Multidisciplinary Consulting Team for Complicated Cases of Neurodevelopmental and Neurobehavioral Disorders: Assessing the Opportunities and Challenges of Integrating Pharmacogenomics into a Team Setting.

Neurodevelopmental disorders have steadily increased in incidence in the United States. Over the past decade, there have been significant changes in clinical diagnoses and treatments some of which are due to the increasing adoption of pharmacogenomics (PGx) by clinicians. In this pilot study, a multidisciplinary team at the Arkansas Children's Hospital North West consulted on 27 patients referred for difficult-to-manage neurodevelopmental and/or neurobehavioral disorders. The 27 patients were evaluated by the team using records review, team discussion, and pharmacogenetic testing. OneOme RightMed® (Minneapolis, MN, USA) and the Arkansas Children's Hospital comprehensive PGx test were used for drug prescribing guidance. Of the 27 patients' predicted phenotypes, the normal metabolizer was 11 (40.8%) for CYP2C19 and 16 (59.3%) for CYP2D6. For the neurodevelopmental disorders, the most common comorbid conditions included attention-deficit hyperactivity disorder (66.7%), anxiety disorder (59.3%), and autism (40.7%). Following the team assessment and PGx testing, 66.7% of the patients had actionable medication recommendations. This included continuing current therapy, suggesting an appropriate alternative medication, starting a new therapy, or adding adjunct therapy (based on their current medication use). Moreover, 25.9% of patients phenoconverted to a CYP2D6 poor metabolizer. This retrospective chart review pilot study highlights the value of a multidisciplinary treatment approach to deliver precision healthcare by improving physician clinical decisions and potentially impacting patient outcomes. It also shows the feasibility to implement PGx testing in neurodevelopmental/neurobehavioral disorders.

Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome.

Kosaki overgrowth syndrome is a recently described syndrome characterized by distinctive facial features, brain white matter lesions, and developmental delay. Germline activating heterozygous PDGFRB mutations have been reported in this condition. Systemic connective tissue-type findings have been described in some individuals. We describe a 19-year-old Caucasian female with a history of hydrocephalus, Dandy-Walker malformation, cervical spine arachnoid cyst, progressive scoliosis, and overgrowth. Her physical exam included distinctive craniofacial dysmorphism, as well as soft and hyperextensible skin. Cardiovascular imaging during adolescence revealed saccular aneurysms in both coronary artery systems and subtle tortuosity of the cervical vertebral arteries. Exome sequencing trio analysis identified a de novo previously reported pathogenic variant in PDGFRB, c.1696T>C (p.[Trp566Arg]). Further functional studies included platelet-derived growth factor cellular metabolic pathway activity that confirmed the variant causes a constitutive activation of the PI3K-AKT pathway. This is the first report to characterize the activating nature of this PDGFRB variant. We also highlight the connective tissue findings seen in Kosaki overgrowth syndrome and recommend baseline echocardiographic evaluation in all individuals with this condition with particular emphasis on coronary arteries.

The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey.

While X-linked intellectual disability (XLID) syndromes pose a diagnostic challenge for clinicians, an increasing number of recognized disorders and their genetic etiologies are providing answers for patients and their families. The availability of clinical exome sequencing is broadening the ability to identify mutations in genes previously unrecognized as causing XLID. In recent years, the IQSEC2 gene, located at Xp11.22, has emerged as the cause of multiple cases of both nonsyndromic and syndromic XLID. Herein we present a case series of six individuals (five males, one female) with intellectual disability and seizures found to have alterations in IQSEC2. In all cases, the diagnostic odyssey was extensive and expensive, often including invasive testing such as muscle biopsies, before ultimately reaching the diagnosis. We report these cases to demonstrate the exhaustive work-up prior to finding the changes in IQSEC2 gene, recommend that this gene be considered earlier in the diagnostic evaluation of individuals with global developmental delay, microcephaly, and severe, intractable epilepsy, and support the use of intellectual disability panels including IQSEC2 in the first-line evaluation of these patients.

Severe Metabolic Acidosis and Hepatopathy due to Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate.

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a recently described autosomal recessive mitochondrial disease characterized by early onset of neurological symptoms, a biphasic clinical course, and distinctive neuroimaging. Pathogenic variants in the EARS2 gene that encode for mitochondrial glutamyl-tRNA synthetase are responsible for LTBL. Here, we describe the clinical course of an infant diagnosed with an acute crisis of LTBL and severe liver disease. This article illustrates the utility of blood lactate quantification in addition to basic metabolic testing and brain imaging in a child with low tone and poor growth. In addition, this case demonstrates the utility of current genetic diagnostic testing, in lieu of more invasive procedures, in obtaining rapid answers in this very complicated group of disorders.

Cerebral Arteriopathy in a Newborn With Incontinentia Pigmenti.

BACKGROUND: Incontinentia pigmenti is a rare X-linked neurocutaneous disorder that can present in the neonatal period with seizures and encephalopathy. Brain magnetic resonance imaging and magnetic resonance angiography may reveal cerebral infarction and arteriopathy. PATIENT DESCRIPTION: We describe a neonate with the typical rash of incontinentia pigmenti along with seizures and brain magnetic resonance imaging abnormalities. RESULTS: Brain magnetic resonance imaging, magnetic resonance angiography, and magnetic resonance spectroscopy at age one week revealed chronic and acute brain injury, arteriopathy of the small and medium-sized cerebral vessels, and elevation of a lactate metabolite peak. By age six months, her magnetic resonance angiogram had normalized. At age 2.5 years, she has well-controlled complex partial seizures, global developmental delay, and residual hemiplegia. CONCLUSION: Despite extensive cerebral arteriopathy in association with incontinentia pigmenti, this girl had a relatively stable early clinical course, steady developmental progress over time, and seizures that have been well controlled. Later brain imaging revealed resolution of the arteriopathy.

Pharmacokinetics of levetiracetam in neonates with seizures.

The pharmacokinetics of levetiracetam were determined prospectively in 18 neonates with seizures. Neonates were found to have lower clearance, higher volume of distribution, and a longer half-life as compared with older children and adults. Mild somnolence was the only adverse effect.

Neurologic outcome in neonatal temporal lobe hemorrhagic venous infarcts.

Consequences of neonatal cerebral venous infarct can be severe. However, we have identified a series of neonates with unilateral temporal lobe infarcts, suspected to be secondary to superficial cortical venous thrombosis, who have had relatively normal outcomes. Medical records were reviewed retrospectively. History, relevant studies, and outcomes for 7 patients are described. Most patients presented with neonatal seizures. Neuroimaging showed unilateral temporal lobe hemorrhage and surrounding ischemic change, which was initially attributed to thrombosis of the vein of Labbe; however, magnetic resonance venogram findings suggest that thrombosis of other superficial temporal lobe veins may also be involved. Seizure control was achieved in all cases. Development and neurologic examination at follow-up were usually normal. We conclude that neonatal temporal lobe hemorrhagic infarct secondary to suspected superficial temporal venous thrombosis appears to have a good clinical outcome. This is surprising, given the dramatic imaging and clinical presentations.