Acta neurologica Belgica · 2026
Efficacy of risperidone and behavioral delineation in METTL5-related syndrome: a pooled analysis of literature and report of a novel variant.
СтатьяМетаанализОбзорНазвание и аннотация: Перевод в очереди
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Gündoğdu Öğütlü Özge Beyza, Baştan Furkan, Erdem Zeynep Sever, Öğütlü Hakan, Erdem Haktan Bağış
Аннотация
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.
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.