Brothers in Arms or Innocent Bystanders? The Coexistence of Rare Heterozygous CNNM2 and TRAPPC11 Variants in a Neuro-renal Syndrome
Sudhir Kumar Palat Chirakkara1, Qiang Zhang2
1Neurology, Movement, University of Iowa Healthcare, 2Neurology, Movement, University of Iowa, Hospitals and Clinics
Objective:

This case is interesting for the co-occurrence of  heterozygous variants of  CNNM2 and TRAPPC11, manifesting as a neuro-renal syndrome with dystonia as a new phenotypical expression.

Background:
Mutations in CNNM2 (chromosome 10q24.32), a gene encoding a magnesium transporter, cause hypomagnesemia with neurological features, including epilepsy, intellectual disability, and tremor. This condition is exceptionally rare (approximately 40 cases documented globally). TRAPPC11 (chromosome 4q35.1) mutations primarily cause limb-girdle muscular dystrophy, typically in an autosomal recessive pattern (roughly 50-60 cases) 
Design/Methods:

A 60-year-old Caucasian male with adolescent-onset epilepsy, progressive tremor, and cervical dystonia. The tremor, affecting his head, hands (worse in left with dystonia), and voice, significantly worsened in recent months, impairing his ability to perform daily tasks. O/E action and resting tremors, cervical dystonia, dysphonia, mild hand dystonia with a flexed posture and a slow small stepped gait. Family history : maternal aunt with late-onset tremor.

Results:

Genetic analysis revealed a heterozygous partial deletion in CNNM2 and a maternally inherited heterozygous missense variant (D302N) in TRAPPC11, with no second pathogenic TRAPPC11 allele. Laboratory studies confirmed mild hypomagnesemia at 1.5 mg/dL (1.6-2.6) due to renal magnesium wasting (Fractional excretion Mg 6.4% normal < 4). Brain MRI disclosed extensive T2 hyperintensities and the DAT scan was normal. Standard therapies and magnesium supplementation provided minimal benefit so far.

Conclusions:

This report documents a novel co-occurrence of heterozygous CNNM2 and TRAPPC11 variants. While the symptoms align predominantly with CNNM2-related disorders, the isolated heterozygous TRAPPC11 variant raises questions about its clinical significance. It may exert a modifying effect on the CNNM2 phenotype, potentially contributing to the progressive adult-onset movement disorder with dystonia as an additional expression.

 

This case extends the phenotypic and genotypic spectrum of CNNM2-related disorders and highlights the importance of comprehensive genetic evaluation in complex adult-onset neurological syndromes, suggesting a potential novel interaction warranting further research into digenic contributions.

10.1212/WNL.0000000000215363
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