Table 1.
Clinical, biochemical and neuroradiological data of patients with CNNM2 variants.
| Stuiver et al. ( 2011 ) | Arjona et al. ( 2014 ) | Accogli et al. (2019) | Bamhraz et al. (2020) | Our case | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | II.3 | III.2 | I.2 | II.1 | F1.1 | F1.2 | F2.1 | F3.1 | F4.1 | F5.1 | III.1 | NA | proband |
| Gender | M | F | F | M | M | F | F | F | M | F | M | F | F |
| Ethnicity | Dutch | Dutch | Czech Republic | Czech Republic | Serbian | Serbian | German | German | German | Polish | Moroccan | NA | Chinese |
| Age onset | 15 years | 1 year | NA | 16 years | 1 day | 6 days | 7 months | 1 year | 4 months | 1 6years | 1 day | 15 years | 3 years |
| Symptoms at onset | Muscle spasms Headache, palpitations |
Muscle spasms, stuttering, loss of consciousness |
Symptomless | Weakness, Vertigo, headache |
Seizure | Seizure | Seizure | Seizure, paresthesia |
Seizure | Myoclonus, paresthesia |
Seizure | Anorexia nervosa | Seizure |
| Initial serum Mg2+(mmol/L) | 0.46 | 0.51 | 0.52 | 0.36 | 0.5 | 0.5 | 0.56 | 0.44 | 0.5 | 0.66 | 0.38 | 0.53 | 0.74 |
| Mg2+ after supplementation (mmol/L) | NA | 0.58 | NA* | 0.61 | 0.66 | 0.54 | 0.56 | 0.53 | 0.68 | NA | 0.49 | 0.56 | 0.78* |
| Epilepsy treatment | N | N | N | N | Response to valproate and Lamotrigine | Resistance to Valproate and Levertiracetam | Response to Phenobarbital | Response to Valproate | Response to Clobazam | NA | Drug-resistant | N | Drug-resistant |
| Intellectual disability | N | N | N | N | Severe | Severe | Moderate | Moderate | Moderate | Mild | Severe | Mild | Mild |
| Language impairment | N | N | N | N | N | N | ELD | ELD | ELD | NA | N | NA | ELD |
| Motor skills impairment | N | N | N | N | Very limited | Very limited | Impaired | Impaired | Impaired | NA | Very limited | NA | Delayed walking |
| malformation | N | N | N | N | Microcephaly | Microcephaly | NA | NA | NA | NA | wide mouth, pectus xcavatum, Microcephaly |
N | pectus excavatum |
| Abnormal brain development | NA | NA | NA | NA | Widened outer cerebrospinal liquor space, myelination defects, opercularization defect |
NA | N | N | N | NA | Global reduction of white matter, cerebral cortical atrophy | - | NA |
| variant (DNA level) |
c.117delG | c.117delG | c.1703C > T | c.1703C > T | c.364G > A | c.364G > A | c.1069G > A | c.806C > G | c.1069G > A | c.988C > T | c.1642G > A | NA | c.2228C > T |
| variant (Protein level) |
p.Ile40SerfsX15 | p.Ile40SerfsX15 | p.Thr568Ile | p.Thr568Ile | p.Glu122Lys | p.Glu122Lys | p.Glu357Lys | p.Ser269Trp | p.Glu357Lys | p.Leu330Phe | p.Val548Met | p.Arg366Pro | p.Ser743Phe |
| variant domain | Extracellular | Extracellular | Bateman module | Bateman module | Extracellular | Extracellular | DUF21 | DUF21 | DUF21 | DUF21 | Bateman module |
DUF21 | CNBH |
| Zygosity | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Homozygous | Homozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Homozygous | Heterozygous | Heterozygous |
| Kosmicki et al. ( 2017 ) | Snoeijen-Schouwenaars et al. ( 2019 )3 | Franken et al. ( 2021 ) | |||||||||||
| Patient | NA | NA | F1 | F2 | F3 | F4 | F5 | F6 | F7 | F8 | F9 | ||
| Gender | NA | NA | F | M | M | M | M | M | F | F | F | ||
| Ethnicity | NA | Netherlands | Caucasian | Sub-Saharan African | Caucasian | Caucasian | Sub-Saharan African | Caucasian | Caucasian | Caucasian | Caucasian | ||
| Age onset | NA | NA | 6 years | 3 months | 2 years | 3 years | 8 months | 13 months | 16 years | 8 months | 1–1.5 year | ||
| Symptoms at onset | Epilepsy, autism spectrum disorder | Autism spectrum disorder, Intellectual disability, seizures and epilepsy |
seizures | seizures | seizures | N | seizures | seizures | seizures | N | seizures, autism spectrum disorder | ||
| Initial serum Mg2+(mmol/L) | NA | NA | 0.63 | 0.57 | 0.45 | 0.48 | 0.5 | 0.54 | 0.49 | 0.72 | 0.57 | ||
| Serum Mg2+ after supplementation (mmol/L) |
NA | NA | 0.65 | NA | 0.53-0.66 | NA | 0.51 | 0.52 | 0.58 | 0.7 | 0.69 | ||
| Epilepsy treatment | NA | NA | NA | NA | NA | N | NA | NA | NA | N | NA | ||
| Intellectual disability | NA | NA | Y | Y | N | Y | Y | Y | Y | Y | Y | ||
| Language impairment |
NA | NA | ELD | N | ELD | N | ELD | ELD | NA | ELD | ELD | ||
| Motor skills impairment | NA | NA | Y | Y | Y | N | Y | Y | N | Y | N | ||
| Malformation | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | ||
| Abnormal brain development | NA | NA | N | N | N | N | N | N | N | N | slightly hyperintense white matter | ||
| Mutation (DNA level) |
c.154C>T | c.2291G>A | Del ex1-4 | Del ex3-8 | c.143T>C | c.942C>G | c.961_963del | c.970G>A | c.1253T>C | c.2384C>T | c.2389C>T | ||
| Mutation (Protein level) |
p.Leu52Phe | p.Arg764Gln | NA | NA | p.Leu48Pro | p.Tyr314* | p.Leu321del | p.Val324Met | p.Leu418Pro | p.Ser795Leu | p.Arg797* | ||
| Mutational domain | Extracellular | CNBH | NA | NA | signal peptide domain | DUF21 | DUF21 | DUF21 | DUF21 | CNBH | CNBH | ||
| Zygosity | NA | NA | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | Heterozygous | ||
NA, not available; ELD, expressive language disorder; F, female; M, male.
*
no Mg2+ supplementation; Y, yes; N, no.