Purpose: X-linked myotubular myopathy (XLMTM) is a rare condition of centronuclear myopathy caused by myotubularin 1 (MTM1) mutations. Patients with XLMTM show different neurodevelopmental outcomes after the neonatal period depending on age and acquired hypoxic damage. We aim to evaluate the clinical characteristics and neurodevelopmental outcomes of patients with XLMTM who were followed up at a single center. It is essential to understand the volume and conditions to prepare for being a candidate for new therapeutic strategies. Methods: Patients diagnosed with centronuclear myopathy by muscle pathology and MTM1 mutation analysis were included. We retrospectively investigated motor milestones, communication skills, and bulbar and respiratory function in the patients. The patients were categorized into two groups: with and without hypoxic insults (HI). Results: All 13 patients were severely affected by neonatal hypotonia and required respiratory support and a feeding tube during the neonatal period. The follow-up duration was 4.4 years (range, 0.3 to 8.9). In the non-HI group, developmental milestones were delayed but were slowly achieved. Some patients underwent training in oral feeding with thickened foods and weaning from ventilation. Patients with HI showed poor motor function catch-up and communication skills. Three deaths were associated with acute respiratory failure.Conclusion: Patients with XLMTM without HI can survive long-term with the slow achievement of motor milestones and bulbar and respiratory function. However, hypoxic brain damage following acute respiratory failure negatively influences their developmental potential or even lead to death. Therefore, parental education for proper respiratory management is necessary, especially for young children.
The Korean Undiagnosed Diseases Program (KUDP) was launched in January 2017 as a one-year pilot project to address the increasing global interest in patients with undiagnosed rare diseases. The purpose of this paper is to summarize the project results and emphasize the unmet research needs among patients with undiagnosed rare diseases in Korea. Patient enrollment, assessment, and diagnostic processes were determined by the KUDP clinical expert consortium. Patients followed a diagnostic workflow after being categorized into one of four groups: I) insufficient clinical information or lack of standard diagnostic processes; II) undiagnosed due to low disease awareness; III) clinically diagnosed but unconfirmed genetically due to genetic heterogeneities; or IV) unknown disease due to complex, atypical clinical presentations. After excluding two patients from group I, 97 patients were enrolled, including 10 in group II, 67 in group III, and 20 in group IV. Most of them (92 of 97, 94.8%) were pediatric patients (< 18 years old) and 59 (60.8%) were male. The primary symptoms for 80 patients (82.5%) were neurologic. During the one-year pilot study, 72 patients completed a diagnostic assessment including clinical and molecular genetic analyses; some patients also underwent pathological or biochemical analysis. Twenty-eight of these patients (28/72, 38.9%) achieved molecular genetic diagnosis. Thirteen patients were diagnosed based on traditional tests, including biochemical assay, single or targeted genetic analysis, and chromosomal microarray. We performed whole exome sequencing on 52 patients, among whom 15 (28.8%, 15/52) reached a final diagnosis. One new disorder was identified via international collaboration. Using an efficient clinical diagnostic workflow, this KUDP pilot study resulted in a fair diagnostic success rate, improving the potential for additional diagnoses and new scientific discovery of complex and rare diseases. KUDP also satisfied unmet needs for rare diseases with multisystem involvement, highlighting the value of emerging genomic technologies for further research into rare and still-undiagnosed conditions.
Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.
A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.
Seungbok Lee, Sesong Jang, Youngkyu Shim, Woo Joong Kim, Soo Yeon Kim, Anna Cho, Hunmin Kim, Jong-Il Kim, Byung Chan Lim, Hee Hwang, Jieun Choi, Ki Joong Kim, and Jong Hee Chae. J Genet Med 2019;16:67-70. https://doi.org/10.5734/JGM.2019.16.2.67
ISCA2 loss of function leads to leukodystrophy and developmental regression (multiple mitochondrial dysfunctions syndrome 4 (MMDS4)). We present a first Korean case of MMDS4 presenting with rapid developmental regression and leukodystrophy after febrile episode, mimicking post-infectious encephalitis. The patient had displayed normal development until 12 months of age. At 13 months of age, one month after experiencing a post-vaccination fever, she quickly progressed to being unable to sit unassisted nor speak any words. Analysis of the cerebrospinal fluid (CSF) revealed lympho-dominant pleocytosis. Amino acid analysis of both the serum and CSF demonstrated elevated glycine exclusively in the CSF. Diffuse leukodystrophy was noted in the brain magnetic resonance image. Whole exome sequencing revealed compound heterozygous ISCA2 variants of c.166T>G, p.C56G and c.422A>C, p.Q141P. No evidence of mitochondrial disease other than bilateral optic atrophy was noted. In cases of early onset rapid developmental regression with leukodystrophy, MMDS4 should be considered.
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