Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants.

OBJECTIVE: To provide an overview of clinical and MRI characteristics of the different variants of the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) and identify possible differentiating features. METHODS: We performed an international multi-institutional, cross-sectional observational study of the clinical and MRI characteristics in patients with genetically confirmed MLC. Clinical information was obtained by questionnaires for physicians and retrospective chart review. RESULTS: We included 204 patients with classic MLC, 187 of whom had recessive mutations in MLC1 (MLC1 variant) and 17 in GLIALCAM (MLC2A variant) and 38 patients with remitting MLC caused by dominant GLIALCAM mutations (MLC2B variant). We observed a relatively wide variability in neurologic disability among patients with classic MLC. No clinical differences could be identified between patients with MLC1 and MLC2A. Patients with MLC2B invariably had a milder phenotype with preservation of motor function, while intellectual disability and autism were relatively frequent. Systematic MRI review revealed no MRI features that distinguish between MLC1 and MLC2A. Radiologic improvement was observed in all patients with MLC2B and also in 2 patients with MLC1. In MRIs obtained in the early disease stage, absence of signal abnormalities of the posterior limb of the internal capsule and cerebellar white matter and presence of only rarefied subcortical white matter instead of true subcortical cysts were suggestive of MLC2B. CONCLUSION: Clinical and MRI features did not distinguish between classic MLC with MLC1 or GLIALCAM mutations. Absence of signal abnormalities of the internal capsule and cerebellar white matter are MRI findings that point to the remitting phenotype.

Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases.

The adult-onset Alexander disease (AOAD) dramatically differs from the early onset AD with respect to clinical and neuroradiological findings. Herein we report the detailed clinical and neuroradiological findings of a Turkish family with AOAD. In all three cases, magnetic resonance imaging revealed marked atrophy of the mesencephalon, bulbus, and cervical spinal cord accompanied with signal abnormalities in the same regions along with supratentorial white matter. Basal ganglia were affected in two cases. Molecular genetic analysis revealed heterozygous mutation in the 8th exon of the glial fibrillary acidic protein gene M451I (c.1245G>A), leading to the diagnosis of AOAD in all cases.

Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Management of a Klippel-Trenaunay syndrome in pregnant women with mega-cisterna magna and splenic and vulvar varices at birth: a case report.

Klippel-Trenaunay syndrome (KTS) is a rare, sporadic and complex malformation characterized by the clinical triad of: (i) capillary malformation (port-wine stain); (ii) soft tissue and bone hypertrophy or occasionally, hypertrophy of one lower limb; and (iii) atypical lateral varicosity. The maternal and fetal risks associated with pregnancy in women with KTS are proportional to disease severity, which can be exacerbated by pregnancy. Complications include bleeding, disseminated intravascular coagulation, thromboembolic events and pain. Here, we report the case of a pregnant woman with KTS who had an uneventful pregnancy, labor and postpartum course, but had splenic and large vulvar vein varices. The obstetrical course of women with KTS varies. Management is largely conservative and multidisciplinary approaches form the mainstay for managing these patients based on their symptoms.

Therapy-resistant leg ulcer in a patient with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare genodermatosis with characteristic skin changes such as atrophy, abnormal pigmentation and telengiectasias, skeletal abnormalities, short stature, juvenile cataract and predisposition to skin and bone malignancies. Data from the literature suggest that cutaneous findings of the syndrome include genetically programmed ageing changes and DNA repair abnormalities related to photosensitivity. Our patient is a 23-year-old male who presented with an unhealing ulcer for one and a half year on his left leg. Although he had received many various treatments, there had been no significant improvement during this period. We believe that this failure of healing might be to DNA repair abnormalities of fibroblasts. To our knowledge, this is the first case reported with coexistence of an unhealing ulcer without any findings of malignancy and RTS.

Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency.

Leigh syndrome is an inherited, progressive neurodegenerative disorder of infancy and childhood. Mutations in the nuclear SURF-1 gene are specifically associated with cytochrome C oxidase-deficient Leigh syndrome. This report describes two patients with similar facial features. One of them was a 2(1/2)-year-old male, and the other was a 3-year-old male with a mutation in SURF-1 gene and facial dysmorphism including frontal bossing, brachycephaly, hypertrichosis, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, hypertrophic gums, irregularly placed teeth, upturned nostril, low-set big ears, and retrognathi. The first patient's magnetic resonance imaging at 15 months of age indicated mild symmetric T2 prolongation involving the subthalamic nuclei. His second magnetic resonance imaging at 2 years old revealed a symmetric T2 prolongation involving the subthalamic nuclei, substantia nigra, and medulla lesions. In the second child, at the age of 2 the first magnetic resonance imaging documented heavy brainstem and subthalamic nuclei involvement. A second magnetic resonance imaging, performed when he was 3 years old, revealed diffuse involvement of the substantia nigra and hyperintense lesions of the central tegmental tract in addition to previous lesions. Facial dysmorphism and magnetic resonance imaging findings, observed in these cases, can be specific findings in Leigh syndrome patients with cytochrome C oxidase deficiency. SURF-1 gene mutations must be particularly reviewed in such patients.

The role of CYP1A1 Msp1 gene polymorphisms on lung cancer development in Turkey.

Polymorphisms for genes encoding the metabolic enzymes cytochrome P450 1A1 (CYP1A1) might contribute to the variability in individual susceptibility to lung cancer. The role of CYP1A1 in lung carcinogenesis might be more important at low levels of exposure to carcinogens. In our study, CYP1A1 gene polymorphisms were investigated in healthy subjects and lung cancer patients in Turkish population. This case-control study encompassed 31 lung cancer patients and randomly selected 37 healthy individuals in control group. DNA samples, extracted from the whole blood were amplified using polymerase chain reaction (PCR) method. The prevalence of CYP1A1 Msp1 (-/+ or +/+) polymorphism in the lung cancer patients was 19.4%, compared to 16.2% in control group but the result was not statistically significant (OR= 1.24, 95% CI= 0.36-4.32, p= 0.74). Another important result obtained in this study is that 16.2% of Turkish population carries a CYP1A1 Msp1 polymorphism. The analysis of patients by histological type of lung cancer showed no association between histopathologic type of lung cancer and CYP1A1 Msp1 polymorphism (p= 0.6). Genetic researches using specific biomarkers are expected to be helpful in monitorizing the risk of lung cancer. Multicenter cohort studies are necessary to be able to obtain reliable and correct statistical information.