A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss.

Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p.R569H, p.V617M or p.I684T missense mutation. None of these heterocompound missense mutations have previously been reported as homozygous states. Here we present the clinical features of 2 siblings with a homozygous p.I684T mutation in GLE1. The patients suffered from similar, but milder symptoms than in LCCS1 and LAAHD, surviving up to 6 months before they died due to a progressive disease course including respiratory failure. Arthrogryposis, lack of spontaneous movements, and epilepsy were notable in both cases and lack of anterior horn cells was identified in autopsy samples. Our studies on patient-derived fibroblasts show that the homozygous p.I684T impairs the nuclear localization of GLE1 further confirming the pathogenic role of this mutation.

Elevation of surfactant protein A in plasma and sputum in cigarette smokers.

Serum surfactant protein (SP)-A has been postulated to associate with pulmonary fibrosis, but its role in cigarette smoking-related lung diseases is undefined. SP-A levels in plasma and induced sputum in nonsmokers, smokers with respiratory symptoms (cough and/or phlegm) and symptom-free smokers were assessed using a validated EIA method. A total of 474 current smokers without any diseases or medications were enrolled and followed for 2 yrs with 111 of them succeeding in stopping. Plasma SP-A level was detectable in all subjects and elevated in smokers independently of the symptoms compared to nonsmokers (p = 0.001). After 2 yrs of follow-up, the SP-A level was higher in those who continued smoking compared to the quitters (p<0.001). Plasma SP-A levels were associated with age, smoking history and lung function. Sputum (n = 109) SP-A was nondetectable in most nonsmokers, whereas smoking and symptoms increased sputum SP-A highly significantly (p = 0.001). In conclusion, SP-A may be involved in pathogenesis of cigarette smoking-related lung diseases. Further studies are needed to elucidate the role of SP-A in chronic obstructive pulmonary disease.

Diminished inducible nitric oxide synthase expression in fulminant early-onset neonatal pneumonia.

OBJECTIVE: Fulminant early-onset neonatal pneumonia is associated with ascending intrauterine infection (IUI), prematurity, persistent pulmonary hypertension (PPHN), and septicemia. Nitric oxide (NO) as an inflammatory mediator is included in antimicrobial defense and has a role in pathogenesis of septic shock. The aim was to study the role of inflammatory NO in neonatal pneumonia. METHODS: Lungs from 36 autopsies were studied: 12 had fulminant early-onset neonatal pneumonia, 5 pneumonia of later onset, and 19 controls had similar gestational and postnatal age. In addition, airway specimens from 21 intubated newborns were analyzed: 7 with fulminant early-onset pneumonia, 7 apparently noninfected infants born prematurely attributable to IUI, and 7 premature infants of similar gestation. Specimens were analyzed for inducible NO synthase (NOS2) and nitrotyrosine, an indicator of NO toxicity. The degree of staining was analyzed. RESULTS: In fulminant pneumonia, alveolar macrophages (AM) showed significantly less NOS2 immunoactivity than the controls. In the airway specimens, the infants with fulminant pneumonia 0 to 2 days after birth had significantly lower intracellular NOS2 and nitrotyrosine and significantly lower interleukin-1beta and surfactant protein-A than apparently noninfected IUI infants. NOS2 and the other indices increased significantly during the recovery. CONCLUSIONS: For the first time, we report NOS2 expression by macrophages from human neonates. In fulminant early-onset neonatal pneumonia, delayed production rather than excess of pulmonary inflammatory NO is associated with severe symptoms.

Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders.

OBJECTIVES: To assess the frequency of mitochondrial abnormalities in muscle histology, defects in respiratory chain enzyme activities, and mutations in mitochondrial DNA (mtDNA) in children with unexplained psychomotor retardation in the population of Northern Finland. BACKGROUND: The frequency of mitochondrial diseases among patients with childhood encephalopathies and myopathies is not known. Frequencies are difficult to estimate because the clinical presentation of these disorders is variable. METHODS: A total of 116 consecutive patients with undefined encephalopathies and myopathies were enrolled during a 7-year period in a hospital serving as the only neurologic unit for a pediatric population of 97 609 and as the only tertiary level neurologic unit for a pediatric population of 48 873. Biochemical and morphologic investigations were performed on muscle biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, electron microscopy, and molecular analysis of mtDNA. RESULTS: Ultrastructural changes in the mitochondria were the most common finding in the muscle biopsies (71%). Ragged-red fibers were found in 4 cases. An oxidative phosphorylation defect was found in 26 children (28%), complex I (n = 15) and complex IV (n = 13) defects being the most common. Fifteen percent of patients (n = 17/116) with unexplained encephalomyopathy or myopathy had a probable mitochondrial disease. Common pathogenic mutations were found in the mtDNA of only 1 patient (.9%). CONCLUSIONS: The common known mutations in mtDNA are rarely causes of childhood encephalomyopathies, which is in contrast to the considerable frequency of the common MELAS mutation observed among adults in the same geographical area. Biochemically and morphologically verified mitochondrial disorders were nevertheless common among the children, making the analysis of a muscle biopsy very important for clinical diagnostic purposes.

Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease.

The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.

Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals.

Lethal congenital contracture syndrome (LCCS) is an autosomal recessive disease leading to death before the 32d gestational week. It is characterized by the fetal akinesia phenotype, with highly focused degeneration of motoneurons in the spinal cord as the main neuropathological finding. We report here the assignment of the LCCS locus to a defined region of chromosome 9q34, between markers D9S1825 and D9S1830. The initial genome scan was performed with the DNA samples of only five affected individuals from two unrelated LCCS families. The conventional linkage analysis performed with 20 affected individuals and their families was focused on those chromosomal regions in which the affected siblings were identical by descent in the initial scan. One core haplotype of 3 cM was observed in LCCS alleles, supporting the assumption of one major mutation underlying LCCS, and linkage disequilibrium analysis restricted the critical chromosomal region to <100 kb in the vicinity of marker D9S61. Two genes, NGAL (neutrophil gelatinase-associated lipocalin and NOTCH 1, were excluded as causative genes for LCCS

New lethal disease involving type I and III collagen defect resembling geroderma osteodysplastica, De Barsy syndrome, and Ehlers-Danlos syndrome IV.

We describe the clinical findings and biochemical features of a male child suffering from a so far undescribed lethal connective tissue disorder characterised by extreme hypermobility of the joints, lax skin, cataracts, severe growth retardation, and insufficient production of type I and type III procollagens. His features are compared with Ehlers-Danlos type IV, De Barsy syndrome, and geroderma osteodysplastica, as these disorders show some symptoms and signs shared with our patient. The child died because of failure of the connective tissue structures joining the skull and the spine, leading to progressive spinal stenosis. The aortic valve was translucent and insufficient. The clinical symptoms and signs, together with histological findings, suggested a collagen defect. Studies on both skin fibroblast cultures and the patient's serum showed reduced synthesis of collagen types I and III at the protein and RNA levels. The sizes of the mRNAs and newly synthesised proteins were normal, excluding gross structural abnormalities. These findings are not in accordance with any other collagen defect characterised so far.

Lethal arthrogryposis with anterior horn cell disease.

Fifteen infants (11 families) with lethal arthrogryposis and anterior horn motor neuron loss are described. The clinical presentation was the fetal akinesia deformation sequence (FADS) with multiple contractures and facial anomalies. At autopsy neurogenic muscular atrophy was present in all infants. The spinal cord showed a paucity of anterior horn motor neurons in the 12 infants studied. Both male and female infants were affected. Nine cases were sporadic, whereas in two families there were three affected cases. Consanguinity between the parents was reported in one family with one affected child. This and the recurrence of the condition speak for autosomal recessive inheritance. Detailed neuropathological examination and documentation of the clinical features are needed for a better delineation of and genetic counseling for perinatally lethal arthrogryposis.

Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus.

The lethal congenital contracture syndrome (LCCS) is an autosomal recessive syndrome (McKusick 253310) leading to perinatal death owing to early onset degeneration of the anterior horn motor neurones of the spinal cord. The neuropathological findings in the LCCS closely resemble those of spinal muscular atrophy (SMA). Since all the three types of SMA have been localised to the same gene locus on the long arm of chromosome 5, we analysed samples from seven families with 10 LCCS fetuses with the microsatellite markers assigned to the SMA 5q region. Linkage analyses between the SMA linked DNA markers and the disease allele in the LCCS families excluded the critical chromosomal region around the SMA locus as the critical chromosomal region for the LCCS locus.

Familial fetal akinesia deformation sequence with a skeletal muscle maturation defect.

Two female siblings with the fetal akinesia deformation sequence (FADS) are described. Both showed facial anomalies, arthrogrypotic extremities, hypoplastic lungs, and fetal growth retardation. The central nervous system of the second sibling, including the spinal cord, was normal. The skeletal muscle was studied by immunohistochemistry for the expression of several myosin heavy chain isoforms, M-band proteins and intermediate filament proteins. The skeletal muscle was immature and atypical muscle spindles containing up to 31 intrafusal fibers were found. These findings suggest that a lethal FADS phenotype may involve a maturation defect of the skeletal muscle, and, in this family, may be inherited in a recessive fashion.

Lethal arthrogryposis in Finland--a clinico-pathological study of 83 cases during thirteen years.

Eighty-three cases of multiple congenital joint contractures, i.e., arthrogryposis, which were related with either a stillborn fetus, a termination of pregnancy following prenatal diagnosis or death within 28 days postnatally, were studied. Sixty-seven cases were neurogenic in origin, including forty-one with the lethal congenital contracture syndrome (LCCS, McKusick 253310), fifteen with milder anterior horn cell involvement, and ten with dysgenesis and degeneration of the CNS. Congenital muscular dystrophy was seen in two cases and nemaline myopathy in one case. A non-neuromuscular basis was established in ten cases, and the cause remained obscure in three cases. Apart from the autosomal recessive LCCS, the fifteen cases with anterior horn cell involvement made up a uniform clinico-pathological entity. In two families this disease recurred twice, and autosomal recessive inheritance is therefore likely. Recurrence was also seen twice in a family with central nervous system degeneration and in another with the oligohydramnios sequence. There are apparently several recessively inherited entities among the arthrogryposis phenotype. A careful clinical study and a neuropathological examination are essential for estimating the recurrence risk.

Lethal congenital contracture syndrome: further delineation and genetic aspects.

In a national morphology based study of lethal arthrogryposis between 1979 and 1992, 40 fetuses and infants with lethal congenital contracture syndrome (LCCS, McKusick 253310) were found in Finland. The incidence of LCCS in Finland was 1:19,000 births. There were 20 affected males and 20 affected females in 26 families. In 16 cases the pregnancy was terminated after the prenatal diagnosis of total akinesia and fetal hydrops on ultrasound. There were 19 stillborn infants and five were born showing signs of life, but died within one hour. The segregation analyses yielded 0.45 affected by the "singles" method and 0.34 by the "sib" method. The birthplaces of the grandparents were located in the sparsely populated north east of Finland. This finding supports the existence of an autosomal recessive LCCS gene in Finland, particularly in the north eastern part.