An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome.

BACKGROUND: Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug's effect on the cognitive and behavioral manifestations of the disorder. METHODS: Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η(2)) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett's post hoc testing. RESULTS: Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period. CONCLUSION: The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted. TRIAL REGISTRATION: NCT01531582 - clinicaltrials.gov.

Challenges in Diagnosing and Treating Myasthenia Gravis in Infants and Children with Presentation of Cases.

Myasthenia gravis (MG) is a rare condition that impairs function at the neuromuscular junction of skeletal muscles, seen less commonly in children. Causes include autoimmune MG, congenital myasthenic syndromes, and transient neonatal myasthenia gravis. Symptoms of weakness, hypotonia, and fatigability can be reasonably explained by more common causes, thus children with MG disorders commonly experience delays in treatment with severe consequences. This leads to the progression of disease and serious complications including myasthenic crises and exacerbations. We describe 5 cases of MG, which illustrate clinical and genetic challenges in establishing diagnosis and subsequent consequences of delayed diagnosis.

Spinal muscular atrophy: an update.

Spinal muscular atrophy (SMA) is the most common childhood neurodegenerative disease. We report an infant with SMA type 1 and discuss the recent developments in SMA genetics, pathophysiology, and possible treatment options. Because SMA type 1 remains a fatal illness for which there is not yet a cure, the focus of patient care continues to be symptomatic. Thus, the most appropriate aspects of care at present and future are also discussed.

A novel mutation in GLUD1 causing hyperinsulinism-hyperammonemia in a patient with high density of homozygosity on microarray: a case report.

BACKGROUND: Hyperinsulinism-hyperammonemia syndrome is the second most common cause of congenital hyperinsulinism and is easily treated with diazoxide; however, the symptoms in our patient were very difficult to control with typical medical therapy. To the best of our knowledge, neither our patient's mutation, nor a case of hyperinsulinism-hyperammonemia presenting with dysmorphic features and intrauterine growth restriction has previously been reported. CASE PRESENTATION: We describe a 2-year-old Hispanic girl with an unusual presentation of dysmorphic features and intrauterine growth restriction who was later found to have hyperinsulinism-hyperammonemia syndrome. Chromosomal microarray analysis revealed no copy number variants but demonstrated a high density of noncontiguous regions of homozygosity consistent with limited outbreeding. Sequencing of her GLUD1 gene revealed a previously undescribed mutation of cytosine to thymine at position 1519 resulting in an amino acid change of histidine to tyrosine at position 507. Although no functional studies were performed, function prediction tools in combination with our patient's phenotype support the hypothesis that the mutation is deleterious. Despite treatment with a maximum dose of diazoxide (15 mg/kg/day), phenobarbital (8.5 mg/kg/day divided twice daily) and a protein-restricted diet, she has global developmental delay, and continues to have seizures and recurrent episodes of hypoglycemia. CONCLUSIONS: It remains unclear if her clinical presentation can be solely explained by hyperinsulinism-hyperammonemia syndrome or is the result of an undiagnosed recessive disorder related to her homozygosity. It is our hope that clinicians may learn from our patient when formulating treatment plans for refractory cases of hyperinsulinism-hyperammonemia and avoid the morbidities associated with delayed diagnosis and treatment.

Neuromyelitis optica in child: diagnostic and therapeutic challenges.

Neuromyelitis optica (NMO) is a rare syndrome of severe inflammatory demyelination of the central nervous system, causing attacks of optic neuritis and transverse myelitis. Although uncommon, attention should be given to the proper identification and management of the affected patients. We present a case of a 13-year-old girl with severe neuromyelitis optica. The patient's initial presentation consisted of encephalopathy and optic neuritis. Approximately 2 months later, coinciding with the weaning of steroid treatment, she presented with ascending paralysis and respiratory failure. She was seropositive for NMO-IgG. Treatment included intravenous immune globulin, steroids, plasmapheresis, and rituximab and was complemented with proper nutrition, vitamins, minerals, and intense rehabilitation. Two years after the initial presentation and one short relapse, the patient has made a remarkable recovery without neurologic deficit. This report underscores the difficulty in making the initial diagnosis, choosing the best treatment, and the need for more streamlined pediatric guidelines for diagnosis, treatment, and prevention of relapses of pediatric NMO.

Early testing for Huntington disease in children: pros and cons.

We report 2 young children who are examples of the consequences of premature testing for Huntington disease. Premature testing of a child or fetus carries complex medical and psychological issues to both the child and the family that need to be considered and explored more than in an adult with Huntington disease. We suggest that a child at risk for juvenile Huntington disease not be tested until symptoms are progressive and consistent with the disease and all other mimickers are excluded. When testing is indicated, a multidisciplinary approach is essential to educate the family about the risks and benefits of testing and improve their coping skills when the final diagnosis is made.

Hypoxic-ischemic encephalopathy in infants: new challenges.

The subject of hypoxic-ischemic encephalopathy (HIE) is hardly new and yet remains an every day challenge to clinicians, mainly neonatologists and child neurologists. However, technological advances in neuroimaging do help in the diagnosis, but prevention of hypoxic-ischemic insults, ability to change the course of the disease, and treatment of the devastating consequences of HIE are lagging behind. With these issues in mind, we reviewed the literature on this subject and our own clinical experience in search of new developments in this area. The pathology and clinicopathologic correlates of HIE are emphasized as well.

Pontine hypoplasia in Carey-Fineman-Ziter (CFZ) syndrome.

We describe an infant with multiple congenital anomalies including cleft palate and micrognathia, Möbius sequence, developmental delay, myopathy, hydronephrosis, and bilateral clubfeet. These features are consistent with Carey-Fineman-Ziter (CFZ) syndrome (MIM 254940), which has been previously reported in six children (including two sibling pairs). Cranial magnetic resonance imaging (MRI) revealed an unusually small pons, a finding not previously described in CFZ syndrome.