Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate ...N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.
Fetal head and neck tumors Feygin, Tamara; Bilaniuk, Larissa T.
Pediatric radiology,
12/2020, Letnik:
50, Številka:
13
Journal Article
Recenzirano
Imaging plays a leading role in detection and diagnosis of fetal head and neck lesions. These lesions comprise a heterogeneous group of congenital tumors and malformations. Complementary imaging ...modalities that can be used in prenatal medicine are ultrasound and MRI. The authors discuss imaging characteristics of fetal lesions, assessment of potential complications and pregnancy management options for the most common pathology of the fetal head and neck.
Unilateral cochlear nerve deficiency in children Clemmens, Clarice S; Guidi, Jessica; Caroff, Aviva ...
Otolaryngology-head and neck surgery,
August 2013, Letnik:
149, Številka:
2
Journal Article
Recenzirano
Cochlear nerve deficiency (CND) is increasingly diagnosed in children with sensorineural hearing loss (SNHL). We sought to determine the prevalence of CND, its imaging characteristics, and ...correlations with audiologic phenotype in children with unilateral SNHL.
Case series with chart review.
Tertiary pediatric hospital.
In 128 consecutive children with unilateral SNHL who underwent high-resolution magnetic resonance imaging, the diameters, area, and signal intensity of the cochlear nerve (CN) were measured and normalized to the ipsilateral facial nerve. Presence of CND was determined by comparison to normative data. Relationships among hearing loss severity, progression, and nerve size were investigated.
Cochlear nerve deficiency was present in 26% of children with unilateral SNHL. Its prevalence was higher (48%) in severe to profound SNHL, especially when in infants (100%). Width of the bony cochlear nerve canal (BCNC) correlated strongly with relative CN diameter, density, and area (R = 0.5); furthermore, a narrow BCNC (<1.7 mm) strongly predicted CND. Severity of hearing loss modestly correlated with nerve size, although significant variability was observed. Progression never occurred unless there were other inner ear malformations, whereas in the non-CND group, it occurred in 22%. Ophthalmologic abnormalities were very common (67%) in CND children, particularly oculomotor disturbances.
Cochlear nerve deficiency is a common cause of unilateral SNHL, particularly in congenital unilateral deafness. Width of the BCNC effectively predicts CND, a finding useful when only computed tomography imaging is available. In an ear with CND, hearing can be expected to remain stable over time. Diagnosis should prompt evaluation by an ophthalmologist.
Abstract Breakdown of neuro-glial N -acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused ...by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation “oligotropic” adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase.
Imaging of Pediatric Hearing Loss Shekdar, Karuna V; Bilaniuk, Larissa T
Neuroimaging clinics of North America,
02/2019, Letnik:
29, Številka:
1
Journal Article
Recenzirano
Temporal bone high-resolution computed tomography (HRCT) and magnetic resonance (MR) imaging are valuable tools in the evaluation of pediatric hearing loss. Computed tomography is important in the ...evaluation of pediatric conductive hearing loss and is the imaging modality of choice for evaluation of osseous abnormalities. MR imaging is the modality of choice for evaluation of sensorineural hearing loss. A broad spectrum of imaging findings can be seen with hearing loss in children. HRCT and MR imaging provide complementary information and are often used in conjunction in the preoperative evaluation of pediatric candidates for cochlear implantation.
Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after ...chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.
OBJECTIVE:The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 ...(NF1)-associated optic pathway glioma (OPG) clinical trials.
METHODS:The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials.
RESULTS:Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Childrenʼs Visual Function Questionnaire as a secondary endpoint is also proposed.
CONCLUSIONS:The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.
Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000–4000 live births. Patients with 22q11.2DS have a broad spectrum of ...phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype. Methods We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals. Results and conclusions In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.
Head injury is the leading cause of death in abused children under 2 years of age. Evidence for establishing guidelines regarding screening for occult head injury in a neurologically asymptomatic ...child with other evidence of abuse is lacking. This is particularly important given that many children with acute inflicted head injury have evidence of old injury when they are diagnosed. The primary aim of this study was to estimate the prevalence of occult head injury in a high-risk sample of abused children with normal neurologic examinations. The secondary aim was to describe characteristics of this population.
