Introduction

Angelman syndrome (AS) is a rare genetic disorder characterized as autosomal dominant with a phenotype defined by the lack of expression of the ubiquitin-protein ligase E3A (UBE3A) gene inherited maternally in the brain. It is also associated with the presence of an abnormal chromosome 15q11-q13¹,². AS has a prevalence ranging from 1 in 20,000 to 1 in 12,000 individuals. Although more common in childhood, few cases are identified in adulthood³. This condition affects males and females equally, and many cases remain undiagnosed due to diagnostic errors or underreporting⁴.

Due to its early onset, global developmental delay, and motor dysfunction, AS may initially mimic cerebral palsy (CP). However, certain features help distinguish AS from CP, including the absence of perinatal hypoxic-ischemic injury, the presence of paroxysmal laughter, minimal or absent speech, severe intellectual disability out of proportion to motor findings, characteristic electroencephalogram electroencephalogram (EEG) abnormalities, and confirmation by molecular testing of chromosome 15q11-q13 deletion involving UBE3A.

Previous reports have also described cases of AS initially misdiagnosed as CP, underscoring how overlapping early motor and developmental findings can mask the underlying genetic condition. Lorenzo-Ruiz et al. (2023) documented adults who were labeled as having CP in childhood until molecular testing revealed deletions in chromosome 15q11-q13. Similarly, Liu et al.² (2022) and Triono et al.¹ (2021) reported children with hypotonia and delayed milestones who were reclassified after identification of the UBE3A mutation¹-³. These studies highlight consistent early red flags – such as inappropriate laughter, minimal or absent speech, non-progressive hypotonia, and characteristic EEG abnormalities – that may guide clinicians toward earlier suspicion of AS.

Recognizing these distinguishing characteristics is crucial, since misdiagnosis can delay appropriate genetic counseling and multidisciplinary management. Our case involves a patient with AS, mimicked by CP, causing severe delay, stereotypical autistic behavior, hypotonia, and difficult-to-control epilepsy.

A structured comparison between AS and CP highlights that, while both share early hypotonia and developmental delay, AS exhibits distinctive behavioral (frequent laughter, minimal speech), electrophysiological (EEG patterns), and genetic (UBE3A deletion) hallmarks that are absent in CP. Emphasizing these red flags can guide clinicians toward earlier suspicion and appropriate testing.

Clinical case

We describe the case of a 3-year and 10-month-old male patient, born via normal delivery at 37 weeks, discharged with his mother. He denies allergies or prior surgeries. He has a family history of a cousin with autism spectrum disorder (ASD) and a sister with attention deficit hyperactivity disorder. He was referred to the Neurology outpatient clinic due to motor delay, presenting with severe hypotonia, brachycephaly, absence of trunk control, a history of difficult-to-control epilepsy, and severe developmental delay (he does not walk or speak).

The patient was first evaluated in early childhood for delayed motor development and generalized hypotonia. At the time, due to marked muscle weakness, absence of trunk control, and failure to reach expected motor milestones, an initial diagnosis of CP was made. This hypothesis was reinforced by the presence of developmental delay and abnormal motor patterns, although no history of perinatal asphyxia or brain injury was identified.

At the age of 1 year and 11 months, he could not sit up by himself, still could not crawl, and had difficulty swallowing. A videofluoroscopic swallowing study was ordered, and risperidone 0.3 mL was prescribed at night, with a follow-up in 1 month. At 2 years of age, he presented a tonic-clonic seizure with a stare that lasted for 5 min, followed by hypotonia of both upper and lower limbs in the postictal period, along with a new episode of hypotonia. The diagnostic hypothesis at that point included chronic non-progressive encephalopathy with epilepsy, and valproic acid 3 mL (20 mg/kg/day) every 12 h was introduced. In the same age, the patient developed a 3-day fever and another seizure. After 3 days, the dose of valproic acid was increased to 5 mL every 12 h, showing a positive response, although episodes of fixed staring persisted. Clonazepam 10 mg, ¼ tablet every 12 h, was added. At 2 years and 3 months of age, the dose of valproic acid was further increased to 7 mL every 12 h, clonazepam was replaced with phenobarbital 0.9 mL every 12 h, and levetiracetam 4.5 mL every 12 h was introduced.

