Angels García-Cazorla

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins

The analysis of biogenic amines (BA) and pterins in cerebrospinal fluid (CSF) is essential for the early diagnosis of neurotransmission defects in the paediatric age. Our aim was to standardize previously reported HPLC procedures for the analysis of BA and pterins in CSF and to establish reference values for a paediatric population. Samples from 127 subjects (age range 11 days to 16 years; average 3.8) were analyzed by HPLC with electrochemical and fluorescence detection. Both BA (homovanilic and 5-hydroxyindoleacetic acid) and pterins (neopterin and biopterin) concentrations in CSF showed a negative correlation with age. This finding led us to stratify reference values into six groups according to age. In conclusion, analysis of BA and pterins in CSF by HPLC procedures is a useful set of tools for the diagnosis of inborn errors of metabolism of these compounds. The establishment of reference intervals may be difficult, since there is a strong correlation between BA concentrations and the age of controls and, as a result, a large number of CSF samples from control populations would be necessary for this purpose.

Mutation Spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and Genotype–Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal‐recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One‐hundred and forty‐four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype–phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.

Development of the serotonergic cells in murine raphe nuclei and their relations with rhombomeric domains

The raphe nuclei represent the origin of central serotonergic projections. The literature distinguishes seven nuclei grouped into rostral and caudal clusters relative to the pons. The boundaries of these nuclei have not been defined precisely enough, particularly with regard to developmental units, notably hindbrain rhombomeres. We hold that a developmental point of view considering rhombomeres may explain observed differences in connectivity and function. There are twelve rhombomeres characterized by particular genetic profiles, and each develops between one and four distinct serotonergic populations. We have studied the distribution of the conventional seven raphe nuclei among these twelve units. To this aim, we correlated 5-HT-immunoreacted neurons with rhombomeric boundary landmarks in sagittal mouse brain sections at different developmental stages. Furthermore, we performed a partial genoarchitectonic analysis of the developing raphe nuclei, mapping all known serotonergic differentiation markers, and compared these results, jointly with others found in the literature, with our map of serotonin-containing populations, in order to examine regional variations in correspondence. Examples of regionally selective gene patterns were identified. As a result, we produced a rhombomeric classification of some 45 serotonergic populations, and suggested a corresponding modified terminology. Only a minor rostral part of the dorsal raphe nucleus lies in the midbrain. Some serotonergic neurons were found in rhombomere 4, contrary to the conventional assumption that it lacks such neurons. We expect that our reclassification of raphe nuclei may be useful for causal analysis of their differential molecular specification, as well as for studies of differential connectivity and function.

Analysis of Coenzyme Q10 in muscle and fibroblasts for the diagnosis of CoQ10 deficiency syndromes

OBJECTIVES To study CoQ(10) concentrations in muscle and fibroblast from 6 patients with a CoQ(10) deficiency syndrome. DESIGN AND METHODS CoQ(10) was quantified by HPLC with electrochemical detection. RESULTS Four out of the 6 cases showed muscle CoQ(10) deficiency plus a reduction of mitochondrial respiratory chain enzyme activities. All cases showed decreased CoQ(10) values in fibroblasts when compared with controls. CONCLUSIONS Biochemical study of CoQ(10) in both muscle and fibroblasts seems advisable to demonstrate the deficiency in all patients.

Mental retardation and inborn errors of metabolism

SummaryIn countries where clinical phenylketonuria is detected by newborn screening inborn errors of metabolism are rare causes of isolated mental retardation. There is no international agreement about what type of metabolic tests must be applied in patients with unspecific mental retardation. However, and although infrequent, there are a number of inborn errors of metabolism that can present in this way. Because of the high recurrence risk and the possibility of specific therapies, guidelines need to be developed and adapted to different populations. The application of a universal protocol may result in a low diagnostic performance in individual ethnic populations. Consideration of associated signs (extraneurological manifestations, psychiatric signs, autistic traits, cerebellar dysfunction, epilepsy or dysmorphic traits) greatly improves the diagnostic fulfilment.

Epilepsy and inborn errors of metabolism in children

SummaryEpilepsy is a frequent symptom in inborn errors of metabolism, with virtually no specific seizure types or EEG signatures. It is most important to look quickly for those few inborn errors of metabolism in which specific therapies such as supplementation of cofactors or diets can make all the difference. If these investigations remain negative, epilepsy has to be treated with conventional antiepileptic drugs. Still, epilepsy is a potentially treatable symptom of many inborn errors of metabolism, and optimal treatment is of great importance for patients and their families.

Mitochondrial diseases mimicking neurotransmitter defects

OBJECTIVES Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease. METHODS We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies. RESULTS The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with L-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement. CONCLUSIONS Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.

Inborn errors of metabolism and motor disturbances in children

SummaryMotor disturbances are very common in paediatric neurology. Often families can be reassured that these are just variants of normal development. However, abnormal movements can also be the hallmark of severe brain dysfunction of different and complex origins. This review concentrates on motor disturbances as frequent and important symptoms of inborn errors of metabolism. A structured diagnostic approach is developed taking into account age-dependent physiological developments and pathophysiological responses of gross and fine motor functions. A series of investigations are presented with the primary aim of early diagnosis of treatable conditions. The correct recognition and differentiation of movement disorders (ataxia, rigid akinetic syndrome (‘parkinsonism’), dystonia, athetosis, tremor, and others), spasticity, and neuromuscular disorders, requires profound neurological expertise. A high level of suspicion and close interaction between paediatric neurologists and specialists in inborn errors of metabolism are indispensable to effectively and timely identify patients in whom motor disturbances are the presenting and/or main symptom of an inborn error.

Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders.

To determine the prevalence of dopaminergic abnormalities in 1388 children with neurological disorders, and to analyse their clinical, neuroradiological, and electrophysiological characteristics.