Recessive TTN truncating mutations define novel forms of core myopathy with heart disease.

Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.

Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: comparison with studies in muscle biopsy.

Making a diagnosis of mitochondrial disease (MD) is extremely challenging and often employs the analysis of respiratory complex (RC) activities in biopsied skeletal muscle. Given both the invasive nature and expense of biopsied-muscle based testing for mitochondrial defects, buccal swab enzyme analysis has been explored as an alternative approach to the more invasive muscle biopsy. Case studies have recently suggested that buccal swabs from patients can be used to accurately assess mitochondrial enzyme activities including RC I and RC IV using a dipstick methodology combined with spectrophotometric analysis. In this study, forty patients with suspected MD who have previously been found to have significant defects in either RC I or RC IV in skeletal muscle were assessed by buccal swab analysis and compared to enzyme values obtained with unaffected controls (n=106) in the same age range. Buccal citrate synthase was used as an indicator of overall mitochondrial content, correlating well with overall buccal mitochondrial frataxin levels and was found to be elevated above control levels in 28% of the patients in this cohort. Of 26 cases with significant muscle RC I deficiency, 20 displayed significantly reduced levels of buccal RC I activity. All 7 of the patients with muscle RC IV deficiency showed significant buccal RC IV defect and 6 of the 7 patients with combined defects in muscle RC I and IV activity levels also exhibited analogous deficiencies in both buccal RC I and RC IV activities. In conclusion, the relatively high correlation (over 82%) of buccal and muscle RC deficiencies further supports the validity of this non-invasive approach as a potentially useful tool in the diagnosis of MD.

Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Sleep study abnormalities in children with attention deficit hyperactivity disorder.

The study objective was to describe polysomnographic findings in children with attention deficit hyperactivity disorder (ADHD) with diverse sleep problems. Polysomnographic data were retrospectively analyzed for 33 children (age 3-16 years) with ADHD who had sleep studies performed for diverse sleep complaints. Eight patients (24%) had obstructive sleep apnea, 10 (30%) had periodic limb movements of sleep, 8 (24%) had upper airway resistance syndrome, and 5 (15%) had obstructive hypoventilation. The ADHD group showed decreased sleep efficiency, increased arousal index, increased wake after sleep onset, decreased oxygen saturation nadir, and increased snoring, compared with control subjects. Compared with ADHD children without sleep disordered breathing, those who had sleep disordered breathing were significantly more obese and had more sleep architectural abnormalities (including increased sleep latency, increased rapid eye movement latency, increased wake after sleep onset, and increased arousal index with more oxygen desaturations), although total sleep time and sleep efficiency were not significantly different. Sleep disordered breathing and periodic limb movements of sleep appear to be common among children with ADHD who have symptoms of disturbed sleep.

Spinocerebellar ataxia type 7 mimicking Kearns-Sayre syndrome: a clinical diagnosis is desirable.

Spinocerebellar ataxias are a group of autosomal dominant cerebellar degenerative disorders, which are characterized by clinical and genetic variability. Spinocerebellar ataxia type 7 (SCA7) is less variable in clinical presentation than other SCAs. We present a pediatric patient with 13 and 70 trinucleotide CAG repeats within SCA7 gene and no family history, whose presentation mimicked Kearns-Sayre syndrome (KSS). We review the differential diagnosis of cerebellar ataxia with vision loss secondary to retinal pigmentary dystrophy. This paper supports concept of a desirable clinical diagnosis to avoid multiple genetic or invasive testing in children with neurodegenerative disorders.

Treatment of drop attacks in Coffin-Lowry syndrome with the use of sodium oxybate.

Coffin-Lowry syndrome is a well-defined clinical entity classically associated with moderate to severe mental retardation, characteristic facial features, skeletal deformities, and tapering fingers. A characteristic paroxysmal disorder was described in up to 10% patients with Coffin-Lowry syndrome, characterized by sudden loss of muscle tone induced by unexpected tactile or auditory stimuli. These events were given several names, including cataplexy, nonepileptic collapses with atonia, exaggerated startle responses, hyperekplexia, and stimulus-induced drop episodes. Various therapies were undertaken for these drop attacks, including clonazepam, tiagabine, felbamate, selective serotonin reuptake inhibitors, and tricyclics, with variable improvement. We report on a 22-year-old man with Coffin-Lowry syndrome with stimulus-induced drop episodes, who failed therapy with clonazepam, several antiepileptic drugs, and escitalopram, and who was given a trial of sodium oxybate with complete resolution of the drop attacks.

Oxcarbazepine monotherapy in children and adolescents: a single-center clinical experience.

