Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect.

FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.

Frameless robot-assisted pallidal deep brain stimulation surgery in pediatric patients with movement disorders: precision and short-term clinical results.

OBJECTIVE: The purpose of this study was to verify the safety and accuracy of the Neuromate stereotactic robot for use in deep brain stimulation (DBS) electrode implantation for the treatment of hyperkinetic movement disorders in childhood and describe the authors' initial clinical results. METHODS: A prospective evaluation of pediatric patients with dystonia and other hyperkinetic movement disorders was carried out during the 1st year after the start-up of a pediatric DBS unit in Barcelona. Electrodes were implanted bilaterally in the globus pallidus internus (GPi) using the Neuromate robot without the stereotactic frame. The authors calculated the distances between the electrodes and their respective planned trajectories, merging the postoperative CT with the preoperative plan using VoXim software. Clinical outcome was monitored using validated scales for dystonia and myoclonus preoperatively and at 1 month and 6 months postoperatively and by means of a quality-of-life questionnaire for children, administered before surgery and at 6 months' follow-up. We also recorded complications derived from the implantation technique, "hardware," and stimulation. RESULTS: Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus-dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months. The average accuracy in the placement of the electrodes was 1.24 mm at the target point. At the 6-month follow-up, patients showed an improvement in the motor (65%) and functional (48%) components of the Burke-Fahn-Marsden Dystonia Rating Scale. Patients with myoclonus and SGCE mutations also showed an improvement in action myoclonus (95%-100%) and in functional tests (50%-75%) according to the Unified Motor-Rating Scale. The Neuro-QOL score revealed inconsistent results, with improvement in motor function and social relationships but worsening in anxiety, cognitive function, and pain. The only surgical complication was medial displacement of the first electrode, which limited intensity of stimulation in the lower contacts, in one case. CONCLUSIONS: The Neuromate stereotactic robot is an accurate and safe tool for the placement of GPi electrodes in children with hyperkinetic movement disorders.