NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction.

Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas.

We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma.

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort.

[Lobotomy].

Lobotomy was the first psychosurgical method which aroused interest. It was developed by António Egas Moniz in 1935. Lobotomy was understood to be a promising treatment in schizophrenia and in 1940-ies and -50-ies about 1600 patients were operated in Finland.

Cord blood chemokines differentiate between spontaneous and elective preterm births in singleton pregnancies.

Background: Signals originating from both maternal and fetal compartments participate in the preterm labor process.

Objective: To investigate whether cord blood immunoproteins predict spontaneous preterm labor.

Methods: Cord blood from 125 very preterm (gestational age <32weeks) singleton infants and 33 term infants was collected after birth and analyzed for 107 immunoproteins on microarrays.

Chemokine CCL18 predicts intraventricular hemorrhage in very preterm infants.

Background: Intraventricular hemorrhage (IVH) in very preterm infants is a common disease associated with long-term consequences. Risk factors of IVH remain to be further defined.

Aims: To determine whether specific immunoproteins at birth predict the risk of IVH and whether their receptors are localized at the bleeding site.

[Abdominal pregnancy].

Abdominal pregnancy is a rare form of ectopic pregnancy with potentially life-threatening complications both to mother and the fetus. Due to infrequency of abdominal pregnancy, it is often unsuspected and remains a diagnostic challenge despite improvements in imaging techniques. We report a case of advanced abdominal pregnancy after in vitro-fertilization.

No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. Cutaneous and uterine leiomyomas are the most common clinical manifestations of HLRCC, whereas only approximately 20% of the families display renal cell cancer (RCC). The number of RCC cases in these families varies from one to five.

Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome with cutaneous and uterine leiomyomatosis as well as renal cell cancer (RCC) as its clinical manifestations. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (fumarase) gene. In this study, we used array comparative genomic hybridization to identify the specific copy number changes characterizing the HLRCC-associated RCCs.

Digenic mutations in severe myoclonic epilepsy of infancy.

The clinical features of severe myoclonic epilepsy of infancy (SMEI) resemble those of mitochondrial diseases, although most patients have the sodium channel (SCN1A) mutation. We describe a patient with SMEI and enlarged muscle mitochondria associated with mutations in mitochondrial polymerase gamma 1 (POLG1) and SCN1A. Due to increased risk of valproate-induced liver failure in patients with POLG1 mutations, we recommend POLG1 gene analysis for SMEI patients before valproate administration.

Radiation-induced meningiomas: a shadow in the success story of childhood leukemia.

While the prognosis of acute childhood leukemia has improved, long-term survivors are increasingly experiencing late effects of the treatment. Cranially irradiated survivors are predisposed to the development of CNS tumors. Our aim was to describe the incidence of secondary brain tumors and to define the significance of treatment-related risk factors and host characteristics in a cohort of childhood leukemia survivors.

Cord immunoproteins as predictors of respiratory outcome in preterm infants.

Objective: The purpose of this study was to evaluate the role of cord blood proteins and antenatal factors in the prediction of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD).

Study Design: The prospectively collected cohort included 163 infants. All infants were born between 1998-2002 in a single regional hospital before 32 weeks of gestation and survived the first hospitalization.

Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome.

Mitochondrial DNA depletion syndrome (MDS) is a severe recessively inherited disease of childhood. It manifests most often in infancy, is rapidly progressive and leads to early death. MDS is caused by an increasing number of nuclear genes leading to multisystemic or tissue-specific decrease in mitochondrial DNA (mtDNA) copy number.

Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia.

Objective: To evaluate the influence of chorioamnionitis (CA) on plasma cytokines and the cytokine-associated risk of bronchopulmonary dysplasia (BPD) during the perinatal period.

Study Design: Eleven cytokines from 128 very low gestational age infants were analyzed from cord blood and from plasma at ages 1 day and 7 days after birth. The diagnosis of CA was based on histology of the placenta, fetal membranes, and umbilical cord.

Hydrolethalus syndrome: neuropathology of 21 cases confirmed by HYLS1 gene mutation analysis.

Hydrolethalus syndrome is a lethal malformation syndrome with a severe brain malformation, most often hydrocephaly and absent midline structures. Other frequent findings are micrognathia, polydactyly, and defective lobation of the lungs. Hydrolethalus syndrome is inherited in an autosomal recessive manner and is caused by a missense mutation in the HYLS1 gene.

Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome predisposing to cutaneous and uterine leiomyomatosis as well as renal cell cancer and uterine leiomyosarcoma. Heterozygous germline mutations in the fumarate hydratase (FH, fumarase) gene are known to cause HLRCC. On occasion, no FH mutation is detected by direct sequencing, despite the evident HLRCC phenotype in a family.

Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus.

Purpose: Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile-onset Alpers-Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers.

Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.

Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.

Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA). We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement. The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases.

Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability.

Germline mutations in nuclear genes encoding mitochondrial enzymes fumarate hydratase (FH) and succinate dehydrogenase (subunits SDHB/C/D) have been implicated in the development of tumor syndromes referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL), respectively. FH and SDH are operating in the tricarboxylic acid cycle (the TCA cycle, the Krebs cycle). In the FH and SDH deficient tumors, accumulation of the substrates, fumarate and succinate, has been shown to cause stabilization of hypoxia inducible factor 1 alpha (HIF1 alpha).

Expression and localization of SWAP-70 in human fetomaternal interface and placenta during tubal pregnancy and normal placentation.

SWAP-70 has been demonstrated as a multiple functional signaling protein involved in formation of membrane ruffling induced by signal cascade of tyrosine kinase growth factor receptors. In the present study, the spatial and temporal expression pattern of SWAP-70 on human fetomaternal interface was investigated using specimens collected from tubal and normal pregnancies by in situ hybridization, immunohistochemistry, and Western blotting. Data showed an intense expression of SWAP-70 in trophoblasts at weeks 3-6 of fallopian implantation and at weeks 6-7 of normal pregnancy.

Conventional renal cancer in a patient with fumarate hydratase mutation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by mutations in the fumarate hydratase (FH) gene. HLRCC is characterized by uterine and cutaneous leiomyomas, renal cell cancer, and uterine leiomyosarcoma. Typically, renal cell cancers in HLRCC are unilateral and display a papillary type 2 or ductal histology.

Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland--an epidemiological study.

Arthrogryposis multiplex congenita is a heterogeneous group of disorders characterized by multiple contractures with an estimated frequency of 1 in 3,000 births. With improving diagnostic methods, increasing numbers of fetuses with arthrogryposis are found. The pathogenetic mechanisms are relatively well known but the epidemiology and genetics of the prenatally lethal forms of arthrogryposis are less well known.