Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy.

Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants genome-wide and long-range polymerase chain reaction to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCß1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

BACKGROUND AND OBJECTIVES: To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Translational research: Rett syndrome and tuberous sclerosis complex.

PURPOSE OF REVIEW: Rare genetic diseases that affect behavior and cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of animal models, which can lead to development of hypotheses and treatments testable in human beings. Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are both Mendelian disorders that present with autism, epilepsy, and intellectual disability, in which animal model work has been directly translated into clinical treatment trials currently underway. Here, we review the recent advances in our understanding of RTT and TSC pathogenesis and signaling pathways that may be targeted for novel treatments. RECENT FINDINGS: Animal models generated by engineering mutant forms of the mouse homologs of human genes involved in RTT and TSC have allowed dissection of the molecular pathology. They have further acted as in-vivo assays of potential therapeutic strategies that have translated to human clinical trials. SUMMARY: Single-gene disorders associated with neurodevelopmental disorders provide powerful model systems to study the roles of individual molecules and associated signaling pathways in the genesis of autism, epilepsy, cognitive impairment, and neuropsychiatric symptoms. These diseases are leading to disease-modifying human therapies that may eventually translate to wider therapeutic strategies for autism.

Spectrum of neurodevelopmental disabilities in children with cerebellar malformations.

AIM: Advances in perinatal care and neuroimaging techniques have increased the detection of cerebellar malformations (CBMs) in the fetus and young infant. As a result, this has necessitated a greater understanding of the neurodevelopmental consequences of CBMs on child development. The aim of this study was to delineate the impact of CBMs on long-term neurodevelopmental outcomes. METHOD: We conducted a cross-sectional study and systematically identified children with CBMs born between December 2000 and December 2006. We then performed follow-up magnetic resonance imaging studies, neurologic examination, and standardized neurodevelopmental outcome testing (Mullen Scales of Early Learning, Vineland Adaptive Behavior Scale, Child Behavior Checklist, Modified Checklist for Autism in Toddlers, and the Pediatric Quality of Life Inventory). RESULTS: Our sample comprised 49 children (29 males, 20 females; mean age, 28.4 mo, SD 16.4) with a CBM. Infants with evidence of acquired fetal or neonatal brain injury, intracranial birth trauma, inherited metabolic disease, or major pre- or postnatal cerebral ischemia were excluded. Our findings highlight that children with CBMs experience a high prevalence of neurologic, developmental, and functional disabilities including motor, cognitive, language, and social-behavioral deficits, as well as poor quality of life. The associated supratentorial anomalies, chromosomal findings, and malformations affecting the cerebellar vermis were significant independent predictors of neurodevelopmental disabilities in young children with CBMs. The associated supratentorial anomalies and chromosomal findings were also predictive of global developmental delay (p=0.01), cognitive impairment (p=0.03), gross and fine motor delay (p=0.02 and p=0.01 respectively), and positive screening for autism spectrum disorder (p=0.01). Additionally, malformations affecting the cerebellar vermis were significant independent predictors of expressive language (p=0.04) and gross motor delays (p=0.02). INTERPRETATION: Developmental surveillance and early intervention programs should be an integral part of the long-term follow-up of survivors of CBM.

How accurately does current fetal imaging identify posterior fossa anomalies?

