Expanding the spectrum of clinical severity of AICA-ribosiduria: Report of two siblings with mild phenotype caused by a novel pathogenic variant in ATIC gene

5-Amino-4-imidazolecarboxamide-ribosiduria (AICA-ribosiduria) is an extremely rare inborn error of purine biosynthesis metabolism caused by pathogenic variants in ATIC gene that encodes a protein catalyzing the last steps of the de novo purine biosynthesis. To date, only six cases have been reported presenting a severe phenotype characterized by coarse facies and variable dysmorphic features, intrauterine and postnatal growth retardation, severe and early neurodevelopment delay, profound congenital visual deficit, scoliosis and, less frequently, epilepsy, aortic coarctation, chronic hepatic cytolysis, nephrocalcinosis and mild genitalia malformation. In this article, we report two new cases of AICA-ribosiduria carrying new pathogenic variants in ATIC (c.421C>T;p.Arg141Ter and c.1753A>G p.Thr585Ala) associated to a milder phenotype compared to previously reported patients. Particularly, the children showed few dysmorphic features (bulging forehead, depressed nasal bridge, and flat nasal tip), postnatal growth impairment, psychomotor delay since the second year of life, reduction of visual acuity (from mild impairment to low vision from the age of 5 years and to partial blindness from the age of 7 years) and mild hepatic dysfunctions. Scoliosis as well as epilepsy, renal involvement, or genitalia malformation were not detected. According to literature data, we found an abnormal accumulation of intermediates of de novo purine biosynthesis in the urine of both siblings. This report expands the spectrum of phenotypic severity associated to ATIC biallelic pathogenic variants and prompts the need to investigate ultra-rare causes of metabolic disorders such as AICA-ribosiduria in subjects with early neurological and sensory involvement of uncertain etiology.     

Periventricular heterotopia in a male child with USP9X missense variant

The ubiquitin-specific protease USP9X has been found to play a role in multiple aspects of neural development including processes of neuronal migrations. In males, hemizygous partial loss of function variants in USP9X lead to a clinical phenotype primarily characterized by intellectual disability, hypotonia, speech and language impairment, behavioral disturbances accompanied by additional clinical features with variable expressivity. Structural brain abnormalities are reported in all cases where neuro-imaging was performed. The most common radiological features described include hypoplasia/agenesis of the corpus callosum, widened ventricles, white matter disturbances, and cerebellar hypoplasia. Here we report a child harboring a missense variant in USP9X presenting with the classical neurodevelopmental phenotype and a previously unreported radiological picture of periventricular heterotopia. This case expands the phenotypic landscape of this emergent condition and supports the critical role of USP9X in neuronal migration processes.     

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging

Background and purpose

Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage.

Methods

In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach.

Results

Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = −0.43, p = 0.0002) and T1LV/T2LV (r = −0.37, p = 0.0004), but not with T2LV.

Conclusions

GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.     

Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients

Introduction

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects.

Methods

Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.

Results

365 patients were enrolled, and 289 patients with follow-up (age 67.7 ± 7.3 years, 237 males, mean follow-up 40 ± 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project.

Conclusions

Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization.