Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

Exploring Autoimmunity in a Cohort of Children with Genetically Confirmed Aicardi-Goutières Syndrome.

PURPOSE: The purpose of this study was to explore the presence of autoimmune manifestations and characterize the autoantibody production in a cohort of patients with Aicardi-Goutières syndrome (AGS). METHODS: Seventeen patients with a genetically-confirmed diagnosis of AGS were recruited. At the time of enrollment, past medical and family history was reviewed, looking for possible signs or symptoms of autoimmune disorders. Blood samples were taken, for the detection of a panel of autoantibodies: anti-nuclear, anti-double-stranded-DNA, anti-nucleosome, anti-extractable nuclear antigens, anti-cardiolipin IgG/IgM, anti-ß2glycoprotein I IgG/IgM, and anti-neutrophil cytoplasmic. We also measured complement levels determined as C3 and C4 quantification and total complement activity, measured as CH50. RESULTS: Nine of seventeen patients presented with at least one first- or second-degree relative with a history of autoimmune diseases (the childrens' mother or grand-mother in the majority of cases). A specific autoimmune disease was present in only one AGS patient, namely an autoimmune thyroiditis. Autoantibodies were present in 9/17 patients, with different patterns of positivity. Complement levels were normal in all the patients. There was no correlation between auto-antibody production and personal or family history of autoimmune diseases. CONCLUSIONS: Definite autoimmune diseases are not common in patients with AGS. Autoantibodies are mainly directed towards nucleic acids-containing elements but seem not to be pathogenic and, rather, may represent an epiphenomenon of the enhanced interferon production.

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

A new self-report quality of life questionnaire for children with neuromuscular disorders: presentation of the instrument, rationale for its development, and some preliminary results.

Improvement of quality of life in neuromuscular disorders is a primary objective, both in management of affected children and in the context of therapeutic trials. Quality of life is a subjective concept and it is crucial to gather information directly from patients. We created the SOLE Questionnaire for NMDs, a new instrument designed to investigate quality of life in children with neuromuscular disorders, and tested it in a study population of 78 patients and in 81 healthy children aged 5 to 13 years. The SOLE Questionnaire, characterized by a visual and neutral approach, was well received, practical, rapid to administer, and able to discriminate between patients and controls. We also confirmed the presence of disagreement about children's quality of life between children and their parents. We suggest that our new approach could help to improve understanding of quality of life in children with neuromuscular disorders.

Novel hypomyelinating leukoencephalopathy affecting early myelinating structures: clinical course in two brothers.

A novel leukoencephalopathy, termed hypomyelinating leukoencephalopathy affecting early myelinating structures (HEMS), was recently described. Here we report on two patients affected by HEMS with a clinical picture characterized by early-onset nystagmus and thereafter progressive cerebellar signs and mild spasticity predominantly affecting the legs. In one patient, who has the longest follow-up described to date, we detected a mild worsening of the clinical and neuroradiologic picture after a long period of stability lasting until age 6 years. The most recent magnetic resonance image, performed at the age of 11 years, showed a more severe neuroradiologic picture characterized by involvement of almost the entire supratentorial white matter, with relative sparing of the subcortical fibers. We also provide spectroscopy results, not previously reported in this disorder, that support the idea of a progressive disease course on neuroimaging. Our findings suggest that HEMS patients should undergo a new magnetic resonance imaging evaluation after a certain interval to look for possible progression of the abnormalities.

Outcome of extremely low birth weight infants: what's new in the third millennium? Neuropsychological profiles at four years.

BACKGROUND: Extremely low birth weight (ELBW) infants, even those not presenting severe neuromotor sequelae, continue to be at risk of developing multiple, complex disorders involving the cognitive, emotional and behavioural domains. Follow-up protocols are able, in the short term, to identify subjects at risk of developing major sequelae, however they fail to identify all children at risk of developing disorders. AIMS: To investigate the cognitive, neuropsychological and behavioural outcomes of a sample of ELBW children at the age of four years in order to identify characteristic profiles. STUDY DESIGN: Longitudinal study. SUBJECTS: 16 healthy ELBW children born in 2005 and followed up until the age of four. OUTCOME MEASURE: Performances on standardised tests evaluating intelligence, memory, cognitive visual functions, attention, and executive functions. RESULTS: General intelligence was within normal range. Cognitive profile showed mild or moderate deficits with different levels of involvement in many of the examined functions, in particular executive functions, attention and naming. CONCLUSION: There emerged a wide-ranging spectrum of weaknesses and deficits involving all the functions examined, which together give rise to a dysexecutive syndrome. Analysis of cognitive profiles showed that the sample could be divided into two subgroups of subjects that differ in the quality of their global cognitive and behavioural functioning. Our results confirm the need to continue follow up of ELBW children until school age, as this will allow early detection of at-risk children and the planning of timely preventive interventions.

Sleep disturbances in visually impaired toddlers.

OBJECTIVE: This study set out to describe sleep patterns in visually impaired (VI) children during the first 40 months of life compared to typically developing children. We also evaluated the influence of age, sex and the presence of other disabilities on sleep patterns. PATIENTS AND METHODS: A sleep questionnaire was administered to 154 parents of 10- to 39-month-old children: 36 with visual impairment without associated disability; 68 with visual impairment and associated disabilities (cortical visual impairment); and 50 healthy controls. The groups were balanced by age and gender. The questionnaire was developed at the C. Mondino Institute of Neurology in Pavia, Italy with the aim of investigating sleep patterns and medical history. RESULTS: Within the VI sample, sleep behaviour was not related to the presence of associated disabilities. Visually impaired children had higher sleep disturbance scores than healthy controls using the Richman Criteria. VI children took longer to fall asleep, and their nocturnal awakenings were longer, more frequent per night, and affected more nights per week compared to the controls. CONCLUSIONS: The results of this study show that the sleep of VI children is characterized by increased difficulty in falling asleep and in sleeping through the night, compared with that of their healthy peers. These findings confirm those of other important studies on sleep in VI children and underline the importance of evaluating and taking into account sleep-wake cycle in the care of the VI child.