Limitations of Multigene Next-Generation Sequencing Panel for "Cerebral Palsy" Phenotype and Other Complex Movement Disorders.

In the past couple of decades, literature in pediatric neurology and clinical genetics has identified hundreds of monogenic disorders that can masquerade as infantile cerebral palsy (CP). Accurate and prompt diagnosis in such cases may be challenging due to several reasons. There are commercial multigene CP panels, but their diagnostic yield is often limited compared with exome sequencing because of diverse etiologies that may mimic CP. We report one such case where a patient with spastic hemiplegia underwent a long diagnostic journey before genetic diagnosis was established with exome sequencing and appropriate management was started. TTC19-related mitochondrial complex III deficiency is an ultrarare disorder of energy metabolism that presents with bilateral lesions in the basal ganglia and a degenerative neuropsychiatric phenotype.

KCNN2 Mutation in Pediatric Tremor Myoclonus Dystonia Syndrome with Electrophysiological Evaluation.

BACKGROUND: Here we combine clinical, electrophysiological, and genetic findings to phenotype an unusual childhood movement disorder in a patient with a rare form of KCNN2 mutation. CASE REPORT: A 10-year-old male presented with a clinical syndrome of tremor and myoclonus. Electrophysiology demonstrated muscle activity indicative of myoclonus dystonia, an observation that was not appreciated clinically. Genetic testing revealed an abnormality in the KCNN 2 gene, not present in the parents, known to cause dystonia, as the etiology. DISCUSSION: The value of utilizing noninvasive, electrophysiological recording in pediatric movement disorders expands the precision of diagnosis, potentially informing treatment when correlated with clinical and genetic findings.

Considerations in deep brain stimulation (DBS) for pediatric secondary dystonia.

PURPOSE: There is a paucity of effective long-term medication treatment for secondary dystonias. In situations where significantly impairing secondary dystonias fail to respond to typical enteral medications and intrathecal (or even intraventricular) baclofen, consideration should be given to the use of deep brain stimulation (DBS). While Level I evidence and long-term follow-up clearly demonstrate the efficacy of DBS for primary dystonia, the evidence for secondary dystonia remains mixed and unclear. In this study, we report our experience with pediatric subjects who have undergone DBS for secondary dystonia. METHODS: We discuss the indications and outcomes of DBS procedures completed at our center. We also present a detailed discussion of the considerations in the management of these patients as well as a literature review. RESULTS: Of the four cases retrospectively examined here, all subjects experienced reductions in the severity of their dystonia (ranging from 0 to 100% on both the Barry-Albright Dystonia (BAD) and Burke-Fahn-Marsden Dystonia Rating Scale-Motor (BFMDRS-M) scales). CONCLUSIONS: Pallidal DBS should be considered among children with functionally debilitating, medication-resistant secondary dystonia. Patients without fixed skeletal deformities who have experienced a short duration of symptoms are most likely to benefit from this intervention.

Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy.

BACKGROUND: More than half of patients with genetic leukoencephalopathies remain without a specific diagnosis; this is particularly true in individuals with a likely primary neuronal etiology, such as those in which abnormal white matter occurs in combination with severe epilepsy. PATIENT: A child with a severe early infantile epileptic encephalopathy and abnormal myelination underwent whole exome sequencing. RESULTS: Whole exome sequencing identified a heterozygous de novo mutation in KCNT1, a sodium-gated potassium channel gene. CONCLUSIONS: Severely delayed myelination was anecdotally reported in previous patients with KCNT1 mutations. This case reinforces that KCNT1 sequencing should be included in an investigation of patients with severely delayed myelination and epilepsy.

Human herpesvirus 6 rhombencephalitis in immunocompetent children.

This article describes the clinical presentation, diagnostic workup, and neurologic outcome of 3 immunocompetent pediatric patients diagnosed with human herpesvirus 6 (HHV6) rhombencephalitis. Presentation of HHV6 rhombencephalitis included new onset seizures, ataxia, encephalopathy, and opsoclonus-myoclonus. Neurologic examination revealed cranial neuropathies, cerebellar dysfunction, and extremity weakness. Magnetic resonance imaging abnormalities located in the cerebellum, basal ganglia/thalamus, and cerebral hemispheres were detected in 2 patients. Diagnosis of HHV6 encephalitis was made by real-time and nested polymerase chain reaction of serum and cerebrospinal fluid. The HHV6 variant A was detected in 2 patients by sequence analysis, and HHV6 protein was detected by immunomicroscopy in a patient who underwent biopsy secondary to progressive clinical and neuroradiographic findings. Therapy with intravenous ganciclovir did not correlate with resolution of neurologic symptoms, despite eventual non-detectable HHV6. Human herpesvirus 6 should be considered in the differential diagnosis of unexplained cases of rhombencephalitis in immunocompetent children. Features may be rapidly progressive and include profound encephalopathy, seizures, ataxia, and opsoclonus-myoclonus.

Treatment approaches for children with Tourette's syndrome.

Tourette's syndrome has been of neurologic and psychiatric interest since the original description of this condition by Gilles de la Tourette in 1885, and it has been associated with a wide variety of treatments over the years. With the advent of advances in neurochemistry and neuropharmacology, a neurobiologic approach has emerged with the application of many drugs from the fields of neurology and psychiatry. In addition, many of the comorbid conditions that coexist, such as attention deficit disorder and obsessive compulsive disorder (OCD), are amenable to both pharmacologic and behavioral approaches. Drug treatment has included dopamine receptor blockers for tics, dopamine agonists, dopamine depletors, and stimulants for attention deficit hyperactivity disorder (ADHD), noradrenergic drugs for tics and ADHD, serotonergic drugs for OCD, and chemical denervation for involuntary movements with the use of botulinum toxin and stereotactic surgery. It is the purpose of this review to outline the various approaches that are currently available as treatments, realizing that as new drugs are introduced in neurology and psychiatry, they too will find their way into treatment options.