Antenatal Indicators and Early Fetal Dynamics

Modern fetal neurology relies significantly on dynamic ultrasonography and maternal perception to evaluate early nervous system development. When fetal movement abnormalities manifest in utero, clinicians usually observe a spectrum ranging from marked fetal akinesia to focal epileptic activity. Fetal akinesia traditionally correlates with arthrogryposis multiplex congenita, where joint contractures develop secondary to reduced intrauterine motion. Conversely, increased repetitive fetal movements typically suggest intrauterine seizure activity. However, nonepileptic hyperkinetic movement disorders occurring during the antenatal period remain exceptionally rare and clinically challenging to diagnose. A recent clinical report highlights a female infant presenting with antenatal-onset hyperkinesia associated with neonatal CLPB deficiency. During gestation, antenatal ultrasonography demonstrated severe polyhydramnios, significant fetal growth restriction, and persistent high-frequency clonus-like movements. The mother reported frequent, intense intrauterine shaking sensations throughout the third trimester. Upon delivery, the infant exhibited severe respiratory depression, requiring immediate resuscitation and mechanical ventilation. This unusual clinical presentation emphasizes the necessity of evaluating complex motor phenomena during fetal development. Furthermore, identifying abnormal intrauterine movement patterns early can guide clinicians toward appropriate diagnostic pathways immediately after birth. Integrating antenatal history with advanced postnatal genomic testing provides essential clarity in complex neurometabolic conditions.

Clinical Presentation and Postnatal Phenotype

Physical examination immediately after birth revealed multiple congenital anomalies alongside pronounced neurological deficits. The infant exhibited classic features of arthrogryposis multiplex congenita, including severe joint contractures in both upper and lower limbs. Additionally, clinicians identified ectrodactyly affecting the hands, bilateral congenital cataracts, marked axial hypotonia, and absent primitive reflexes. Despite significant axial weakness, the neonate demonstrated persistent, high-frequency, low-amplitude clonus-like movements measuring approximately 5 Hz. These rapid rhythmic movements affected the extremities continuously throughout the observation period. Electroencephalographic monitoring failed to show any electrographic seizure activity, confirming that these hyperkinetic movements were non-epileptic in origin. Laboratory evaluations revealed markedly elevated serum creatine kinase levels, which clinicians attributed to continuous involuntary muscle contractions. Subsequent biochemical testing demonstrated severe neutropenia and elevated urinary 3-methylglutaconic acid levels, pointing toward a metabolic or mitochondrial etiology. Consequently, supportive management was initiated in the neonatal intensive care unit to stabilize respiratory and metabolic status. Despite comprehensive intensive care, the infant succumbed to progressive respiratory failure on day fifteen of life. This tragic clinical course underscores the rapid progression and severe morbidity associated with underlying primary mitochondrial conditions in neonates.

Pathophysiology of Neonatal CLPB Deficiency

Whole-exome sequencing ultimately established a definitive molecular diagnosis by identifying pathogenic variants in the nuclear-encoded CLPB gene. The CLPB gene encodes caseinolytic peptidase B homolog, an essential mitochondrial chaperone protein involved in protein disaggregation and mitochondrial intermembrane space maintenance. Loss of functional CLPB protein disrupts cellular energy metabolism, leading to a recognized autosomal recessive primary mitochondrial disorder. Patients affected by neonatal CLPB deficiency typically exhibit 3-methylglutaconic aciduria, congenital neutropenia, cataracts, and variable neurological involvement. In this specific case, bi-allelic loss-of-function variants impaired normal mitochondrial protein quality control, resulting in widespread cellular dysfunction. The elevated creatine kinase levels reflected sustained muscle metabolic stress secondary to persistent involuntary contractions. Furthermore, the presence of 3-methylglutaconic aciduria served as a key biochemical marker for mitochondrial membrane destabilization. Neutropenia remains another hallmark feature, frequently predisposing affected neonates to severe systemic infections. Notably, identifying the genetic basis through whole-exome sequencing was instrumental in providing an accurate diagnostic answer to the family. Genetic counseling for parents is critical in such autosomal recessive conditions, as the recurrence risk for subsequent pregnancies is twenty-five percent. Molecular diagnosis also prevents unnecessary invasive diagnostic procedures and guides palliative care strategies.

