Manuela Casarano

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.

Treatment with l-Arginine improves neuropsychological disorders in a child with Creatine transporter defect

Creatine transporter deficit (CT1) is an inherited metabolic disorder that causes mental retardation, epilepsy, speech, language and behavioral deficits. Until now, no treatment has been proven to be successful for this condition. We describe 1-year follow-up study of a child, aged 9.6 years, with CT1 defect, on oral supplementation with l-arginine, a precursor of creatine synthesis. Under supplementation, he showed a noticeable improvement of neurological, language and behavioral status and an increase of brain creatine and phosphocreatine documented with magnetic resonance spectroscopy. The results suggest that children with CT1 disorder show some residual adaptive plasticity for certain functions even at quite an advanced age. Further trials with higher l-arginine dosages and more protracted treatment are encouraged.

Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation

We report on a 9.5‐year‐old Italian boy affected by creatine transporter deficit (CT1), due to a de novo mutation in SLC6A8 gene. The patient was investigated by means of a comprehensive neuropsychological protocol and presented with an unusual alteration of speech and expressive‐language function, associated with mental retardation, that differed from CT1 patients described to date. In particular, he exhibited a developmental apraxia of speech (DAS) with motor planning and execution deficit, while receptive language was consistent with his mental age.

Variant of rett syndrome and CDKL5 gene: Clinical and autonomic description of 10 cases

UNLABELLED Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant.

Arginine and glycine stimulate creatine synthesis in creatine transporter 1-deficient lymphoblasts.

Creatine transporter 1 (CT1) defect is an X-linked disease that causes severe neurological impairment. No treatment has been available for this condition so far. Because the transport of creatine (Cr) precursors Gly and Arg is not affected in this disorder, we tested the possible corrective effect of these two amino acids on Cr depletion in lymphoblasts lacking the transporter. Substrates enriched with Arg or Arg plus Gly increased the concentration of intracellular Cr in affected cells as well as in control cells. The greatest effect was obtained with 10 and 15 mM Arg and 10mM Arg plus Gly. These results encourage an in vivo trial with Cr precursors in CT1 defect.

Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency

BackgroundSLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain–blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial.MethodsIn this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24–36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations.ResultsDuring L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range.ConclusionThis study provides information to support the effectiveness of L-Arg supplement treatment in CTRT-D patients; in fact the syndromic pattern of cognitive and linguistic deficit presented by CRTR-D patients was partially altered by L-Arg supplementation especially at a qualitative clinical level. Oral L-Arg may represent not only a protective factor towards a further cognitive decline, but can lead to the acquisition of new skills.

Cognitive, adaptive, and behavioral features in Joubert syndrome

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so‐called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty‐four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long‐term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability.

Responsiveness of the MD-Childhood Rating Scale in dyskinetic cerebral palsy patients undergoing anticholinergic treatment

BACKGROUND Movement Disorder-Childhood Rating Scale (MD-CRS) is a new tool for assessment of movement disorders during developmental age. AIM In this study we evaluated a cohort of 47 patients affected by dyskinetic cerebral palsy and treated with anticholinergic drug (trihexyphenidyl) over one year in order to verify the responsiveness of the new scale. METHODS The participants were divided into two groups according to their age (0-3 years; 4-18 years) and were evaluated using MD-CRS 0-3 or MD-CRS 4-18 at baseline, i.e., before starting pharmacological treatment (T0), after 6 (T1) and 12 months (T2) of treatment. Univariate repeated measures ANOVA with a Greenhouse-Geisser correction was performed to analyse the scale responsiveness for the three indexes (e.g., Index I, Index II and Global Index) in each group with time (T0, T1 and T2). In addition, Bonferroni test was performed to identify the source of significant differences among means. RESULTS Significant differences were found between time points (T1 vs T0, T2 vs. T0 and T2 vs. T1) in both scales for all indexes with the exception for T2 vs. T1 for Index II in both scales and for T2 vs. T1 for the Global Index in the older age group. There was not significant correlation between observed changes in the scores and age of children, either for MD-CRS 0-3 or MD-CRS 4-18. CONCLUSIONS Our results suggest that MD-CRS is a suitable tool to detect changes and could be used as outcome measure for clinical trials. Further studies will be necessary to prove the efficacy of trihexyphenidyl for dyskinetic cerebral palsy.

Efficacy of Vigabatrin Intervention in a Mild Phenotypic Expression of Succinic Semialdehyde Dehydrogenase Deficiency

We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism presenting with heterogeneous neurological symptoms such as psychomotor delay, seizures, intellectual disability and it is characterized by increased urinary excretion of N-acetylated amino acids. We report on a new patient who presented ACY1 deficiency in association with isolated mild intellectual disability, but neither neurological symptoms nor autistic features. The child showed a compound heterozygous mutation (p.Glu233Asp) and a novel p.Ser192Arg fs*64, predicting an unstable transcript and resulting in very low protein levels.This new ACY1 deficient child was identified through regular screening for inborn error of metabolism adopted in our department in all cases of intellectual disability. This report supports a recommendation to perform metabolic investigations in patients with isolated mild intellectual disability.