KIF1A – PEHO syndrome

PEHO syndrome (Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy) is a severe early-onset neurodevelopmental disorder characterized by infantile spasms, myoclonic jerking, profound psychomotor retardation, early loss of visual fixation with optic atrophy, hypotonia, and progressive brain atrophy. Trio whole-exome sequencing in an affected girl identified a de novo heterozygous missense variant c.296C>T (p.Thr99Met) in the motor domain of KIF1A as the pathogenic lesion (PMID:26486474). A literature review revealed an additional 24 unrelated cases harboring heterozygous motor-domain missense variants, of which three met full PEHO criteria and several others met modified criteria including convulsive disorders and attenuated features.

The disease follows an autosomal dominant inheritance pattern with de novo occurrence in all reported cases; no multiplex families with segregation were observed. Across two cohorts, at least 25 probands carried de novo KIF1A motor-domain missense variants with no reported familial transmission or segregation beyond the index cases, underscoring the sporadic nature of PEHO syndrome due to KIF1A mutations ([PMID:26486474]).

The variant spectrum in PEHO syndrome is restricted to missense substitutions in the highly conserved kinesin motor domain. Recurrent mutations include c.296C>T (p.Thr99Met), c.646C>T (p.Arg216Cys), c.647G>A (p.Arg216His) (PMID:26486474), and c.757G>A (p.Glu253Lys) (PMID:30385166). No truncating or splice variants have been reported in this phenotype.

Clinically, affected individuals present with infantile spasms (HP:0012469), myoclonus (HP:0001336), profound developmental delay with progressive encephalopathy (HP:0002448), hypotonia (HP:0001252), and optic atrophy (HP:0000648) within the first year of life. Neuroimaging shows progressive cerebral and cerebellar atrophy consistent with PEHO syndrome.

Functional studies in patient muscle biopsies demonstrated an isolated mitochondrial respiratory chain complex IV deficiency, linking motor-domain KIF1A variants to impaired organelle transport and secondary mitochondrial dysfunction (PMID:30385166). Additionally, independent in vitro assays of KIF1A motor activity in neuronal models have shown that motor-domain missense mutations disrupt ATP hydrolysis and microtubule gliding, supporting a dominant-negative mechanism.

No conflicting or refuting evidence has been reported that challenges the association between KIF1A motor-domain variants and PEHO syndrome. Together, genetic and experimental data robustly support a strong causative role for de novo heterozygous KIF1A missense variants in PEHO syndrome.

Key Take-home: De novo autosomal dominant missense mutations in the KIF1A motor domain cause PEHO syndrome by impairing axonal transport and mitochondrial function, enabling precise molecular diagnosis and genetic counseling.

References

• European journal of human genetics • 2016 • De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome. PMID:26486474
• Journal of clinical neuroscience • 2019 • PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex. PMID:30385166

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