Children under 2 years of age admitted to an urban children's hospital between January 1998 and December 2001 with injuries suspicious for child abuse were eligible for this study if they had a normal neurologic examination on admission. Subjects were selected if they met 1 of the following "high-risk" criteria: rib fractures, multiple fractures, facial injury, or age <6 months. Subjects were excluded if they had a history of neurologic dysfunction, seizures, respiratory arrest, or if their initial physical examination revealed scalp injury.
Of the 65 patients who met these criteria, 51 (78.5%) had a head computed tomography or magnetic resonance imaging in addition to skeletal survey. Of these 51 patients, 19 (37.3%, 95% confidence interval 24.2-50.4%) had an occult head injury. Injuries included scalp swelling (74%), skull fracture (74%), and intracranial injury (53%). All except 3 of the head-injured patients had at least a skull fracture or intracranial injury. Skeletal survey alone missed 26% (5/19) of the cases. Head-injured children were younger than non-head-injured children (median age 2.5 vs 5.1 months); all but 1 head-injured child was <1 year of age. Among the head-injured children, 72% came from single parent households, 37% had mothers whose age was <21 years, and 26% had a history of prior child welfare involvement in their families. Ophthalmologic examination was performed in 14 of the 19 cases; no retinal hemorrhages were noted.
Our results support a recommendation for universal screening in neurologically asymptomatic abused children with any of the high-risk criteria used in this study, particularly if that child is under 1 year of age. Ophthalmologic examination is a poor screening method for occult head injury, and one should proceed directly to computed tomography or magnetic resonance imaging. Given the high prevalence of occult head injury detected in this study, further study is warranted to estimate the prevalence of occult head injury in lower risk populations of abused children.
Purpose
The shape and size of the foramen magnum (FM) can be altered in craniosynostoses. However, few studies have investigated these changes. In this paper, we investigate the morphology of the ...foramen magnum in syndromic and non-syndromic brachycephaly.
Methods
Surface area, anteroposterior (AP) diameter, and transverse diameters of the FM were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre–Chotzen (7) syndromes, and isolated bicoronal synostosis (9) and compared to an age-matched control group (30).
Results
A significantly smaller FM surface area was observed in Crouzon (6.3 ± 1.7 cm
2
) and Pfeiffer (6.4 ± 2.3 cm
2
) syndromes as compared to the control group (7.4 ± 1.3 cm
2
,
p
= 0.006 and
p
= .017, respectively). In comparison to the control group, no statistically significant alteration in FM surface area was noted in patients with Apert, Saethre–Chotzen, or isolated bicoronal synostosis (
p
= 0.37,
p
= 0.71,
p
= 0.40 respectively). The transverse diameter of FM was significantly smaller in Crouzon, Pfeiffer, and Apert syndromes compared to the control group (
p
= 0.005,
p
= 0.002,
p
= 0.03 respectively). In Saethre–Chotzen and isolated bicoronal synostosis, no difference in transverse diameter was demonstrated. Among all groups, only Crouzon syndrome showed reduced anteroposterior diameter as compared to controls (
p
= 0.005). In Pfeiffer and Apert syndromes, there was elongation of the shape of the FM with a relatively narrowed width as demonstrated in a significantly increased AP to transverse diameter ratio (
p
= 0.002 and
p
= 0.019, respectively).
Discussion and conclusions
The FM shape and area is significantly altered in fibroblast growth factor receptor (FGFR)-related brachycephaly syndromes (Crouzon, Pfeiffer, and Apert), whereas in patients with Saethre–Chotzen syndrome (TWIST-1 mutation) and isolated non-syndromic bicoronal synostosis, the shape and mean FM area was not statistically different from that of normals. This study brings to light the important role of FGFRs on FM growth and shape. TWIST-1 mutation (Saethre–Chotzen syndrome) does not appear to have an important effect in shaping the FM.
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