Early and Aggressive Treatment May Modify Anti-Hu Associated Encephalitis Prognosis.

Anti-Hu encephalitis is a paraneoplastic syndrome in adults. In children, rare cases of anti-Hu encephalitis were reported mostly without underlying tumors and clinical outcome are usually severe. Here, we describe a 4-year-old girl who developed cerebellar syndrome with abnormal behavior. The brain magnetic resonance imaging showed several T2/fluid-attenuated inversion recovery bilateral brain lesions and autoimmune assessment showed positive anti-Hu antibodies. Computed tomography scan revealed ganglioneuroblastoma which was surgically removed 3 months after onset. Aggressive immunotherapy including dexamethasone, rituximab, and intravenous immunoglobulins were used and a marked neurological improvement soon after 9 months of onset was observed with the child being able to go back to school. The short delay between diagnosis and start of aggressive immunotherapy demonstrate the paramount importance of early diagnosis and early specific therapy after onset of symptoms.

Recanalization Treatments for Pediatric Acute Ischemic Stroke in France.

Importance: There is to date limited evidence that revascularization strategies are associated with improved functional outcome in children with acute ischemic stroke (AIS). Objectives: To report clinical outcomes and provide estimates of revascularization strategy safety and efficacy profiles of intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) in children with AIS. Design, Setting, and Participants: The KidClot multicenter nationwide cohort study retrospectively collected data of children (neonates excluded) with AIS and recanalization treatment between January 1, 2015, and May 31, 2018. Data analysis was performed from January 1, 2015, to May 31, 2019. Exposure: IVT and/or EVT. Main Outcomes and Measures: Primary outcome was day 90 favorable outcome (modified Rankin Scale [mRs] 0-2, with 0 indicating no symptoms and 6 indicating death). Secondary end points included 1-year favorable outcome (mRs, 0-2), mortality, and symptomatic intracerebral hemorrhage. Other measures included the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), with pedNIHSS 0 indicating no symptoms, 1 to 4 corresponding to a minor stroke, 5 to 15 corresponding to a mild stroke, greater than 15 to 20: severe stroke, and the adult Alberta Stroke Program Early CT Score (ASPECTS), which provides segmental assessment of the vascular territory, with 1 point deducted from the initial score of 10 for every region involved (from 10 [no lesion] to 0 [maximum lesions]). Results: Overall, 68 children were included in 30 centers (IVT [n = 44]; EVT [n = 40]; 44 boys [64.7%]; median [IQR] age, 11 [4-16] years; anterior circulation involvement, 57 [83.8%]). Median (IQR) pedNIHSS score at admission was 13 (7-19), higher in the EVT group at 16 (IQR, 10-20) vs 9 (6-17) in the IVT only group (P < .01). Median time from stroke onset to imaging was higher in the EVT group at 3 hours and 7 minutes (IQR, 2 hours and 3 minutes to 6 hours and 24 minutes) vs 2 hours and 39 minutes (IQR, 1 hour and 51 minutes to 4 hours and 13 minutes) (P = .04). Median admission ASPECTS score was 8 (IQR, 6-9). The main stroke etiologies were cardioembolic (21 [30.9%]) and focal cerebral arteriopathy (17 [25.0%]). Median (IQR) time from stroke onset to IVT was 3 hours and 30 minutes (IQR, 2 hours and 33 minutes to 4 hours and 28 minutes). In the EVT group, the rate of postprocedure successful reperfusion (≥modified Treatment in Cerebral Infarction 2b) was 80.0% (32 of 40). Persistent proximal arterial stenosis was more frequent in focal cerebral arteriopathy (P < .01). Death occurred in 3 patients (4.4%). Median pedNIHSS reduction at 24 hours was 4 (IQR, 0-9) points. Intracerebral hemorrhage occurred in 4 patients and symptomatic intracerebral hemorrhage occurred in 1 patient, all in the EVT group. The median mRS was 2 (IQR, 0-3) at day 90 and 1 (IQR, 0-2) at 1 year, which was not significantly different between EVT and IVT only groups, although different in initial severity. Conclusions and Relevance: The findings of this cohort study suggest that use of EVT and/or IVT is safe in children with AIS.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families. METHODS: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants. RESULTS: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%). CONCLUSION: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Epidemiology, Clinical Features, and Outcome in a Cohort of Adolescents With Cerebral Venous Thrombosis.

