Hypomagnesemia, Seizures, And Mental Retardation 1

A number sign (#) is used with this entry because of evidence that hypomagnesemia, seizures, and mental retardation-1 (HOMGSMR1) is caused by heterozygous mutation in the CNNM2 gene (607803) on chromosome 10q24. One family with a homozygous mutation has also been reported.

Description

HOMGSMR1 is characterized by onset of seizures associated with low serum magnesium in the first year of life. Affected individuals show variable degrees of delayed psychomotor development (summary by Arjona et al., 2014).

Genetic Heterogeneity of Hypomagnesemia, Seizures, and Mental Retardation

HOMGSMR2 (618314) is caused by mutation in the ATP1A1 gene (182310) on chromosome 1p13.

Clinical Features

Arjona et al. (2014) reported 3 unrelated German patients with onset of seizures associated with low serum magnesium in the first year of life. All had delayed psychomotor development, moderate mental retardation, limited speech, and impaired motor skills. Two patients were obese. One patient had autistic features and aggressive behavior. Brain imaging was normal in all 3 patients. Urinary analysis showed abnormally high renal excretion of magnesium, and oral supplementation of magnesium failed to correct the low serum levels.

Clinical Variability

Arjona et al. (2014) reported 2 sibs, born of consanguineous Serbian parents, who presented in the neonatal period with seizures associated with hypomagnesemia. Both had severely delayed psychomotor development, microcephaly, mental retardation, lack of speech, and very limited motor skills. Brain imaging in 1 patient showed myelination defects, opercularization defects, and widened cerebrospinal fluid spaces. Treatment with oral or intravenous magnesium failed to correct the low serum magnesium levels. One child eventually responded to antiepileptic treatment, whereas the other child continued to have generalized myoclonic seizures despite treatment.

Molecular Genetics

In 3 unrelated German patients with HOMGSMR1, Arjona et al. (2014) identified 2 different de novo heterozygous missense mutations in the CNNM2 gene (607803.0004 and 607803.0005). Two sibs from a consanguineous Serbian family with a similar but more severe disorder were homozygous for a missense mutation (607803.0003). In vitro functional expression studies of all the mutations were consistent with a loss of function. The findings indicated that CNNM2 is essential not only for magnesium homeostasis, but also for early brain development and proper neurologic function.

Animal Model

Arjona et al. (2014) found that morpholino knockdown of the zebrafish CNNM2 paralog cnnm2a resulted in enlarged pericardial cavities and notochord defects as well as decreased total body magnesium levels. Knockdown of the other CNNM2 paralog, cnnm2b, resulted in enlarged pericardial cavities, renal cysts, accumulation of cerebrospinal fluid in the brain, and decreased total body magnesium levels. Mutant zebrafish also showed maldevelopment of the midbrain/hindbrain boundary, increased spontaneous contractions, and weaker touch-evoked escape behavior compared to controls.