NTN1 – Familial Congenital Mirror Movements

Congenital mirror movements (CMM) are characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Although netrin-1 (NTN1) was known as a key axon guidance cue, inherited human disease associations had not been reported until recently. A study identified heterozygous NTN1 mutations in 3 probands across two unrelated families and one sporadic case (3 probands) ([PMID:28945198]). These findings implicate NTN1 in the pathogenesis of familial CMM with an autosomal dominant inheritance pattern.

Genetic evidence includes three distinct variants in exon 7 of NTN1: two missense substitutions (c.1801T>C (p.Cys601Arg) and c.1802G>C (p.Cys601Ser)) and one in-frame deletion (c.1549ATC[1] (p.Ile518del)) observed in heterozygosity ([PMID:28945198]). Segregation analysis demonstrated co-segregation of disease with NTN1 variants in two multiplex families (2 affected relatives), consistent with autosomal dominant transmission. No recurrent or founder alleles were reported, and variant spectrum is limited to missense and small in-frame deletions.

Functional studies revealed that all three mutant netrin-1 proteins are predominantly retained intracellularly in HEK293 and HeLa cells, in contrast to wild-type netrin-1, which is secreted ([PMID:28945198]). This secretion defect supports a loss-of-function mechanism leading to disrupted midline crossing. Neuroimaging of affected individuals demonstrated abnormal corticospinal tract (CST) decussation, aligning with the clinical mirror movement phenotype.

Clinically, NTN1-related CMM presents as isolated mirror movements from early childhood without additional neurological or systemic features. Affected individuals maintain normal cognitive development and no other organ involvement has been observed.

Integrating genetic segregation in multiple families with concordant cellular and neuroimaging data yields a Moderate level of clinical validity under ClinGen criteria. Further evidence from animal models or rescue experiments could elevate this classification. Key take-home: Heterozygous NTN1 loss-of-function variants cause autosomal dominant familial congenital mirror movements by impairing netrin-1 secretion and CST guidance, supporting genetic testing in CMM evaluation.

References

• The Journal of clinical investigation • 2017 • Mutations in the netrin-1 gene cause congenital mirror movements. [PMID:28945198]

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