Summary Background Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0·604; serum, r=−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union’s Seventh Framework Programme; European Research Council.

We describe five patients from three different families with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), which was molecularly confirmed by homozygosity for the g.51G >A and g.55G >A mutations in RNU4ATAC, respectively. The patients showed the classical phenotype and demonstrated in addition variable degrees of gyration abnormalities and malformations of the callosal body with an interhemispheric cyst. One patient also showed underdevelopment of the cerebellar vermis. This confirms that cortical malformations should be considered cardinal manifestations of MOPD I. Oculocutaneous albinism, brain hemorrhage and chilblains have been found to be associated with MOPD I. The present study showed lack of retinal pigmentation in three patients of whom two had an unusually fair complexion of hair and skin. One patient was found to have a hematoma in the left thalamus. This may indicate that both pigmentary abnormalities and vascular anomalies may be part of the phenotype of MOPD I as well.

The designation microcephalic osteodysplastic primordial dwarfism (MOPD) refers to a group of autosomal recessive disorders, comprising microcephaly, growth retardation, and a skeletal dysplasia. The different types of MOPD have been delineated on the basis of clinical, radiological, and genetic criteria. We describe two brothers, born to healthy, consanguineous parents, with intrauterine and postnatal growth retardation, microcephaly with abnormal gyral pattern and partial agenesis of corpus callosum, and skeletal anomalies reminiscent of those described in MOPD type I. This was confirmed by the identification of the homozygous g.55G > A mutation of RNU4ATAC encoding U4atac snRNA. The sibs had yellowish-gray hair, fair skin, and deficient retinal pigmentation. Skin biopsy showed abnormal melanin function but OCA genes were normal. The older sib had an intracranial hemorrhage at 1 week after birth, the younger developed chilblains-like lesions at the age 2½ years old but analysis of the SAMHD1 and TREX1 genes did not show any mutations. To the best of our knowledge, vasculopathy and pigmentary disorders have not been reported in MOPD I.

IntroductionDietary control of classic phenylketonuria (PKU) needs restriction of natural proteins; adequate protein intake is achieved by adding low phenylalanine (phe) formulae. The adequacy of this diet for normal bone mineralization had not been sufficiently evaluated. Our aim was to evaluate and follow up bone mineral density (BMD) in children and adolescents with PKU within a 2-year time interval to assess the adequacy of a phenylalanine restricted diet for bone mineralization and to search for a possible relationship between BMD, dietary control and blood phenylalanine (phe) concentrations.Material and methodsThirty-two patients with classic PKU (3-19 years) were evaluated for their bone mineral status using dual energy X-ray absorptiometry (DEXA) both at the beginning (baseline) and the end (follow-up) of the study.ResultsLow BMD was detected in 31.25% at the start and in 6.25% of patients after 2 years follows-up. No relationship was found between BMD and the duration of diet compliance and phe level as well.ConclusionsIn this study the low BMD detected in our patients was both at baseline and follow-up independent of diet restriction. A yearly DEXA would be highly beneficial for early detection and treatment, thus preventing osteoporosis and decreasing the risk of fractures. We also suggest the importance of searching for new emerging therapies such as enzyme substitution or gene therapy as low protein diet compliance was not enough to maintain normal bone mineral density.

Autosomal recessive primary microcephaly (MCPH) is an abnormal proliferation of neurons during brain development that leads to a small brain size but architecturally normal in most instances. Mutations in the ASPM gene have been identified to be the most prevalent. Thirty-seven patients from 30 unrelated families with a clinical diagnosis of MCPH were enrolled in this study. Screening of ASPM gene mutations was performed by targeted linkage analysis followed by direct sequencing. Thirteen protein truncating mutations of the ASPM were identified in 15 families (50%), eight of which were novel mutations. The mutations detected were eight nonsense, four frameshift, and one splice site. Two of these mutations (p.R1327* and p.R3181*) were recurrent and shared similar haplotypes suggesting founder effect. Patients with ASPM mutations had mild to severe intellectual disability and variable degrees of simplified gyral pattern and small frontal lobe. In addition, hypoplasia of corpus callosum (18 patients), mildly small cerebellar vermis (10 patients), and relatively small pons (13 patients) were found in 85.7%, 47.6%, and 61.9%, respectively. Furthermore, one patient had porencephaly and another had a small midline cyst. Epilepsy was documented in two patients (9.5%). Non-neurologic abnormalities consisted of growth retardation (four patients), and co-incidental association of oculo-cutaneous albinism (one patient). Our study expands the mutation spectrum of ASPM. Moreover, the simplified gyral pattern and small frontal lobe together with hypoplastic corpus callosum, small cerebellum and pons enable ASPM mutated patients to be distinguished. © 2016 Wiley Periodicals, Inc.