Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy.

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Delineation of the phenotype of MED17-related disease in Caucasus-Jewish families.

BACKGROUND: and Purpose: Postnatal progressive microcephaly, with seizures and brain atrophy (OMIM # 613668) is a rare disorder caused by a homozygous founder missense mutation c.1112T>C (p.L371P) in the MED17 gene on chromosome 11 that was identified in 2010 in Caucasus Jewish families. The present study aimed to delineate the phenotype and developmental outcomes in patients diagnosed with this mutation to date. METHODS: We conducted a medical charts review to collect the clinical, laboratory and neuroimaging findings in patients from several unrelated families of Caucasus-Jewish origin, who were diagnosed with the same homozygous c.1112T>C MED17 mutation. RESULTS: The study cohort, including the previously reported patients, comprised 10 males and 5 females from 11 families. All subjects had at birth a normal head circumference, which steeply declined to -6SD within a few months. None of the patients achieved developmental milestones. All patients had progressive spasticity and were wheelchair bound due to spastic quadriplegia. All of them eventually developed profound intellectual disability. Epilepsy of varied severity was present in all patients. Most patients required enteral feeding due to aspirations. Eight patients died before puberty (age range 2-13 years). Brain MRI showed marked cerebral atrophy and early prominent cerebellar atrophy (vermian > hemispheres) accompanied by pontine ventral flattening. CONCLUSIONS: The founder c.1112T>C mutation in MED17 gene is expressed by a unique and homogeneous clinical phenotype with distinctive MRI findings. This mutation should be considered in patients of Caucasus-Jewish ancestry presenting with clinical features and a MRI pattern of progressive cerebral and cerebellar atrophy.

Increased Intracranial Pressure in Acute Disseminated Encephalomyelitis.

OBJECTIVE: To assess the intracranial pressure in pediatric acute disseminated encephalomyelitis using spinal tap opening pressure on lumbar puncture, which is routinely performed as part of suspected acute disseminated encephalomyelitis workup. Compared to other cerebrospinal fluid parameters such as cell count, protein concentration, and presence of oligoclonal bands, cerebrospinal fluid opening pressure is infrequently recorded. METHODS: A retrospective chart review of demographic, clinical, and laboratory data of children diagnosed with acute disseminated encephalomyelitis admitted to a tertiary referral hospital between 2005 and 2016. RESULTS: Of the 36 children diagnosed with acute disseminated encephalomyelitis, 24 had the cerebrospinal fluid opening pressure documented in their records. The mean cerebrospinal fluid opening pressure was 27.6±12.6 cmH2O, range 9-55 cmH2O (95% confidence interval 21.9-33.6). Cerebrospinal fluid opening pressure in the acute disseminated encephalomyelitis group was statistically significantly higher ( P = .0013, 95% confidence interval 4.2-15.0) than the accepted upper limit in this age group (18 cmH2O). In 10 of 24 patients (42%), the opening pressure was above 28 cmH2O. CONCLUSIONS: Increased opening pressure was the most frequent cerebrospinal fluid abnormal finding in our cohort, which suggests a potential role of increased intracranial pressure in the acute disseminated encephalomyelitis pathophysiological disease mechanism. In certain cases, the opening pressure value could have monitoring and therapeutic implications, and therefore its measurement is highlighted by this study.

Copy number variations in cryptogenic cerebral palsy.

OBJECTIVE: To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population. METHODS: Fifty-two participants (age 10.5 ± 7.8 years; Gross Motor Function Classification System scale 2.8 ± 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant. RESULTS: Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p < 0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p < 0.05 for both). CONCLUSION: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology.

Effects of regional brain injury on the newborn autonomic nervous system.

OBJECTIVE: Cerebral mapping of central autonomic nervous system (ANS)(1) function in mature animals and humans lateralizes sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. Spectral analysis of heart rate variability (HRV)(2) is an established measure of ANS function. We examined whether such lateralization is present in the term newborn. METHODS: We retrospectively reviewed records of infants >36 weeks of gestation diagnosed with hypoxic ischemic encephalopathy (HIE).(3) We included infants with neonatal EEG and regional injury on brain MRI, which was scored using a schema. We extracted ECG signals from the EEG recording, but excluded periods of electrographic seizure activity to eliminate possible seizure influence on HRV. HRV was evaluated by spectral analysis in the high frequency (HF(4); 0.3-1 Hz) and low frequency (LF(5); 0.05-0.25 Hz) ranges, and the LF/HF ratio was examined to assess sympatho-vagal balance. The relation between the injured brain regions and HRV was studied using multiple linear regression models. RESULTS: We studied 40 neonates with HIE. Injury to the right cerebral cortex (p=0.009) and right cerebellum (p=0.041) predicted a decreased LF/HF ratio. Injury to the left cerebral cortex (p=0.035) and left cerebellum (p=0.041) was associated with an increased LF/HF ratio. The association between brain injury location and the individual LF or HF spectral powers of brain injury did not reach significance. CONCLUSIONS: Our data suggest that a functional lateralization for cerebral autonomic influence is established by term gestation.

Does a normalizing electroencephalogram in benign childhood epilepsy with centrotemporal spikes abort attention deficit hyperactivity disorder?

This retrospective study delineated the efficacy of antiepileptic drugs in preventing the need for methylphenidate in patients with benign childhood epilepsy with centrotemporal spikes and attention deficit hyperactivity disorder. Seventeen patients were identified. A reduction of electroencephalogram pathologic activity by more than 50% was achieved in some patients with the antiepileptic drugs levetiracetam, sulthiame, lamotrigine, clobazam, and valproic acid. Complete normalization was achieved in two patients with sulthiame. Improvement in attention along with the reduction of pathologic electroencephalogram activity was observed in four patients, two with sulthiame, and one each with lamotrigine and levetiracetam (which was ceased because of suicidal tendencies). However, this improvement in attention was either temporary or not significant enough to discontinue methylphenidate. Methylphenidate was eventually prescribed to all patients.