LAUSR

I read with interest the article by Pauly and colleagues about a family in which the father carried the variants c.844T>G in POLG1 and c.937G>A in CLCN1. The POLG1 variant manifested with ptosis, ophthalmoparesis, parkinsonism, and depression, and the CLCN1 variant with myotonia (myoclonic twitches and muscle cramping triggered by rapid movements or sneezing) and muscle hypertrophy. All of his 3 children carried his POLG1 variant and 1 the CLCN1 variant, but only 2 manifested clinically. The study has a number of shortcomings. Missing are the results of cerebral magnetic resonance imaging and the electroencephalogram. “Twitching” and “cramping” may not only be attributable to the CLCN1 variant but also to the POLG1 variant. POLG1 variants may manifest with myoclonic epilepsy, which needs to be excluded as it requires a completely different therapy. This is of relevance as the deceased daughter had Alpers-Huttenlocher disease, thus intractable epilepsy. Because “twitching” was triggerable, we should know if the clinical phenomenon correlated with the occurrence of myotonic discharges on needle electromyography. Because the father and his son both had myopathy of the extraocular eye muscles and POLG1 variants can also manifest with myopathy of the skeletal muscles, we should know if the father or his son had undergone muscle biopsy to see if features for a mitochondrial disorder (MID) were present or not. Missing are results of mitochondrial DNA (mtDNA) investigations. Because POLG1 variants may secondarily cause mtDNA depletion or multiple mtDNA deletions, we should know if the amount of mtDNA was reduced or if there were multiple mtDNA deletions. There is no explanation provided why the second girl did not manifest clinically from the POLG1 variant. Because MIDs frequently manifest subclinically, we should know if the girl was investigated for subclinical involvement of the brain, eyes, ears, endocrine organs, heart, intestines, or kidneys. Early detection of clinical manifestations is crucial as early treatment may improve the outcome in these patients. Assuming that the girl did not even manifest subclinically, the missing penetrance of the variant should be explained. It is conceivable that secondary damage of mtDNA was not present in this girl but only in her sister and brother. It is also not discussed why the mother of the 3 children who carried the POLG1 variant c.1399GA>A did not manifest clinically. Cardiac complications may not only derive from the CLCN1 variant but also from the POLG1 variant. Because cardiac involvement in MIDs strongly determines the outcome of these patients, it is crucial that they undergo regular follow-up investigations and long-term electrocardiogram recordings. If ventricular arrhythmias are recorded, implantation of an implantable cardioverter-defibrillator may strongly improve the survival and outcome of these patients. Cardiac surveillance is crucial in the light of the side effects of flecainide. It should be mentioned that, among the syndromic MIDs, POLG1 variants can also cause Leigh syndrome; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers; myoclonic epilepsy myopathy sensory ataxia; sensory ataxic neuropathy, dysarthria, ophthalmoparesis; and chronic progressive external ophthalmoplegia syndrome. Overall, this study has a number of shortcomings that should be addressed and considered for modifying the conclusions. Genetic findings need to be related to the clinical presentation, and factors determining phenotypic variability need to be discussed.