| LETTER TO THE EDITOR |
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Krankenanstalt Rudolfstiftung, Vienna, Austria
Corresponding Author: Finsterer J, MD, PhD, Postfach 20, 1180 Vienna, Austria, Europe. Tel: +43-1-71165-92085; Fax: +43-1-4781711; E-mail: fipaps@yahoo.de.
Note: Williams-Beuren syndrome diagnostics
Author contribution: JF: design, literature search, discussion, first draft.
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INTRODUCTION |
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ABSTRACT
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KEY WORDS:
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INTRODUCTION |
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In a recent article about the phenotypic variability of 238 adults carrying the tRNA(Leu) variant m.3243A>G Pickett et al. found indications for nuclear factors influencing the phenotype (1). We have the following comments and concerns.
The main disadvantage of the study is that many of the evaluated clinical items overlap. Stroke-like episodes (SLEs) may manifest as seizures, migraine, migraine-like headache, confusion, cognitive impairment, psychiatric disease, or dysarthria (2). Thus, it is unclear in how many of the included patients “psychiatric involvement”, “cognition”, “seizures”, “migraine”, “dysphonia-dysarthria”, was a manifestation of a SLE and in how many it was independent of a SLE. Precisely, how often were these manifestations erroneously counted several times?
A further possible overlap concerns patients with diabetes and neuropathy. Diabetes frequently goes along with length dependent polyneuropathy, why it should be clearly delineated in how many of the patients with neuropathy diabetes was causative. It is well established that neuropathy may be primary in patients with a mitochondrial disorder (MID), occurring in the absence of any of the classical risk factors (3).
A further point concerns the use of the term “encephalopathy” (1). Encephalopathy simply means cerebral disease. Thus, all cerebral manifestations of a MID (epilepsy, SLEs, spasticity, ataxia, extrapyramidal abnormalities, psychiatric disease, cognitive impairment, migraine, migraine-like headache, pituitary adenoma, hypotonia, respiratory insufficiency) can be classified as “encephalopathy”. Thus, it should be mentioned how many of the patients with “encephalopathy” also fall into any other of the CNS disease categories.
Missing is also the distinction between dysarthria due to cerebellar atrophy and dysarthria due to brain stem, supra-tentorial, smooth muscle, or due to cranial neve involvement. How many of the patients were assigned to more than one clinical item?
It should be also specified what is meant by “visual acuity”. Causes of reduced visual acuity in MIDs are heterogeneous and include cortical or subcortical lesions, optic nerve atrophy, retinal dystrophy, or a cataract. How many of the included patients had visual impairment due to a central nervous system and how many due an ophthalmologic problem?
Explanation is required for the finding that seizures did not increase in frequency with increasing age (1). In most cohort studies epilepsy shows a bimodal prevalence with a peak in young and a second peak in old age groups (4). For how long were patients with epilepsy due to the m.3243A>G followed-up?
A further point that needs to be addressed is the frequency of de novo mutations. In a previous study of 48 families, the m.3243A>G variant occurred de novo in three of these families (5). Since de novo patients develop a more severe phenotype than patients who inherited the variant (5), we should be informed about the number of patients with a de novo mutation.
A final concern regards heteroplasmy rates in blood lymphocytes, which do not correlate with disease severity. Thus, estimates of the proportion of trait variance due to covariates may be misleading.
As long as the basic figures from which statistic calculations were made, are questionable, results need to be interpreted cautiously. In addition to nuclear factors, haplotype and mtDNA polymorphism may additionally contribute to the phenotypic heterogeneity of the m.3243A>G variant.
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