This single-center analysis evaluated the efficacy of oxcarbazepine monotherapy in children and adolescents. A retrospective chart review identified 60 patients (male=33, female=27) aged 6 months to 17.8 years (mean age 8.2+/-4.7 years) with partial onset epilepsy receiving oxcarbazepine monotherapy. The range of oxcarbazepine dose was 6-71 mg/kg/day (mean 26.3+/-11.4 mg/kg/day). The duration of therapy ranged from 3 months to 8 years (mean duration 16.7+/-14.3 months). Fifty-one patients (85%) achieved>or=50% reduction in seizure frequency, and 25 of 60 patients (42%) achieved seizure freedom. Ten patients (16.67%) reported adverse events including drowsiness, aggressive behavior, ataxia, dizziness, diplopia, and leg cramps. No hyponatremia or skin rash was observed. Twenty-four patients were switched from carbamazepine to oxcarbazepine monotherapy. In these patients carbamazepine was discontinued because of incidence of adverse events, poor seizure control, or both. Seventy-nine percent of patients switched from carbamazepine to oxcarbazepine monotherapy had >or=50% reduction in seizure frequency, and 37.5% became seizure-free. These findings suggest that oxcarbazepine monotherapy is effective and well tolerated in children and adolescents with partial epilepsy.

Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis.

AIM: Mitochondrial function studies in autism spectrum disorders (ASD) have detected skeletal muscle mitochondrial enzyme deficiencies in respiratory complex (RC) activities. As a muscle biopsy is expensive and invasive, we assessed RC-I and RC-IV activities in buccal swabs. METHODS: 92 children with ASD and 68 controls were studied with immunocapture for RC-I and microspectrophotometry for RC-IV. RESULTS: Significant RC activity deficiencies were found in 39 (42%) ASD patients (p < 0.01) and more prevalent in more severe cases. Aberrant RC overactivity was seen in 9 children. RC-I/RC-IV activity ratio was significantly increased in 64% of the entire ASD cohort including 76% of those more severely affected (p < 0.05). CONCLUSION: Buccal swab analysis revealed extensive RC abnormalities in ASD providing a noninvasive biomarker to assess mitochondrial function in ASD patients.

5q14.3 deletion manifesting as mitochondrial disease and autism: case report.

Mitochondrial disorders are usually associated with defects of 1 or more of the 5 complexes (I to V) of the electron transport chain, or respiratory chain. Complex I and IV are the 2 most frequent abnormalities of the electron transport chain in humans. The authors report the case of a 12-year-old boy with dysmorphic facies, mental retardation, autism, epilepsy, and leg weakness. Buccal swab electron transport chain analysis revealed severe decrease in complex IV and mild reduction in complex I activity levels. Chromosomal microarray studies, using array-based comparative genomic hybridization, revealed a 1-Mb deletion in the 5q14.3 region. This case illustrates that this deletion can be associated with complex I and IV deficits, hence manifesting as a mitochondrial disease. It could be hypothesized that genes that either encode or regulate the expression and/or assembly of complex IV or I subunits are located within the deleted region of 5q14.3.

Microarray analysis in children with developmental disorder or epilepsy.

The technique of chromosomal microarray analysis identifies genetic imbalance. Evaluation of its diagnostic role in pediatrics is still underway. We describe our experience with chromosomal microarrays. We retrospectively reviewed the charts of children in the Sections of Neurology and Clinical Genetics at St. Christopher's Hospital for Children who had undergone microarray analysis between 2006 and 2009. Collected data included age, sex, and the presence of mental retardation, developmental delay, autism, learning disability, hypotonia, dysmorphic features, and epilepsy, and the use of microarray technique. Statistical analysis was performed using SPSS. There were 82 children (mean age ± S.D., 5.7 ± 5 years), including 45 (55%) boys and 37 (45%) girls. All patients exhibited a normal karyotype. Microarray analysis produced abnormal results in 20 (23.5%). Deletions comprised 74% of all abnormalities. Patients with ≥ 4 clinical variables demonstrated a 30.5% incidence of abnormal chromosomal microarray findings, compared with 8.7% of patients with ≤ 3 clinical variables (P = 0.039, χ(2) test). Logistic regression indicated that motor impairment (P = 0.039) and presence of epilepsy (P = 0.024) independently contributed to the model. The likelihood of an abnormal microarray result increased with the number of clinical abnormalities. Microarray analysis will likely become the diagnostic genetic test of choice in children with neurodevelopmental disorders or epilepsy.

Subacute sclerosing panencephalitis (SSPE) presenting as acute disseminated encephalomyelitis in a child.

Subacute sclerosing panencephalitis (SSPE) typically presents with progressive mental deterioration, behavioral changes, and myoclonic jerks. Atypical presentations are not unknown and may result in diagnostic delays. A 9-year-old girl presented with poor balance and ataxia following an episode of upper respiratory tract infection. Neurological examination revealed mild hemiparesis and ataxia. Brain magnetic resonance imaging revealed scattered areas of T2 and fluid-attenuated inversion recovery hyperintensities in the white matter consistent with acute disseminated encephalomyelitis. Despite treatment with intravenous methylprednisolone, intravenous immunoglobulins, and plasmapheresis, progressive neurological worsening occurred. Later during the course of her illness, subacute sclerosing panencephalitis was suspected from the appearance of burst-suppression pattern on electroencephalogram, and the diagnosis confirmed by elevated titers of measles antibodies in cerebrospinal fluid. Physicians taking care of children need to be aware of atypical presentations of subacute sclerosing panencephalitis and must have a high index of suspicion to prevent diagnostic delays and avoid unnecessary diagnostic and therapeutic interventions.

