Startle‐sensitive myoclonus with spastic–ataxic gait in 4p duplication: A clinical vignette

A 23-year-old woman with lifelong neurodevelopmental disability presented with sound and movement-triggered brief, sudden, shock-like jerks involving both upper and lower limbs starting at 4 years of age, initially infrequent, occurring 4–5 times per day, escalating in adolescence to near hourly events, violent enough to cause recurrent falls and occasional impaired awareness. Developmental history featured delayed head control (9 months), sitting (10 months), walking (2 years), and late bladder control (8 years); speech was markedly delayed (bisyllables at 2 years, single words at 4 years). She completed secondary schooling with support. Family history included a paternal uncle with intellectual disability. On examination, she was shy but cooperative with cranio-facial dysmorphism, which included synophrys, depressed nasal bridge, pinched nose, crowded teeth with a high arched palate, short neck, micrognathia/retrognathia, long slender fingers, and bilaterally long, flat feet (Figure 1A,B). Mini Mental State Examination was 23/30 with prominent visuospatial and executive deficits. Language and cranial nerves were normal. Tone was reduced with mild proximal weakness (Medical Research Council grade 4/5) in all limbs; tendon reflexes were exaggerated with flexor plantar responses. Gait assessment revealed a spastic–ataxic gait with a broad-based stance, reduced stride length, scissoring movements of the lower limbs, poor foot placement with irregular stepping, and multiple falls forward and laterally. Moreover, she relied heavily on visual cues during ambulations. There was bilateral postural/kinetic hand tremor affecting writing and drinking and truncal swaying when sitting unsupported. Routine hematologic and metabolic evaluations were unremarkable. Brain MRI demonstrated partial agenesis of the corpus callosum with diffuse cerebral atrophy and ventriculomegaly. Scalp EEG showed high voltage spike-and-wave discharges maximal over the right frontal region with secondary generalization on a preserved alpha background (Figure 1C). Startle-evoked myoclonic bursts were reproducible to sudden auditory stimulation. In view of the syndromic gestalt and combined movement disorder, genomic testing was undertaken. Whole-exome sequencing with exome-based copy number analysis identified a heterozygous duplication spanning 4p15 to the telomere (≈13.19 Mb) overlapping the Wolf–Hirschhorn critical region (copy number state 3). No pathogenic single-nucleotide or indel variants were detected. Parental studies were recommended to establish whether the duplication was de novo or segregated from a balanced parental rearrangement. Management focused on optimizing anti-myoclonic antiseizure therapy alongside structured neurorehabilitation. A pragmatic regimen of lamotrigine (250 mg/day), clobazam (15 mg/day), and sodium valproate (500 mg/day), titrated over 1 month, reduced startle jerks to two to three brief events daily and enabled the patient to resume basic activities of daily living. Targeted physiotherapy with gait training, balance, and core strengthening and stretching to limit spasticity and prevent contractures improved postural stability and reduced falls. Occupational therapy addressed tremor-related fine motor impairment. On longitudinal follow-up, functional gains were maintained with the same pharmacotherapy and ongoing rehabilitation. Partial trisomy 4p is rare and exhibits broad phenotypic variability. Increased dosage of genes within 4p16.3—including NSD2/WHSC1, NELFA/WHSC2, LETM1, FGFRL1, and TACC3—has been linked to neurodevelopmental disability and craniofacial dysmorphism; duplications distal to or encompassing this interval yield overlapping but heterogeneous presentations.1, 2 Seizures are reported in roughly one-third of patients and are often responsive to broad-spectrum antiseizure medicines, yet startle-sensitive myoclonus persisting into young adulthood with a mixed spastic–ataxic gait appears uncommon.3 It is important to distinguish 4p duplication from other genetic causes of startle-sensitive myoclonus because many of these disorders may be clinically similar but have different testing pathways and treatment implications. Classic hyperekplexia (GLRA1/SLC6A5) presents with prominent neonatal stiffness and improves with clonazepam, whereas developmental epileptic encephalopathies (STXBP1/KCNC1, PRRT2, and GAD1/ARX) show broader seizure types and are pharmacoresistant, with myoclonus that may worsen with certain antiseizure medications. This vignette, therefore, expands the neurological phenotype of 4p duplication to include persistent reflex myoclonus with co-existing cerebellar and pyramidal gait disorder and underscores the diagnostic utility of exome-based CNV pipelines in early onset startle epilepsy accompanied by complex motor features.1 This vignette highlights three practical points for clinicians. First, reflex startle epilepsy in the context of dysmorphism and movement disorder should prompt consideration of a chromosomal etiology and early copy number analysis even when single gene panels are unrevealing.4 Second, coupling broad-spectrum anti-myoclonic pharmacotherapy (valproate, lamotrigine, benzodiazepines) with structured physiotherapy can deliver meaningful functional gains, whereas carbamazepine and other narrow-spectrum sodium channel agents may aggravate myoclonus.5 Third, multidisciplinary follow-up including orthopedic surveillance for scoliosis and contractures, periodic ophthalmologic and cardiac evaluations, speech therapy, special education supports, and psychosocial counseling helps address the multisystem needs of patients with genetic epilepsies and sustains independence.6 AN conceived the case report, performed the literature review, collected and interpreted the clinical and imaging details, and drafted the manuscript. AMK and PR contributed to the literature review and assisted in refining the clinical discussion. PS supervised the work and critically revised and edited the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work. The authors thank the clinical and departmental staff involved in the patient's care for their support and assistance in retrieving relevant clinical information. No professional medical writing assistance was used. This work received no specific funding from any public, commercial, or not-for-profit funding agency. The authors declare no conflicts of interest relevant to this manuscript. The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s)/relative(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. All data relevant to this case report are included in the article. Additional de-identified information may be made available by the corresponding author upon reasonable request, subject to institutional policies and patient confidentiality considerations. Data S1. Data S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. In a patient with sound-triggered events, which finding most reliably distinguishes startle epilepsy from hyperekplexia? For a patient with reflex epilepsy, developmental delay, and dysmorphic features, which single assay best maximizes detection of both SNVs/indels and exon-level CNVs in one workflow? Which statement best reflects current understanding of 4p dosage imbalance and epilepsy risk? Answers may be found in the supporting information.