Despite multiple therapeutic adjustments, seizure control remained suboptimal, and developmental progress continued to lag. These atypical findings – especially the absence of spasticity, the persistence of severe hypotonia, the lack of speech development, and episodes of spontaneous laughter – prompted reconsideration of the initial CP diagnosis.

A comprehensive reevaluation was performed, including genetic testing, which revealed a deletion of the critical region for Prader-Willi/ASs (OMIM #176270/#1055830), with a copy number variation indicating a 4.7 Mb deletion in chromosome 15q11.2q13.1 in heterozygosity.

Following confirmation of AS, the antiepileptic regimen was maintained, as the combination of valproic acid, phenobarbital, and levetiracetam achieved partial control of seizures. This therapeutic profile aligns with typical management patterns for AS, where valproate and phenobarbital are among the most effective agents. After diagnosis, dosages were adjusted to optimize seizure control and minimize sedation, leading to a reduction in frequency and duration of tonic-clonic episodes. Carbamazepine and vigabatrin were avoided due to their reported potential to exacerbate seizures in AS. Clinical photographs of the patient are shown in figure 1, illustrating the typical behavioral phenotype of AS, characterized by persistent laughter, hypotonia, and a happy facial expression despite developmental delay.

Figure 1 Clinical features of the patient with Angelman syndrome. A: hypotonic posture and limited trunk control. B: persistent smiling and laughter, demonstrating the characteristic “happy puppet” facial expression. C: facial hypotonia with open-mouth smiling and wide-spaced teeth, consistent with the behavioral and orofacial phenotype typical of Angelman syndrome. All identifying features were removed to preserve anonymity. 

The genetic result confirmed AS the definitive diagnosis. The patient is currently clinically stable under a multidisciplinary follow-up program for neurodevelopmental stimulation and seizure management.

Discussion

AS typically presents with speech impairment (absent or minimal), psychomotor developmental delay, movement and balance disorders (ataxia), inappropriate laughing episodes accompanied by hand movements (happy puppet), and seizures. Patients with Angelman syndrome face significant complications due to associated comorbidities. Seizures and ataxia can lead to frequent injuries, while hyperactivity, exploratory behavior, and intellectual disability increase the risk of accidents. These combined factors elevate morbidity and mortality in AS patients⁴.

Although AS and CP may share early manifestations such as hypotonia, delayed motor milestones, and global developmental delay, several key differences help clinicians distinguish them. In AS, motor dysfunction is typically non-progressive and accompanied by disproportionate speech impairment, paroxysmal laughter, and characteristic facial features, whereas in CP the neurological findings are secondary to a defined brain injury, often with spasticity or dystonia, and no distinctive behavioral phenotype. In addition, AS demonstrates specific EEG abnormalities (high-amplitude slow waves and rhythmic theta activity) and confirmatory molecular findings involving the UBE3A gene at chromosome 15q11-q13, which are absent in CP.

From a diagnostic perspective, early recognition of these features is essential. A systematic diagnostic approach should include initial suspicion based on phenotype and behavioral patterns, followed by neuroimaging and electrophysiological studies, and ultimately confirmed by molecular testing. Other neurodevelopmental pathologies that may resemble AS should be excluded, including Phelan-McDermid Syndrome (22q13.3 deletion), MBD5 haploinsufficiency syndrome (22q13.1 deletion), and KANSL1 haploinsufficiency syndrome (17q21.31 deletion). Other examples of single-gene disorders include Christianson syndrome, Mowat-Wilson syndrome, Kleefstra syndrome, and Rett syndrome⁴.