Efficacy and tolerability of topiramate in pediatric migraine.

About 5-10% of school-age children manifest migraine headaches. Treatment options for pediatric migraine are limited. Topiramate is approved for migraine prophylaxis in adults, but its use in children is limited. We retrospectively reviewed the records of 37 patients, i.e., 22 (60%) girls and 15 (40%) boys (mean age, 14 years; range, 7.3-20.5 years), diagnosed with migraine without aura in 30 (81%), with aura in four (11%), and abdominal, ophthalmoplegic, and catamenial in one each. The mean follow-up was 12 +/- 5 months standard deviation (S.D.). Clinical response was qualified as excellent, good, no change, or worse. Numbers of headaches per month were 15 +/- 7 S.D. prior to treatment and 3 +/- 3.4 S.D. (P < 0.001) after treatment. An excellent or good response (>50% migraine reduction) was attained in 28 patients (76%). Ten (27%) patients exhibited adverse effects. Patients taking >2 mg/kg/day were more likely to demonstrate side effects. The mean dose for patients without adverse effects was 1.27 +/- 0.7 mg/kg/day S.D. Those who reported adverse effects were taking a mean dose of 2.8 +/- 1.5 mg/kg/day S.D. This study demonstrated that topiramate is an effective, safe alternative for the prophylaxis of pediatric migraine. An acceptable risk/benefit maintenance dose was < or =2 mg/kg/day.

Efficacy and safety of lamotrigine monotherapy in children and adolescents with epilepsy.

Lamotrigine (LTG) has shown to confer broad-spectrum, well-tolerated control of epilepsy. Monotherapy is preferable over polytherapy because of better compliance, fewer adverse events, less interactions, lower teratogenicity and lower cost. The aim of this study is to evaluate the efficacy and safety of LTG monotherapy on seizure control in a cohort of children and adolescents with epilepsy. We retrospectively reviewed the records of children and adolescents treated with LTG monotherapy at our institution between 2001 and 2006. Data collected included demographics, seizure type, etiology of seizures, age at onset of seizures and at initiation of LTG treatment, number of antiepileptic drugs (AEDs) prior to LTG, dose of LTG, length of follow-up, treatment response, and adverse events. Seventy-two children and adolescents were identified (mean age 12.1 years); 37.5% had mental retardation. Age at onset of epilepsy was 5.7 years (0-16). Twenty three percent had symptomatic focal epilepsy, 15.5% idiopathic focal epilepsy, 19.4% symptomatic generalized epilepsy and 41.6% idiopathic generalized epilepsy. LTG was used as first-line monotherapy in 26.4% of patients and as a second-line monotherapy in 73.6%. Age at initiation of LTG therapy was 10 years (2.8-19). Mean number of AEDs tried prior to LTG was 1.3 (0-6). Mean dose of LTG was 5.5mg/kg/day (1.1-13.7). Mean follow-up period was 33 months (3 weeks to 11.5 years). The degree of seizure reduction was as follows: seizure free in 42%, 75-90% reduction in 17.4%, 50-74% in 11.6%, 25-49% in 10%. Sixteen percent had no change in seizure control and 3% became worse. The most common adverse event was rash (6.9%). Six (8.3%) patients discontinued LTG because of the adverse events. No patient had Stevens-Johnson syndrome. In conclusion, LTG was effective and well-tolerated as monotherapy in children and adolescents for both focal and generalized epilepsies.

A PLP splicing abnormality is associated with an unusual presentation of PMD.

We report that a deletion of 19 base pairs (bp) in intron 3 of the proteolipid protein (PLP/DM20) gene causes a neurological disease characterized by mild developmental delay, followed by progressive decline of acquired motor and cognitive milestones. The clinical features are associated with mild delay in myelination demonstrated by magnetic resonance imaging studies and with ongoing demyelination and axonal loss demonstrated by magnetic resonance spectroscopy. We demonstrate that the purine-rich 19bp element regulates PLP-specific splice site selection in transient transfections of chimeric constructs into cultured oligodendrocytes. Runs of 4 and 5 Gs centered in the 19bp element are critical for efficient PLP-specific splicing. The intronic element is sequence specific in oligodendrocytes and is not a repressor of PLP-specific splicing in nonglial cells. These data support the conclusion that deletion of the 19bp purine-rich region in PLP intron 3 causes a reduction in PLP message and protein, which affects myelin stability and axonal integrity.