BACKGROUND AND OBJECTIVES: We aimed to analyze the epidemiologic, clinical, and paraclinical features of adolescents with cerebral venous thrombosis (CVT) and its therapeutic management and outcome. METHODS: This multicenter retrospective cohort included patients 10 to 18 years of age hospitalized for a first episode of CVT in 2 French regions between 1999 and 2019. The number of cases was compared to the number recorded by the French health insurance system. The CVT registry of the Lariboisière hospital allowed comparisons with adults. RESULTS: One hundred two patients were included (52.9% female; median age 15.1 years). Estimated incidence was 0.37 to 0.38 per 100,000 adolescents per year; 45.5% of patients presented with focal deficits or seizures or in a coma. Male patients were younger than female patients (14.2 vs 15.6 years; p < 0.01) and more often admitted to intensive care (52.1% vs 24.1%; p = 0.0,035). The lateral sinus was the most common CVT location (72.3%), and 29.4% of adolescents had associated venous infarction or hematoma. Most patients (94.1%) received anticoagulation. Treatment also included an endovascular procedure (2.9%), decompressive craniectomy (4.9%), and CSF shunt (6.9%). The most frequently identified CVT-associated condition was local infection in male (18.6%) and systemic disease in female (14.8%; p < 0.001) patients. The proportion of CVTs in adolescents without an identified associated condition or risk factor was low (1.9% vs 11.4% in adults; p < 0.002). Adverse outcome at 1 year was more frequent than in adults (33.3% vs 11.8%; p = 0.0,001). DISCUSSION: CVT in adolescents is rare and complex with specific epidemiology, including differences in clinical presentation and associated conditions between sexes, and more severe outcomes than in adults. Careful specialized management and follow-up are therefore recommended.

Long-Term Follow-Up of Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

In 2009, cerebral adrenoleukodystrophy (c-ALD) became the first brain disease to be treated with lentiviral (LV)-based hematopoietic stem cell gene therapy with the ABCD1 gene in four boys (P1-P4) who had demyelinating lesions expected to be lethal in the short term and no bone marrow donor. We report the clinical and magnetic resonance imaging (MRI) follow-up over a mean of 8.8 years posttransplant. In parallel, vector genome copies, expression of transgenic ALD protein (ALDP), and viral integration sites were determined in peripheral blood cells. Prior to transplant, the four patients had a normal or near normal neurocognitive status but gadolinium-enhanced demyelination in various brain regions. Gadolinium diffusion disappeared during the first year posttransplant. P3 kept a near normal status until 8.3 years of follow-up, but P1, P2, and P4 showed major cognitive degradation around 9, 28, and 60 months posttransplant. Neurological status and demyelination stabilized until last evaluation in P2, but deteriorated in both P1 at 10 years and P4 at 3 years posttransplant. The proportion of myeloid and lymphoid cells expressing transgenic ALDP decreased by half within 5 years then stabilized around 5% to 10%. Integration site analysis revealed a durable polyclonal distribution of genetically corrected hematopoietic cells. No adverse effects were observed. The long-term arrest of demyelination at MRI and persistence of transduced hematopoietic progenitors support that LV gene therapy may be a safe and durable treatment of c-ALD. However, the neurological degradation observed in three out of four patients mitigates the benefit of this therapy, calling for an earlier intervention, more potent vectors, and additional therapeutic strategies.

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

OBJECTIVE: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation. METHODS: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed. RESULTS: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved (p < 0.0001 and p = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved (p = 0.0007). Severe sepsis (p = 0.011) and intensive care unit admission (p = 0.001) before LT were significantly associated with death. CONCLUSIONS: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.

Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome: An unusual presentation of anti-GFAP astrocytopathy.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare recently defined antibody-mediated encephalitis. Meningo-encephalomyelitis presentation is frequent with lymphocytic pleiocytosis in the cerebro-spinal fluid and brain MRI classically demonstrates in 50% of cases, a linear perivascular enhancement extending radially from the ventricles. Here, we describe 2 cases of pediatric autoimmune GFAP astrocytopathy with limbic encephalitis presentation and peculiar MRI characteristics: one with normal MRI and the second suggestive of Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome (MERS). These two cases illustrate that anti-GFAP antibodies should be sought in children presenting limbic encephalitis with a normal and/or MERS suggestive MRI, as treatment strategies may differ.

Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases.

AIM: To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS). METHOD: Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation. RESULTS: Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007). INTERPRETATION: This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal. WHAT THIS PAPER ADDS: Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning.

FATIGA, DEPRESIÓN Y CALIDAD DE VIDA EN NIÑOS CON ESCLEROSIS MÚLTIPLE: UN ESTUDIO COMPARATIVO CON OTRAS ENFERMEDADES DESMIELINIZANTES: OBJETIVO: evaluar fatiga, depresión y calidad de vida (CDV) de niños con esclerosis múltiple y comparar con otros síndromes desmielinizantes agudos (SDA). METODO: Se incluyeron en el estudio los niños seguidos en el centro de referencia de enfermedades espinales y cerebrales inflamatorias raras. Se usaron para la evaluación la Escala de Estado de Discapacidad Expandida, la escala de severidad de fatiga, el inventario de puntaje múltiple de depresión para niños, y el inventario de calidad de vida pediátrico. RESULTADOS: Se incluyeron en este estudio 37 niños (23 niñas, 14 niños). Se diagnosticó esclerosis múltiple en 26 niños y SDA en 11 niños. Aunque no fue significativo, la fatiga se reportó en menor frecuencia en pacientes con esclerosis múltiple que en niños con SDA (44% vs 63%, p=0,2). Se reporto con más frecuencia depresión en el grupo de esclerosis múltiple en comparación con el grupo de SDA (24% vs 18%, p=0,6). En lo que concierne a la calidad de vida en pacientes con esclerosis múltiple, tanto los padres como los niños reportaron funciones emocionales y escolares disminuidas. Las funciones físicas y sociales fueron puntuadas como buenas en ambos grupos, y fue significativamente más alta en el grupo de los niños. (p=0,007). INTERPRETACION: este estudio resalta la importancia de la fatiga y la depresión en niños con SDA y particularmente con el inicio infantil de esclerosis múltiple. Además, las dificultades en la escuela y el funcionamiento emocional fueron las principales preocupaciones de los padres y los niños en el grupo de esclerosis múltiple que deben tenerse en cuenta durante el planeamiento de atención de la salud y tratamiento.

FADIGA, DEPRESSÃO E QUALIDADE DE VIDA EM CRIANÇAS COM ESCLEROSE MÚLTIPLA: UM ESTUDO COMPARATIVO COM OUTRAS DOENÇAS DESMIELINIZANTES: OBJETIVO: Avaliar fadiga, depressão e qualidade de vida (QV) de crianças com esclerose múltipla, e comparar com outras síndromes desmielinizantes agudas (SDA). MÉTODO: Crianças acompanhadas em um centro de referência nacional de doenças inflamatórias cerebrais e espinhais raras foram incluídas no estudo. A Escala Expandidade de Estado da Deficiência, a escala de severidade da fadiga, o Inventário multiescore de depressão para crianças, e o Inventário Pediátrico de Qualidade de Vida foram usados na avaliação. RESULTADOS: Trinta e sete crianças (23 do sexo feminino, 14 do sexo masculino) foram incluídas neste estudo. A esclerose múltipla foi diagnosticada em 26 crianças e SDA em 11 crianças. Embora não significativa, a fadiga severa foi menos frequentemente reportada por pacientes com esclerose múltipla do que em crianças com SDA (44% vs 63%, p=0,2). A depressão foi reportada mais frequentemente no grupo com esclerose múltipla comparado ao grupo com SDA. (24% vs 18%, p=0,6). Com relação à QV em pacientes com esclerose múltipla, pais e crianças reportaram pobre funcionamento emocional e escolar. O funcionamento físico e social foram pontuados como bons em ambos os grupos, sendo significativamente maior no grupo de crianças (p=0,007). INTERPRETAÇÃO: Este estudo destaca a importância da fadiga e depressão em crianças com SDA e particularmente nos casos de esclerose múltipla de início pediátrico. Além disso, dificuldades no funcionamento escolar e emocional foram as principais preocupações dos pais e crianças no grupo com esclerose múltipla, o que deve ser levado em conta durante a proposta de cuidado e tratamento.