OBJECTIVE: The first objective of our study was to describe the prevalence and spectrum of posterior fossa anomalies over 5 years in a major fetal care center where the referral diagnosis (by fetal sonography) was investigated by fetal MRI and, if confirmed, by postnatal MRI if possible. The second objective was to assess the accuracy with which fetal MRI predicts postnatal MRI findings in this population. MATERIALS AND METHODS: We retrospectively identified all cases of suspected fetal posterior fossa anomalies referred to our center from 2002 through 2006. We reviewed maternal, fetal, neonatal, and follow-up records of all cases and fetal and early postnatal imaging studies. RESULTS: Of the 90 cases of suspected fetal posterior fossa anomalies (by fetal sonography) referred over the study period, 60 (67%) were confirmed by fetal MRI. Of 42 live-born infants, 39 (93%) underwent postnatal MRI. There was complete agreement in fetal and postnatal MRI diagnoses in 23 infants (59%). In 16 cases (41%), fetal and postnatal MRI diagnoses disagreed; postnatal MRI excluded fetal MRI diagnoses in six cases (15%) and revealed additional anomalies in 10 cases (26%). CONCLUSION: Although a valuable adjunct to fetal sonography in cases of suspected posterior fossa anomaly, current fetal MRI, particularly in early gestation, has limitations in accurately predicting postnatal MRI abnormalities. Advancing the accuracy of MRI for the diagnosis of posterior fossa anomalies will require greater understanding of normal brain development and improved tissue resolution of fetal MRI. During the interim, our findings strongly support the need for postnatal MRI follow-up in cases with suspected posterior fossa anomalies by fetal MRI.

Detecting autonomic response to pain in Rett syndrome.

OBJECTIVE: To quantify pain response in girls affected by Rett syndrome (RTT) using electrodermal activity (EDA), a measure of skin conductance, reflecting sympathetic activity known to be modulated by physical and environmental stress. METHODS: EDA increase, heart rate (HR) increase and Face Legs Activity Cry Consolability (FLACC) values calculated during venipuncture (invasive) and vital signs collection (non-invasive) events were compared with values calculated during a prior baseline and a RTT clinical severity score (CSS). RESULTS: EDA and HR increase were significantly higher than baseline during venipuncture only and not significantly correlated with FLACC or CSS. EDA increase was the most sensitive measure of pain response. CONCLUSIONS: These preliminary findings revealed that motor impairment might bias non-verbal pain scales, underscore the importance of using autonomic measures when assessing pain and warrant further investigation into the utility of using EDA to objectively quantify RTT pain response to inform future RTT pain management.

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

OBJECTIVE: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. METHODS: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. RESULTS: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. CONCLUSIONS: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.

Basilar meningitis associated with ethmoid and sphenoid cephaloceles.

Nontuberculous causes of basilar meningitis are rare. This study presents the case of a male who developed fever and meningitis caused by Streptococcus pneumoniae. He developed multiple cranial nerve palsies and imaging findings consistent with basilar meningitis and ventriculitis. Computed tomographic scans of the floor of the anterior fossa were performed after the detection of a cephalocele on magnetic resonance imaging. This imaging revealed a defect in the cribiform plate and fovea ethmoidalis with a large nasoethmoidal cephalocele. There was a second separate defect and cephalocele involving the middle cranial fossa. The association of basilar meningitis with an atypical organism should lead to a careful search for disruption in the floor of the anterior or middle cranial fossa.

Monozygotic twins with trisomy 21 and partial agenesis of the corpus callosum.

Trisomy 21 is the most common viable trisomy. Although it is invariably associated with mild to severe developmental delay and intellectual disability, no gross central nervous system malformation has been consistently identified in individuals with trisomy 21. We present the case of a monozygotic twin pregnancy in which both fetuses were identified as having trisomy 21 and partial agenesis of the corpus callosum. We discuss this rare association in the context of an emerging understanding of the neurobiology of trisomy 21.

Case of infantile onset spinocerebellar ataxia type 5.

Dominant spinocerebellar ataxias are a rare clinically and genetically heterogeneous group of neurodegenerative disorders. They are characterized by progressive cerebellar ataxia resulting in unsteady gait, clumsiness, dysarthria, and swallowing difficulty. The onset of symptoms is usually in the third or fourth decade of life; however, more subtle clinical manifestations can start in early childhood. Spinocerebellar ataxia type 5, a dominant spinocerebellar ataxia associated with mutations involving ß-III spectrin (SPTBN2), has been described in 3 families. It typically consists of a slowly progressive spinocerebellar ataxia with onset in the third decade. The authors present the first case of infantile-onset spinocerebellar ataxia associated with a novel SPTBN2 mutation (transition C>T at nucleotide position 1438), the proband having a much more severe phenotype with global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia.