Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report.

Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.

The Effectiveness of Compression Garments for Reducing Pain in Non-Vascular Ehlers-Danlos Syndromes: A Prospective Observational Cohort Study.

Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare® CGs during a visit to a specialist clinic (visit V0). They were followed up over 2 years with visits every 6 months (V1-V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale (VAS; 0-100 mm). Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance (Berg Balance Scale), and functional independence, amongst others. Data were analyzed for 67 patients with EDS (hypermobile: 91%; classical: 6%; kyphoscoliotic: 3%). For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 (t-tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant (p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients.

Risk-Taking Behaviors of Adult Bedridden Patients in Neurosurgery: What Could/Should We Do?

Risk-taking behaviors of adult bedridden patients in neurosurgery are frequent, however little analyzed. We aimed to estimate from the literature and our clinical experience the incidence of the different clinical pictures. Risk-taking behaviors seem to be more frequent than reported. They are often minor, but they can lead to death, irrespective of the prescription of physical or chemical constraints. We also aimed to contextualize the risks, and to describe the means reducing the consequences for the patients. Two main conditions were identified, the loss of awareness of risk-taking behaviors by the patient, and uncontrolled body motions. Besides, current experience feedback analyses and new non-exclusive technological solutions could limit the complications, while improving prevention with wearable systems, neighborhood sensors, or room monitoring and service robots. Further research is mandatory to develop efficient and reliable systems avoiding complications and saving lives. Ethical and legal issues must also be accounted for, notably concerning the privacy of patients and caregivers.

Disrupted Pallido-Thalamo-Cortical Functional Connectivity in Chronic Disorders of Consciousness.

Chronic disorders of consciousness (DOC) encompass unresponsive wakefulness syndrome and minimally conscious state. Their anatomo-functional correlates are not clearly defined yet, although impairments of functional cortical networks have been reported, as well as the implication of the thalamus and deep brain structures. However, the pallidal functional connectivity with the thalamus and the cortical networks has not been studied so far. Using resting-state functional MRI, we conducted a functional connectivity study between the pallidum, the thalamus and the cortical networks in 13 patients with chronic DOC and 19 healthy subjects. We observed in chronic DOC patients that the thalami were no longer connected to the cortical networks, nor to the pallidums. Concerning the functional connectivity of pallidums, we reported an abolition of the negative correlation with the default mode network, and of the positive correlation with the salience network. The disrupted functional connectivity observed in chronic DOC patients between subcortical structures and cortical networks could be related to the mesocircuit model. A better understanding of the DOC underlying physiopathology could provide food for thought for future therapeutic proposals.

Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

OBJECTIVE: To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. METHODS: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. RESULTS: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. CONCLUSIONS: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Deep brain stimulation in five patients with severe disorders of consciousness.

OBJECTIVE: The efficacy of deep brain stimulation in disorders of consciousness remains inconclusive. We investigated bilateral 30-Hz low-frequency stimulation designed to overdrive neuronal activity by dual pallido-thalamic targeting, using the Coma Recovery Scale Revised (CRS-R) to assess conscious behavior. METHODS: We conducted a prospective, single center, observational 11-month pilot study comprising four phases: baseline (2 months); surgery and titration (1 month); blind, random, crossover, 1.5-month ON and OFF periods; and unblinded, 5-month stimulation ON. Five adult patients were included: one unresponsive-wakefulness-syndrome male (traumatic brain injury); and four patients in a minimally conscious state, one male (traumatic brain injury) and three females (two hemorrhagic strokes and one traumatic brain injury). Primary outcome measures focused on CRS-R scores. Secondary outcome measures focused notably on baseline brain metabolism and variation in activity (stimulation ON - baseline) using normalized fluorodeoxyglucose positron emission tomography maps. Statistical analysis used random-effect models. RESULTS: The two male patients (one minimally conscious and one unresponsive wakefulness syndrome) showed improved mean CRS-R scores (stimulation ON vs. baseline), in auditory, visual and oromotor/verbal subscores, and visual subscores respectively. The metabolism of the medial cortices (low at baseline in all five patients) increased specifically in the two responders. INTERPRETATION: Our findings show there were robust but limited individual clinical benefits, mainly in visual and auditory processes. Overall modifications seem linked to the modulation of thalamo-cortico-basal and tegmental loops activating default mode network cortices. Specifically, in the two responders there was an increase in medial cortex activity related to internal awareness.

A new phenotype linked to SPG27 and refinement of the critical region on chromosome.

Hereditary spastic paraplegias are genetically and clinically heterogeneous. Twenty-six loci have been identified to date. SPG27 was recently mapped to chromosome 10 in a single family with autosomal recessive hereditary spastic paraplegia (AR-HSP) and a pure phenotype. We describe a Tunisian family with a complicated form of AR-HSP also linked to SPG27. The parents are first cousins and 3 out of their 4 children manifest early onset progressive spastic paraparesis associated with sensorimotor polyneuropathy. In addition, the eldest girl had facial dysmorphism and short stature (-3SD). Two of the three patients were mentally retarded, and one of these also had cerebellar signs. Their ages at onset were 2, 5 and 7 years. A genome-wide scan suggested linkage to SPG27 on the long arm of chromosome 10 with a multipoint lod score of 2.54. In addition, a recombination detected in this family by haplotype reconstruction reduced the SPG27 locus from 25 to 19.6 cM. This is the first clinical description of a complicated form of spastic paraplegia, characterized by great phenotypic variability among the sibs, associated with the SPG27 locus.