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Exploring Genotypic Diversity in Angelman-Like Syndromes: Clinical Implications

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Angelman syndrome (AS) is a rare neurogenetic disorder mainly characterized by severe developmental delay, intellectual disability, and a distinct behavioral phenotype. While most AS cases are associated with dysfunction of the UBE3A gene, similar phenotypic features are observed in several other neurodevelopmental syndromes. This study examines the clinical and genetic findings of patients diagnosed with AS and AS-like syndromes, aiming to elucidate the genotypic spectrum and the molecular mechanisms underlying AS-like phenotypes. This study included 40 patients evaluated for AS, with molecular diagnoses distributed among three groups : AS (n:23), AS-like group (n:12), and inconclusive group (n:5) . The mean age of the patients was 8.9 years, with no significant age difference between groups. Clinical presentation was similar across groups, with ataxia observed in 100% of patients, pyramidal signs in 68%, and stereotypic behaviors in 54%. Eye contact was present in 63% of cases, while 48% could respond to commands, although speech was notably absent or minimal in the majority.

Case Presentation
The study involves 40 patients who underwent genetic testing for Angelman syndrome. The diagnostic approach combined genetic testing and clinical observations to classify patients into three groups: Angelman, Normal (The cases that cannot be included in molecular farming), and Other (WES positive cases). Notably, ataxia, microcephaly, and happy mood were significant clinical features found early on, emphasizing their importance in the diagnostic process.

Tests and Findings:

Descriptive Statistics:

Age: The mean age of patients across groups was similar (Angelman: 9.14 years, Normal: 9.20 years, Other: 10.25 years).

Age at First Seizure: There was variability, with Angelman group experiencing seizures earlier (29.14 months) than the Normal group (46.50 months), and Other group at 19.60 months.

Age at Diagnosis: The median age at diagnosis showed delays in the Angelman group (36 months), compared to the Normal group (66 months) and the Other group (24 months).

Clinical Parameters:

The Angelman group exhibited higher rates of ataxia, stereotypic behaviors, and speech impairment compared to other groups. Specifically, 46.2% had pyramidal findings, 36.8% eye contact and 56.4% lacked speech.

Statistical Analysis:

One-way ANOVA and Chi-Square tests revealed no statistically significant differences across the groups in clinical and demographic parameters (p > 0.05).

Seizure Characteristics:

Within the Angelman group, 34.4% of patients had non-resistant seizures, and 15.6% experienced resistant seizures, showcasing the broad spectrum of seizure control challenges in this population.

This study highlights the clinical heterogeneity within Angelman syndrome, underlining the critical role of both genetic testing and clinical assessment in reaching an accurate diagnosis.

 

Diagnostic Workup
All patients underwent methylation analysis for initial AS testing, with follow-up tests including FISH and chromosomal microarray analysis to identify specific genetic defect. The 15q11.2 region deletion was confirmed with FISH or SNP array.Cases with normal Angelman methylation analysis were evaluated using WES analysis.

Treatment and Management
Most patients received antiepileptic therapy, with common medications including valproic acid, levetiracetam, and carbamazepine. Additional supportive treatments, such as special education and vitamin supplementation, were provided. 

Outcome and Follow-Up
While clinical responses varied, seizure control was achieved in several patients, with differences in seizure resistance observed among groups. However, no significant statistical differences were found across groups in terms of age at first seizure or seizure resistance status.

Discussion
These findings emphasize the genetic heterogeneity of AS-like syndromes and the importance of comprehensive genetic testing in differential diagnosis. AS-like phenotypes are associated with a diverse array of genetic alterations beyond UBE3A dysfunction, highlighting the complex etiology of AS-like syndromes and underscoring the need for precise genetic assessments to improve diagnostic accuracy. The genes identified in Angelman-like phenotypes play critical roles in various cellular and neurological functions. Transcriptional regulators such as ELP2, ZEB2, and TCF4 are essential for cellular development and neural function. Ion transporters SLC6A8 and SLC9A6 contribute to brain development and endosomal pH balance. Mitochondrial function is supported by VPS13D and OGDH, which are involved in cellular energy metabolism. The ion channel SCN3A regulates ion flow in neurons, while P4HTM is involved in post-translational modifications that maintain protein stability. STAG2 functions in chromosome segregation during cell division, DENND5A in membrane trafficking, and AP4M1 in vesicular transport, particularly in neurons. CDKL5, a serine/threonine protein kinase, is crucial for synaptic function and is frequently observed in Angelman-like phenotypes. Collectively, these genes provide valuable insights into the molecular basis of Angelman-like neurodevelopmental disorders.

Conclusion
This study expands the understanding of the genetic and clinical spectrum of AS and AS-like syndromes, suggesting that continued genomic research is essential for advancing diagnostic and therapeutic strategies.

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