Neuropediatrics 2020; 51(03): 235-236
DOI: 10.1055/s-0039-3402008
Letter to the Editor
Georg Thieme Verlag KG Stuttgart · New York

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

Josef Finsterer
1   Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria
› Author Affiliations
Funding No funding was received
Further Information

Publication History

Publication Date:
30 December 2019 (online)

With interest, we read the article by Hofmeister et al about an 8-year-old female with failure-to-thrive, multiple dysmorphisms, developmental delay, intellectual disability, epilepsy, and lactic acidosis.[1] The phenotype was classified as overlap between Nicolaides–Baraitser syndrome (NCBRS) and a mitochondrial disorder (MID) due to a variant each in SMARCA2 and POLG1, respectively.[1] We have the following comments and concerns.

The main shortcoming of the study is that the authors did not delineate between phenotypic features attributable to NCBRS and those attributable to the MID. Seizures, developmental delay, intellectual disability, and dysmorphisms are attributable to either disorder. Lactic acidosis and failure to thrive have been only reported in MIDs.

Furthermore, it is unclear if the SMARCA2 variant occurred in the homozygous or heterozygous form. Accordingly, we should know if the family history was positive for any of the phenotypic features of the index case and if first-degree relatives were systematically investigated clinically and genetically. We should also know if either parent or other first-degree relatives carried either the SMARCA2 or POLG1 variant to assess if the mutations occurred spontaneously or were inherited.

There is a discrepancy between the clinical examination revealing microcephaly and the results of the cerebral computed tomography (CT) scan, which was assessed as normal. How do the authors explain this discrepancy?

Concerning the medication with antiseizure drugs (ASDs), we should know if side-effects occurred only after administration of valproic acid (VPA) or also after administration of phenobarbital (PB). From both compounds, it is well appreciated that they are potentially mitochondriontoxic.[2] Particularly from VPA, it is known that it may be hepatotoxic in patients carrying POLG1 variants and may be even fatal in this condition.[3] With regard to POLG1 variants, it has to be stressed that they may not only manifest as Alpers–Huttenlocher disease (AHS) but with a huge number phenotypically heterogeneous conditions ranging from mild to severe. Irrespective of the phenotypic expression, patients carrying POLG1 variants should not receive VPA.

MIDs are usually progressive multisystem disorders, predominantly but not only affecting the brain and the muscles but also the eyes, ears, endocrine organs, heart, kidneys, gastrointestinal tract, cartilage, immune cells, lungs, and skin. This is why the index patient should be prospectively investigated for multisystem disease, since the number of affected organs and the rate of progression may strongly determine the outcome of MID patients.

Reporting serum levels of VPA respectively PB without mentioning appropriate reference limits prevents the reader from assessing if these figures were abnormal or normal.

Overall, this highly interesting case would profit from providing an extensive family history, from prospective clinical and genetic investigations of first-degree relatives, from prospectively investigating the index case for subclinical or mildly manifesting multisystem disease, and from reporting the adherence and tolerability of all ASDs,

Author Contribution

J.F.: design, literature search, discussion, first draft.


 
  • References

  • 1 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 2019; ; (e-pub ahead of print) DOI: 10.1055/s-0039-1694976.
  • 2 Finsterer J. Toxicity of antiepileptic drugs to mitochondria. Handb Exp Pharmacol 2017; 240: 473-488
  • 3 Naess K, Barbaro M, Bruhn H. , et al. Complete deletion of a POLG1 allele in a patient with Alpers syndrome. JIMD Rep 2012; 4: 67-73