ObjectivesTo describe clinical and genetic findings in 2 siblings with slowly progressive ataxia.MethodsWe studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause.ResultsBoth siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) inPNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function.DiscussionOur findings support the theory that biallelic loss-of-functionPNPLA8variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.
The most common mitochondrial disorder in children is Leigh syndrome, which is a progressive and genetically heterogeneous neurodegenerative disorder caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the present study, a novel and robust method of complete mtDNA sequencing, which allows amplification of the whole mitochondrial genome, was tested. Complete mtDNA sequencing was performed in a cohort of patients with suspected mitochondrial mutations. Patients from Latvia and Lithuania (n = 92 and n = 57, respectively) referred by clinical geneticists were included. The de novo point mutations m.9185T>C and m.13513G>A, respectively, were detected in two patients with lactic acidosis and neurodegenerative lesions. In one patient with neurodegenerative lesions, the mutation m.9185T>C was identified. These mutations are associated with Leigh syndrome. The present data suggest that full-length mtDNA sequencing is recommended as a supplement to nuclear gene testing and enzymatic assays to enhance mitochondrial disease diagnostics.
We report on a patient with p.Lys106Glu mutation of SOX9 gene causing acampomelic campomelic dysplasia and present comprehensive prenatal and postnatal clinical findings.A 28-year-old primigravida was referred for a first trimester scan at 14 weeks of amenorrhea. The couple was nonconsanguineous and healthy. She had neither a history of prenatal exposure to teratogenic agents nor any family history of congenital malformations. A prenatal ultrasound showed a live fetus with micrognathia, narrow thorax, bilateral renal pyelectasis (3.5 mm), grade 3 echogenic bowel, bowing of tibia and fibula (angulation of the deformity 31 degrees), and talipes equinovarus (Fig. 1A). The crown-rump length was 80.2 cm, the head circumference was 9.98 cm (37th centile), and the femur and humerus measured 1.51 cm (3rd centile) and 1.8 cm (3rd centile), respectively. Nuchal translucency thickness was 0.9 mm. Amniocentesis at 16 weeks of gestation revealed a normal female karyotype. A follow-up ultrasound at 18 weeks unexpectedly demonstrated straight tibia (Fig. 1B). The head circumference of the fetus was 14.48 cm (4th centile), and the femur and humerus measured 2.61 cm (26th centile) and 2.75 cm (66th centile). A 4D ultrasound examination at 21 weeks of gestation further demonstrated micrognathia and low set ears. Proptosis and microstomia were additionally noted at 28 weeks of gestation.After premature rupture of membranes at 38 weeks of gestation, a Caesarean section was performed. The female infant weighed 2,456 g (3rd centile), and had a head circumference of 32 cm (3rd centile), a length of 48 cm (10th centile), and Apgar scores of 6 after 1 min. and 8 after 5 min. The condition of the newborn was severe due to respiratory distress. Immediate continuous positive airway pressure was used during the first 3 hr after birth, and within the next few days the oxygen was provided via nasal cannula. Hypotonia manifested from birth. The phenotype was remarkable for a flat face, low-set ears, shallow orbits, Pierre Robin sequence, microstomia, short neck, small chest, scoliosis, congenital bilateral metatarsus varus deformities, congenital dislocation of the hips, clitoromegaly, and tracheobronchomalacia. Radiological findings included scoliosis and kyphosis of the thoracic spine, 11 pairs of ribs, abnormal cervical vertebral bodies, dysplasia of thoracic vertebrae, and no overt bending of the long bones (Fig. 1C). Further investigation such as brain and cervical spine MRI, echocardiography, and renal and abdominal ultrasound examination showed no significant abnormalities. For the correction of clubfeet, plaster casts were applied. Dislocation of the hips was treated with the Frejka pillow. The neonatal period was complicated by feeding problems and poor weight gain. Tube feeding could be terminated 1 month after birth. The girl had a few complicated respiratory infections. During the evaluation at the age of 6 months, the head circumference was 42 cm (25th centile), her weight was 4,520 g (<3rd centile), and her length was 60 cm (<3rd ...
Motivation. Our previous study showed differences in the atherosclerosis phenotype between Lithuanian and Swedish men that could be influenced by complementary factors, namely oxidation processes and/or oxidative stress. The goal of this study was to evaluate the mainstream biological pathways inducing and maintaining the atherosclerotic process by analyzing genetic biomarkers particularly in inflammatory and metabolic pathways where the main focus is laid on the oxidation process.Methods. There were 32 families recruited for the study and clinical as well as biochemical analyses were performed. For genetic analysis 150 SNPs in 89 genes were selected in order to construct a microarray based on Arrayed Primer Extension (APEX) genotyping technology. Genotyping was carried out in 28 families and transmission disequilibrium test (TDT), siblingTDT (STDT), and combined analysis were performed.Results. Clinical and biochemical analysis revealed that probands with premature CAD were more likely to have diabetes mellitus, arterial hypertension, dyslipidemia and were male with high body mass index. Genetic analysis showed six SNPs statistically significantly associated with the atherosclerosis phenotype in the candidate genes ITGA2, IL1B, ALOX5A, OR13G1, MMP9 and NFKB1. These genes belong to different biological pathways: trombocyte adhesion and vessel damage, inflammation response, cholesterol and lypoxygenase metabolic pathway and nutrition.Conclusions. Generalized clinical, biochemical, bioinformatical and candidate genes association results support our hypothesis and indicate that the oxidation process may be of key importance in the formation of atherosclerosis.
Background Kearns‐Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder characterized by onset before 20 years of age and a typical clinical triad: progressive external ophthalmoplegia, pigmentary retinopathy and cardiac conduction anomalies. In most cases KSS is caused by spontaneous heteroplasmic single large‐scale mitochondrial DNA (mtDNA) deletions. Long‐range polymerase chain reaction (LR‐PCR), next generation sequencing (NGS) and multiplex ligation‐dependent probe amplification (MLPA) are the most widely applied methods for the identification of mtDNA deletions. Here, we report the case of 20‐year‐old male who presented with classic Kearns‐Sayre syndrome, confirmed by novel 5,9 kb mtDNA deletion. Methods and results LR‐PCR and MLPA methods were applied to identify the mitochondrial DNA deletion for the patient, but the results were conflicting. Molecular analysis using primer walking and Sanger sequencing identified a novel 5888 base pairs mtDNA deletion (NC_012920.1:m.6069_11956del) with CAAC nucleotides repeat sequence at the breakpoints. Conclusion Our study enriched the mtDNA variation spectrum associated with KSS and demonstrated the importance of choosing relevant molecular genetic methods.
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