Response To: Overlapping Phenotype from Double Trouble SMARCA2 and POLG1 Variants c.2556A > C and c.3708G > T, Respectively

Overlapping Phenotype from Double Trouble SMARCA2 and POLG1 Variants c.2556A > C and c.3708G > T, Respectively

We thank Prof. Finsterer[1] for the interest in our case report[2] and his valuable comments. The patient we described is part of the doctoral thesis of Benedikt Hofmeister at the Ludwig Maximilian University Munich describing in detail 25 patients with Nicolaides–Baraitser syndrome (NBS) with proven SMARCA2 mutations. A paper about this 25 patients with a review of the literature focusing on epilepsy is in preparation for Neuropediatrics.

We have no doubt that our patient's dysmorphisms, the developmental delay and the course of the epilepsy before VPA treatment is characteristic for a NBS, as it is in line with the phenotype of other NBS patients of our cohort and the one's reported in the literature.[3] A hepatotoxcitiy, nearly fatal in our patient after initiation of VPA, was not observed in any of the other 12 of 20 NBS patients treated with VPA or is described in the literature.

The family history of the patient is negative for epilepsy, mental retardation, or any other characteristic symptom for NBS or a mitochondrial disorder (MID). The SMARCA2 variant occurred de novo, the mother was negative for this mutation, and the father could not be analyzed but is clinically and phenotypically normal. Concerning the POLG1 variant, the parents were not analyzed due to lack of cost coverage. Further genetic investigations in the larger family were not performed as they had inconspicuous phenotypes.

In our article, approximately 25 patients with NBS we will highlight that magnetic resonance imaging (MRI) is nearly almost normal, showing unsignificant findings, like macrocrania, microcephaly, dolichocephaly, and a retrocerebellar accentuation of the cisterna cerebellomedullaris only in four patients, despite the severe dsymorphic signs including microcephaly in NBS. Also electroencephalogram (EEG) investigations and seizure semiology did not show focal but generalized characteristics.

Our index patient (now aged 13 years) did not show subclinical or mildly manifesting multisystem MID symptoms in the long-term follow-up. A new MRI 7 years after the first one, which was reported in the case report, showed further unspecific reduction in brain volume and the microcephaly was proportional to the failure to thrive and the small stature.

The further course of treatment with phenobarbital (PB) was well tolerated without any clinical or laboratory findings for a liver dsyfunction even in high doses and serum levels of 35 mg/mL (normal range: 15–40 mg/L) so that we attribute the hepatotoxicity to the therapy with VPA even though the serum level of VPA 39.6 mg/L was below the therapeutic range (normal range: 50–100 mg/L).

Overall, we think that our patient has a typical NBS due to a de novo SMARCA2 mutation (c.2556A > C; p.Glu852Asp) and the nearly fatal hepatotoxicity after initiation of VPA is most likely explained by the POLG variant. Our case report might contribute to the discussion if POLG mutations should be included in the genetic testing in a patient with dsymorphic signs and epilepsy, before starting a therapy with VPA.

Publication History

Article published online:
28 May 2020

• References

• 1 Finsterer J. Overlapping phenotype from double trouble SMARCA2 and POLG1 variants c.2556A > C and c.3708G > T, respectively. Neuropediatrics 2019
• 2 Hofmeister B, von Stülpnagel C, Berweck S, Abicht A, Kluger G, Weber P. Cooccurrence of two different genetic diseases: a case of valproic acid hepatotoxicity in Nicolaides-Baraitser syndrome (SMARCA2 mutation)-due to a POLG1-related effect?. Neuropediatrics 2020; 51 (01) 49-52
• 3 Sousa SB, Hennekam RC. Nicolaides-Baraitser Syndrome International Consortium. Phenotype and genotype in Nicolaides-Baraitser syndrome. Am J Med Genet C Semin Med Genet 2014; 166C [phone]