Response to comments on: Diagnosis of Kearns-Sayre syndrome requires genetic confirmation

Dear Editor, We sincerely thank Josef Finsterer for showing interest in our article,[1] and we would like to give our response to his comments as follows. The diagnosis of our first patient with Kearns–Sayre syndrome (KSS) was made based on the clinical diagnostic criteria, which included age less than 20 years, progressive external ophthalmoplegia, pigmentary retinopathy, presence of heart block, and cerebellar ataxia.[2] Other conditions which may present with similar systemic symptoms such as myotonic dystrophy and myasthenia had been ruled out with relevant investigations. A muscle biopsy was advised for confirmation of diagnosis. Khambatta et al.[3] described the presenting and follow-up features of a large case series of KSS patients. In their series, only 43% patients underwent genetic testing for mitochondrial DNA (mtDNA) mutations and only 49% patients underwent muscle biopsy for confirming the diagnosis of KSS. Also, 46% of patients did not undergo genetic testing or muscle biopsy, and KSS was diagnosed based on the clinical diagnostic criteria.[3] As mentioned in our cases of KSS, family history was negative for similar complaints. In the series by Khambatta et al.,[3] none of the patients had documented family history of KSS. In general, mtDNA deletions usually occur de novo, and hence usually cause disease in only one family member;[45] this observation was made in our two patients where the family history was negative for KSS. Our second case with KSS had unrestricted ocular movements at presentation, but presented with ptosis, which is a requirement for the clinical diagnosis of KSS. However, Khambatta et al.[3] noted ptosis to be the most common presenting sign (46%) in their series, with ophthalmoplegia developing in 89% of cases on subsequent follow-up. Additionally, in our second patient with KSS, muscle biopsy was performed, which revealed the characteristic ragged red fibers on trichome staining. None of our KSS patients presented with blepharospasm, and this sign has also not been mentioned in our report on KSS patients. Both of our KSS patients did not have dystonia and clinical myotonia was ruled out in them with relevant investigations. Other than pigmentary retinopathy, our patients did not have congenital isocoria, cataract, or normal tension glaucoma. As it has been described, KSS is chronic progressive external ophthalmoplegia (CPEO) beginning before 20 years of age and is associated with retinal pigmentary degeneration and at least one of the following signs: heart block, cerebellar ataxia, and elevated cerebrospinal fluid protein concentration.[6] Both our cases had similar additional systemic findings, suggesting a diagnosis of KSS rather than pure CPEO. We agree with Josef Finsterer that KSS is caused primarily due to mtDNA deletion and transmitted exclusively from the mother via a mitochondrial pattern of inheritance. However, due to the potential for both mtDNA and nuclear DNA defects, the inheritance pattern can be maternal, autosomal recessive, or autosomal dominant.[78] Additionally, Bernal et al.[9] reported recessive inheritance in a large series of KSS patients. Nevertheless, the main feature of the first case was the asymmetric pattern of pigmentary retinopathy, which has not been previously reported in KSS. Also, phenotypic descriptions like in KSS remain useful tools for the clinicians to recognize the disease and Keeping the diagnosis of KSS may help in alerting the physician to perform a complete systemic examination including a cardiac evaluation. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.