan-McDermid syndrome. Both deletions were classified as pathogenic CNVs based on the guidelines of American College of Medical Genetics and Genomics (ACMG) and were not found in their parents.

Conclusion: The 6q14.2q15 deletion and 22q13-31q13.33 deletion probably underlay the developmental delay and intellectual disability in the two children, respectively. Haploinsufficiency of the ZNF292 gene may account for the key clinical features of the 6q14.2q15 deletion.