Acute ischemic stroke in adolescents.

OBJECTIVE: Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents. METHODS: This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation. RESULTS: A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40, p = 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases. CONCLUSIONS: Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe.

Functional classification of ATM variants in ataxia-telangiectasia patients.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

Regional Pediatric Acute Stroke Protocol: Initial Experience During 3 Years and 13 Recanalization Treatments in Children.

BACKGROUND AND PURPOSE: To evaluate hyperacute management of pediatric arterial ischemic stroke, setting up dedicated management pathways is the first recommended step to prove the feasibility and safety of such treatments. A regional pediatric stroke alert protocol including 2 centers in the Paris-Ile-de-France area, France, was established. METHODS: Consecutive pediatric patients (28 days-18 years) with confirmed arterial ischemic stroke who had acute recanalization treatment (intravenous r-tPA [recombinant tissue-type plasminogen activator], endovascular procedure, or both) according to the regional pediatric stroke alert were retrospectively reviewed during a 40-month period. RESULTS: Thirteen children, aged 3.7 to 16.6 years, had recanalization treatment. Median time from onset to magnetic resonance imaging was 165 minutes (150-300); 9 out of 13 had large-vessel occlusion. Intravenous r-tPA was used in 11 out of 13 patients, with median time from onset to treatment of 240 minutes (178-270). Endovascular procedure was performed in patients time-out for intravenous r-tPA (n=2) or after intravenous r-tPA inefficiency (n=2). No intracranial or peripheral bleeding was reported. One patient died of malignant stroke; outcome was favorable in 11 out of 12 survivors (modified Rankin Scale score 0-2). CONCLUSIONS: Hyperacute recanalization treatment in pediatric stroke, relying on common protocols and adult/pediatric ward collaboration, is feasible. Larger systematic case collection is encouraged.

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy.

BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.

Extracranial vertebral artery dissection in children: natural history and management.

INTRODUCTION: The objective of this study is to describe clinical and imaging presentation and outcome in extracranial vertebral artery dissection. METHODS: Single-centre retrospective study over a 14-year period included 20 consecutive patients under the age of 16 years with extracranial vertebral artery dissection. The diagnosis was based on vascular imaging performed at the acute phase and clinical symptoms. RESULTS: A male predominance was observed (sex ratio 9/1). The first symptoms consisted of headache (45%), neck pain (15%), nausea (30%) and vertigo (30%). Clinical signs leading to admission to hospital were hemiparesis (60%), visual disorders with oculomotor disorders (20%) or visual field defects (20%) and cerebellar syndrome (35%). Eight patients (40%) reported repeated transient episodes of neurological deficits, prior to the diagnosis. The segment most commonly affected was V2-V3 (50%), followed by V3 (15%) and V2 (15%), V3-V4 (10%) and proximal V4 (10%). All patients but one presented cerebral infarction. Eleven patients received first-line treatment with low molecular weight heparin (LMWH), and nine patients received aspirin. Three patients experienced a recurrence of symptoms, one under vitamin K antagonist (VKA) and 2 under aspirin. All three were switched to LMWH with success. Fifty-eight percent of the dissected arteries were occluded at long-term follow-up, although 73% of them were patent at the acute phase. CONCLUSION: Initial imaging must include posterior fossa vessels and the craniocervical region with V2-V3 segments. Conventional angiography may be indicated in the absence of a definitive diagnosis on noninvasive imaging. Healing of the dissected vertebral artery predominantly resulted in occlusion, which does not constitute a pejorative factor but indicates good quality healing.

Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.

Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.

Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.