Neuroimaging and EEG findings play a complementary role in narrowing the differential diagnosis. MRI may show hypoplasia of the corpus callosum, enlargement of the lateral ventricles, and cortical atrophy, whereas EEG abnormalities – pseudo arrhythmias and high-amplitude slow wave bursts – are reported in almost all AS patients⁴,⁵.

Non-invasive prenatal screening (NIPS) has recently gained relevance for the early detection of microdeletions and imprinting defects associated with chromosome 15q11-q13. Although it does not replace confirmatory molecular studies, NIPS can alert clinicians and families to an elevated risk of AS during pregnancy, allowing targeted follow-up with chorionic-villus sampling or amniocentesis. Integrating NIPS into prenatal evaluation may prevent years of diagnostic uncertainty and facilitate timely genetic counseling.

The initial evaluation of AS can be performed prenatally by examining fetuses with growth restrictions, and recent studies suggest that NIPS is highly accurate for prenatal AS diagnosis. After birth, if AS is suspected, investigation should begin with methylation tests, as the promoter region of exon 1 of SNRPN exhibits differential methylation, where the paternal allele is unmethylated and the maternal allele is methylated. In 80% of AS cases, including deletions, imprinting center defects, and paternal disomy, the methylated maternal allele is absent. A FISH test should be performed next to identify deletions on the maternal chromosome 15; if negative, imprinting defects or paternal disomy should be considered, confirmed by DNA marker analysis. If both tests are negative, molecular studies of the imprinting center should be pursued. If methylation tests are negative but AS is still suspected, DNA sequencing can be performed to rule out mutations in the UBE3A gene.

Regarding management, early intervention is essential. A tailored program should combine physical therapy, occupational therapy, orthoses, and speech therapy (verbal and non-verbal communication strategies). These improve motor function, prevent contractures, and enhance quality of life. Physical therapy, orthoses, and occupational therapy, which also assist with posture and prevent contractures, are used to improve motor activities. Speech and language therapy (verbal and non-verbal) and the use of computers help improve communication⁴.

Epilepsy management is another cornerstone. Pheno-barbital, sodium valproate, and clonazepam are the most effective drugs, while carbamazepine and vigabatrin should be avoided as they may exacerbate seizures. It is important to monitor treatment response and adjust the antiepileptic regimen according to seizure control and tolerance.

This case emphasizes the need for a systematic and multidisciplinary approach – from clinical suspicion and diagnostic work-up to genetic confirmation and individualized management – to improve early recognition and outcomes in AS.

The present case illustrates the diagnostic challenges of AS presenting as CP and emphasizes the value of a structured, multidisciplinary approach. Awareness of red-flag features – such as inappropriate laughter, minimal speech, and a characteristic EEG pattern – combined with modern genetic tools like NIPS, can lead to earlier recognition, accurate diagnosis, and improved outcomes. Strengthening clinical vigilance and integrating molecular testing into both pediatric and prenatal practice remain key take-home lessons from this case.

Conclusions

AS is characterized by developmental delays, speech impairment, ataxia, and seizures, along with characteristic behaviors such as inappropriate laughter. The comorbidities associated with AS, such as seizures and ataxia, significantly increase the risk of injuries and accidents, leading to higher morbidity and mortality in patients.

Here the initial misdiagnosis of CP delayed appropriate genetic testing and specific management, illustrating how early developmental and motor symptoms can obscure the recognition of AS.

This case underscores the clinical importance of differentiating AS from CP at an early stage. Unlike CP, AS typically lacks a history of perinatal asphyxia or structural brain injury and instead presents with distinctive behavioral and electrophysiological features, such as frequent laughter, minimal speech, and a characteristic EEG pattern.

Timely recognition of these clinical clues allows for earlier genetic testing, accurate diagnosis, and initiation of individualized multidisciplinary therapy that improves neurodevelopmental outcomes and family counseling. Increasing awareness of such atypical presentations is essential to prevent delayed or incorrect diagnoses and to optimize long-term care for affected children.