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Background <p><i>METTL5</i>-related neurodevelopmental disorder is a rare autosomal recessive condition characterized by primary microcephaly, intellectual disability, and variable neurobehavioral manifestations. While the genetic etiology is well-established, targeted pharmacological management for the severe neuropsychiatric components of the syndrome remains undefined.</p> Methods <p>We conducted a comprehensive literature review of all published <i>METTL5</i> cases to analyze the phenotypic spectrum, with a specific focus on behavioral dysregulation. Concurrently, we evaluated the clinical and pharmacological course of an index patient from Türkiye harboring a novel homozygous frameshift variant [NM_014168.4:c.415_416del; p.(Met139Glyfs*23)].</p> Results <p>Analysis of the pooled cohort (<i>n</i> = 16) confirms that primary microcephaly and moderate-to-severe intellectual disability are universal features. Crucially, profound behavioral abnormalities—including attention-deficit/hyperactivity disorder (ADHD), impulsive aggression, and severe self-mutilation—emerge as highly prevalent core characteristics, documented in over 90% of cases. The index patient exhibited severe ADHD and episodic aggression alongside a distinct, previously unrecognized craniofacial dysmorphic profile. Targeted intervention with low-dose risperidone (0.25&#xa0;mg/day) yielded a rapid and robust reduction in impulsivity and behavioral dysregulation, directly facilitating her active engagement in multidisciplinary rehabilitative therapies.</p> Conclusions <p>This study expands the genotypic and phenotypic spectrum of <i>METTL5</i> deficiency and underscores its significant neurobehavioral burden. Our preliminary clinical observation suggests that atypical antipsychotics, such as risperidone, may represent a potential therapeutic option for managing the challenging behavioral components of this disorder, although further studies are needed to confirm these findings.</p>

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Efficacy of risperidone and behavioral delineation in METTL5-related syndrome: a pooled analysis of literature and report of a novel variant

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Özge Beyza Gündoğdu Öğütlü,
  • Furkan Baştan,
  • Zeynep Sever Erdem,
  • Hakan Öğütlü,
  • Haktan Bağış Erdem

摘要

Background

METTL5-related neurodevelopmental disorder is a rare autosomal recessive condition characterized by primary microcephaly, intellectual disability, and variable neurobehavioral manifestations. While the genetic etiology is well-established, targeted pharmacological management for the severe neuropsychiatric components of the syndrome remains undefined.

Methods

We conducted a comprehensive literature review of all published METTL5 cases to analyze the phenotypic spectrum, with a specific focus on behavioral dysregulation. Concurrently, we evaluated the clinical and pharmacological course of an index patient from Türkiye harboring a novel homozygous frameshift variant [NM_014168.4:c.415_416del; p.(Met139Glyfs*23)].

Results

Analysis of the pooled cohort (n = 16) confirms that primary microcephaly and moderate-to-severe intellectual disability are universal features. Crucially, profound behavioral abnormalities—including attention-deficit/hyperactivity disorder (ADHD), impulsive aggression, and severe self-mutilation—emerge as highly prevalent core characteristics, documented in over 90% of cases. The index patient exhibited severe ADHD and episodic aggression alongside a distinct, previously unrecognized craniofacial dysmorphic profile. Targeted intervention with low-dose risperidone (0.25 mg/day) yielded a rapid and robust reduction in impulsivity and behavioral dysregulation, directly facilitating her active engagement in multidisciplinary rehabilitative therapies.

Conclusions

This study expands the genotypic and phenotypic spectrum of METTL5 deficiency and underscores its significant neurobehavioral burden. Our preliminary clinical observation suggests that atypical antipsychotics, such as risperidone, may represent a potential therapeutic option for managing the challenging behavioral components of this disorder, although further studies are needed to confirm these findings.