The Paradoxical Coexistence of Arthrogryposis and Hyperkinesia

Traditionally, medical literature links arthrogryposis multiplex congenita with intrauterine fetal hypokinesia or complete akinesia. Reduced fetal movement prevents normal joint development, leading to secondary fibrosis and fixed joint contractures. However, this case demonstrates a unique neurodevelopmental paradox where arthrogryposis occurred simultaneously with hyperkinesia rather than global hypokinesia. The persistent clonus-like movements observed in utero failed to prevent joint contractures because the movement repertoire was highly restrictive and stereotyped. Although the frequency of movements was high, the functional amplitude and range of motion were insufficient to maintain proper joint mobility during crucial stages of fetal development. Consequently, fixed contractures developed despite continuous hyperkinetic activity. This observation provides important insights into fetal neuromuscular physiology, proving that movement quality and range are as vital as movement quantity for normal joint development. Furthermore, nonepileptic hyperkinetic movements must be carefully distinguished from fetal seizures during routine antenatal ultrasound evaluations. Rhythmic fetal movements without cortical epileptic correlates suggest underlying basal ganglia or brainstem dysfunction rather than cortical hypersynchrony. Recognizing this distinct motor pattern can aid clinicians in narrowing differential diagnoses when evaluating unusual fetal movement profiles.

Diagnostic Strategy and Multidisciplinary Collaboration

Evaluating complex neonatal presentations demands a structured, multidisciplinary approach involving pediatric neurologists, neonatologists, clinical geneticists, and maternal-fetal medicine specialists. When antenatal ultrasonography detects polyhydramnios, fetal growth restriction, and abnormal motor activity, clinicians should maintain a broad differential diagnosis. Postnatal evaluation must combine electroencephalography, detailed metabolic screening, and advanced genomic testing to establish an accurate etiology promptly. Electroencephalography is essential to differentiate non-epileptic hyperkinesia from neonatal status epilepticus, avoiding unnecessary administration of heavy antiseizure medications. Metabolic screening, particularly measuring urinary organic acids like 3-methylglutaconic acid, offers rapid diagnostic clues for mitochondrial disorders. Furthermore, early total serum creatine kinase measurement provides valuable information regarding ongoing muscle strain or necrosis. Genetic confirmation through rapid exome sequencing remains the gold standard for definitive diagnosis in complex neurometabolic syndromes. Early diagnostic confirmation allows medical teams to counsel parents effectively regarding prognosis, management goals, and palliative options. Additionally, multidisciplinary collaboration ensures that supportive care, including mechanical ventilation and hematological monitoring, is optimized. Establishing a clear diagnosis also facilitates appropriate genetic counseling and reproductive planning for affected families.

Frequently Asked Questions

What is CLPB deficiency and how does it manifest in neonates?

CLPB deficiency is an autosomal recessive primary mitochondrial disorder caused by pathogenic variants in the CLPB gene. In neonates, severe forms present with encephalopathy, axial hypotonia, hyperkinetic movement disorders, congenital cataracts, neutropenia, markedly elevated serum creatine kinase, and 3-methylglutaconic aciduria. Most severe neonatal cases lead to early progressive respiratory failure and death.

Why did arthrogryposis develop despite the fetus having hyperkinetic movements?

Arthrogryposis developed because the hyperkinetic movements were high-frequency but low-amplitude and restrictive. Normal joint development requires full-range fetal movements. Stereotyped, restrictive clonus-like shaking failed to provide the necessary dynamic mechanical stimulation to the joints, leading to congenital contractures despite continuous hyperkinetic movement in utero.

How can clinicians differentiate fetal hyperkinesia from intrauterine seizures?

Clinicians differentiate fetal hyperkinesia from intrauterine seizures using continuous postnatal electroencephalography alongside dynamic fetal ultrasonography. Epileptic movements typically correspond with ictal electrographic discharges on electroencephalography. Non-epileptic hyperkinesia, such as clonus-like movements in CLPB deficiency, presents without ictal activity, indicating subcortical or basal ganglia dysfunction.

Disclaimer: This content is for informational and educational purposes only and should not be considered medical advice. Refer to the latest local and national guidelines for clinical practice.

References

1. Yıldız Y et al. Child Neurology: Arthrogryposis and Antenatal-Onset Hyperkinetic Movements in a Newborn. Neurology. 2026 Aug 25. doi: 10.1212/WNL.0000000000218361. PMID: 42497374.

2. Kanabus M et al. CLPB Mutations Cause 3-Methylglutaconic Aciduria, Progressive Brain Atrophy, Intellectual Disability, Severe Neutropenia, and Cataracts. Am J Hum Genet. 2015;97(1):139-147.

3. Wortmann SB et al. CLPB Deficiency: Review of Clinical Presentation and Molecular Findings. J Inherit Metab Dis. 2021;44(5):1105-1115.