Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability.

The FOXP1 gene, located on chromosome 3p13, encodes the Forkhead-box protein P1, one of the four forkhead transcription factors which repress transcription by forming active homo- and heterodimers and regulate distinct patterns of gene expression crucial for embryogenesis and normal development. FOXP1 mutations, mostly truncating, have been described in patients with mild to moderate intellectual disability (ID), autism spectrum disorder (ASD), and speech and language impairment (MIM #613670). Here, we report a small de novo heterozygous balanced inversion of 2.1 Mb located at 3p14.1p13 identified by Whole Genomic Sequencing (WGS) and disrupting the genes FAM19A4 and FOXP1. This inversion was found in a patient with severe ID, ASD, seizures and very unusual vascular anomalies which were never described in the clinical spectrum of FOXP1 mutations. We show that the neurodevelopmental phenotype observed in the patient most likely results from FOXP1 haploinsufficiency as this heterozygous inversion leads to a 60 to 85% decrease of FOXP1 mRNA levels and to the complete absence of FOXP1 full-length protein. These findings, in addition to expanding the molecular spectrum of FOXP1 mutations, emphasize the emerging role of WGS in identifying small balanced chromosomal rearrangements responsible for neurodevelopmental disorders and not detected by conventional cytogenetics.

ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.

Hereditary sensory and autonomic neuropathies (HSAN) type II are characterized by autosomal recessive inheritance, onset at birth and self-mutilating behavior. Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia. Whole-exome sequencing showed a homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37) in ARL6IP1. The protein harbors reticulon-like short hairpin transmembrane domains and has a role in endoplasmic reticulum shaping. The variant causes an additional C-terminus hydrophobic domain which could disrupt its function. ARL6IP1 interacts with atlastin-1 responsible for SPG3A and HSAN type ID. This report highlights the role of ARL6IP1 in the pathophysiology of insensitivity to pain and spastic paraplegia.

Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.

Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.

Audiological findings in 100 USH2 patients.

Bilateral sensorineural hearing loss (HL), classically described as mild to severe with a typically down-sloping audiometric configuration, is the earliest symptom occurring in Usher syndrome type II (USH2). Audiological findings were analyzed in a total of 100 USH2 patients (92 families) divided into three groups according to the gene involved: 88 USH2A, 10 GPR98 and 2 DFNB31 patients. A fine analysis of audiograms was performed (pure tone average, degree of severity, configuration). The median age of HL diagnosis was 5 years (range 8 months-31 years) although the median age at USH2 diagnosis was 34.5 (range 8-76). Moderate HL was predominant (76%) and a gently down-sloping configuration characterized most audiograms (66%). No statistically significant difference was found between USH2A and GPR98 patients but a tendency was clearly noted for more GPR98 patients to present with severe hearing loss. It is not possible to predict the mutated gene from audiograms.

Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France?

Early onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000.

[Clozapine-resistant schizophrenia related to an increased metabolism and benefit of fluvoxamine: four case reports]. / Inefficacité de la clozapine en rapport avec un métabolisme augmenté et intérêt de la fluvoxamine: à propos de quatre cas.

OBJECTIVE: Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them. BACKGROUND: Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders. CASE-REPORTS: We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold. CONCLUSION: Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.

[Serial determination of crimidine by HPLC/SE/SM in a patient ingesting a "mouse trap"]. / Détermination sérique de la crimidine par CLHP/ES/SM chez un patient ayant ingere un "souricide foudroyant".

Crimidine (2 chloro, 4 methyl, 6 dimethyl amidopyrine) is a synthetic rodenticide which causes acute poisonings after oral ingestion in human. Major toxic effects are consciousness disorders, hypertonic coma and convulsions. Toxic level in human is about 5 mg/Kg. An intoxication case is reported. Five serums collected at different times were analyzed with HPLC/ES/MS. Crimidine was extracted with ethylacetate with recovery over 80%. Linearity was up to 800 micrograms/L. LOQ and LOD were 0.5 and 0.3 microgram/L respectively. The coefficients of variation were less than 10% for repeatability and reproductibility. Serum levels varied from 368 micrograms/L for H0 to 64 micrograms/L for H10 and elimination of crimidine was linear in time.

Determination serique de la crimidine par clhp/es/sm chez un patient ayant ingere un « souricide foudroyant ¼.

Crimidine (2 chloro, 4 methyl, 6 dimethyl amidopyrine) is a synthetic rodenticide which causes acute poisonings after oral ingestion in human. Major toxic effects are consciousness disorders, hypertonic coma and convulsions. Toxic level in human is about 5 mg/Kg. An intoxication case is reported. Five serums collected at different times were analyzed with HPLC/ ES/MS. Crimidine was extracted with ethylacetate with recovery over 80 %. Linearity was up to 800 µg/L. LOQ and LOD were 0.5 and 0.3 µg/L respectively. The coefficients of variation were less than 10 % for repeatability and reproductibility. Serum levels varied from 368 µg/L for H0 to 64 µg/L for H10 and elimination of crimidine was linear in time.