Amber Stocco

Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. Method We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. Results The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Conclusions Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.

The spectrum of movement disorders in children with anti-NMDA receptor encephalitis.

Movement disorders are frequent but difficult to characterize in patients with anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis.

Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome

The natural history of NMDA receptor (NMDAR) antibody encephalitis in adults and children is altered by treatment with immunosuppressive therapy or tumor removal.1 In adult cohorts, early initiation of immunotherapy appears to be beneficial.1,2 In the largest series to date, Titulaer et al.1 demonstrated that earlier treatment was associated with a modified Rankin Scale (mRS) score of 2 or less in a cohort of 501 adults and children (univariate analysis p = 0.009, multivariable analysis p < 0.0001). Multivariable analysis on 177 children within the cohort showed that earlier treatment was associated with an mRS score of 2 or less, although this did not reach statistical significance (p = 0.067).1 An mRS score of 2 indicates slight disability and that the patient is unable to carry out all previous activities.

Novel mutation of the WDR45 gene causing beta-propeller protein-associated neurodegeneration

Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of disorders characterized by dysregulation of brain iron metabolism leading to accumulation of iron in the basal ganglia and substantia nigra. The causative genes for some of the core syndromes include pantothenate kinase 2 (PANK2); phospholipase A2, group VI (cytosolic, calcium-dependent) (PLA2G6,); fatty acid 2-hydroxylase (FA2H); chromosome 19 open reading frame 12 (C19orf12); ATPase type 13A2 (ATP13A2); ceruloplasmin (ferroxidase) (CP); and FNSrelated tyrosine kinase 1 (FTL1). De novo mutations in WD repeat domain 45 (WDR45) were recently described that cause static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), a subtype of NBIA. Because WDR45 encodes a beta-propeller scaffold protein, the term beta-propeller protein-associated neurodegeneration (BPAN) was suggested for this entity. We report a novel, heterozygous splice-site mutation in WDR45: c.342-2A>C. A 15 year-old girl was evaluated for intellectual disability, spastic quadriparesis, and dystonia. At age 2 years, she had presented with global developmental delay and spastic quadriparesis. An initial evaluation, including karyotype and metabolic tests, was normal; but brain magnetic resonance imaging (MRI) showed delayed myelination with a hint of cerebral atrophy. She later developed seizures. At age 13 years, she developed generalized dystonia, and repeat brain MRI images showed T2 hypointensities in the globus pallidus, substantia nigra, and red nucleus in addition to cerebral and cerebellar atrophy and hypomyelination (Fig. 1). The respective areas were faintly hyperintense on the T1-weighted images. These findings are now recognized as characteristic for BPAN. In addition, there was bilateral hippocampal sclerosis. Sequence analysis of the PANK2, PLA2G6, and FAH2 genes; chromosome microarray analysis; and mitochondrial genome next-generation sequencing were normal. Whole-exome sequencing identified a novel, de novo splice site mutation, c.342-2A>C, in WDR45. As seen in our patient, BPAN is characterized by global developmental delay, which is static until adolescence or early adulthood, when there is sudden, rapidly progressive onset of parkinsonism, dystonia, and cognitive decline. Epilepsy (either focal or generalized) has been reported in half of patients with WDR45 mutations. Eye movement abnormalities, including supranuclear gaze palsy, can be present in patients with SENDA and other NBIA disorders. Our patient had mild bilateral optic atrophy, which has been described in NBIA type 2 (caused by mutations in PLA2G6) and mitochondrial membrane-associated neurodegeneration, but this is the first report within the subgroup of BPAN. The same applies to the bilateral sensory neural hearing loss seen in our patient. Other comorbidities reported with BPAN are sleep disorders, psychiatric disorders, and stereotypies. Our patient was started on carbidopa/levodopa (L-dopa), which seemed to help with her dystonia. Many drugs, including dopaminergic agents, tetrabenazine, and anticholinergics, have been used for NBIA disorders with some symptom relief but do not halt neurodegeneration. Unfortunately, the effect of carbidopa/L-dopa in BPAN is usually short-lived. Deep-brain stimulation has some benefit in individuals cases of NBIA but has not been reported in patients with BPAN. With a better understanding of the role of beta-propeller scaffold protein in autophagy and neurodegeneration, newer therapeutic interventions may arise. In summary, BPAN is a distinct group of NBIA with characteristic clinical and MRI findings. Testing for WDR45 mutations may help find a definitive diagnosis in patients with NBIA that previously was considered idiopathic. FIG. 1. This image shows bilateral, symmetric, hypointense, T2/gradient-echo signal in the globus pallidus. Diffuse hypomyelination of the peripheral subcortical fibers also is noted bilaterally.

Medullary sponge kidney and urinary calculi: aeromedical concerns.

Medullary sponge kidney (MSK) is a benign disorder associated with a lifetime risk of renal stones in 60% of patients. Patients frequently have episodic painless hematuria, but are often otherwise asymptomatic unless renal calculi or infections complicate the disease. Nephrolithiasis is a relative, but frequently enforced, contraindication to space or other high-performance flight. Two case reports of asymptomatic NASA flight crew with MSK and three cases of United States Air Force (USAF) military aviators diagnosed with MSK are reviewed. All cases resulted in waiver and return to flight status after treatment and a vigorous followup and prophylaxis protocol. MSK in aviation and spaceflight necessitates case-by-case evaluation and treatment to rule out other potential confounding factors that might also contribute to stone formation and in order to requalify the aviator for flight duties.