Vettaikorumakankav Vedanarayanan

Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers

DNA methylation and chromatin DNaseI sensitivity were analyzed in and adjacent to D4Z4 repeat arrays, which consist of 1 to ∼100 tandem 3.3-kb units at subtelomeric 4q and 10q. D4Z4 displayed hypomethylation in some cancers and hypermethylation in others relative to normal tissues. Surprisingly, in cancers with extensive D4Z4 methylation there was a barrier to hypermethylation spreading to the beginning of this disease-associated array (facioscapulohumeral muscular dystrophy, FSHD) despite sequence conservation in repeat units throughout the array. We infer a different chromatin structure at the proximal end of the array than at interior repeats, consistent with results from chromatin DNaseI sensitivity assays indicating a boundary element near the beginning of the array. The relative chromatin DNaseI sensitivity in FSHD and control myoblasts and lymphoblasts was as follows: a non-genic D4Z4-adjacent sequence (p13E-11, array-proximal)> untranscribed gene standards > D4Z4 arrays> constitutive heterochromatin (satellite 2; P < 10−4 for all comparisons). Cancers displaying D4Z4 hypermethylation also exhibited a hypermethylation-resistant subregion within the 3.3-kb D4Z4 repeat units. This subregion contains runs of G that form G-quadruplexes in vitro. Unusual DNA structures might contribute to topological constraints that link short 4q D4Z4 arrays to FSHD and make long ones phenotypically neutral.

Treatment of childhood dermatomyositis with high dose intravenous immunoglobulin

Two children with chronic dermatomyositis who were treated with intravenous immunoglobulin (IVIG) for 28 and 12 months, respectively, are reported. Both patients had received prednisone and immunosuppressive agents prior to IVIG treatments and had experienced significant side effects. Strength and functional abilities improved in both patients in a gradual stepwise fashion with IVIG treatment. One patient achieved remission and continues to do well without any immunosuppressive agents; in the other patient, the dose of oral steroids was reduced and other immunosuppressive agents were discontinued. Use of IVIG was associated with headaches, nausea, and vomiting in both patients. IVIG was an useful adjuvant therapy in these 2 children with dermatomyositis without any significant side effects.

Lethal neonatal autosomal recessive axonal sensorimotor polyneuropathy

Peripheral neuropathy is an uncommon cause of generalized hypotonia and weakness in infancy. It occurs as a part of the clinical syndrome in some neurodegenerative disorders of infancy, but seldom causes respiratory failure or swallowing difficulties. We report a lethal autosomal recessive axonal polyneuropathy with neonatal onset in a large kindred from Northern Mississippi. One patient was studied in detail at our medical center and the information on 12 other affected infants in this large family were gathered from medical records and by interviewing the family members. Patients were symptomatic for the polyneuropathy before birth and died in the first year of life from respiratory complications. Thirteen babies were affected by this clinical phenotype in four generations of this family with a high frequency of consanguinity. Affected babies were of both sexes and were born to healthy consanguineous parents. The clinical phenotype of polyneuropathy in our index patient and other affected babies in this family was similar, and represents a unique form of hereditary neonatal polyneuropathy.

Carpal Tunnel Syndrome in Children

BACKGROUND Carpal tunnel syndrome or median neuropathy at the wrist is a rare condition in children. Of the reported patients with carpal tunnel syndrome, mucopolysaccharidoses and the mucolipidoses are the most common causes. PATIENTS We report 13 patients between the ages of 2 and 17 years of age with carpal tunnel syndrome. RESULTS Mucopolysaccharidoses was the cause in one child. In other children, trauma to the median nerve, malformations of the wrist, brachial plexopathy, obesity, inherited susceptibility to pressure palsies (PMP 22 gene deletion), and family history of median neuropathy at the wrist were identified. All patients had hand pain, numbness, and paresthesias in their hands. The nerve conduction studies showed prolongation of median sensory nerve latency and distal motor latency in median nerve. CONCLUSIONS Carpal tunnel syndrome occurs in children and a variety of risk factors predispose to its occurrence.

Optic nerve morphology as marker for disease severity in cerebral palsy of perinatal origin

BACKGROUND It is difficult to predict the neurologic outcome and ambulatory status in children with perinatal neurologic insult until 2-5years age. This study aims to correlate clinical optic nerve head (ONH) findings-cupping, pallor and hypoplasia, with gestational period and neurologic (motor) outcomes in patients with cerebral palsy (CP) from perinatal insults. METHODS 54 consecutive patients with CP from perinatal insults were enrolled. Patients with intraocular disease, retinopathy of prematurity and hydrocephalus were excluded. ONH was labeled as pale, hypoplastic or large cup (cup/disc ratio≥0.5) if 2 ophthalmologists independently agreed after an ophthalmoscopic examination. Inter-rater reliability was excellent. RESULTS Mean age at examination was 10.98±6.49years; mean gestational period was 33.26±4.78weeks. Abnormal ONH (pallor, cupping or hypoplasia) was seen in 38/54 (70%) patients. Of patients with pallor (n=17), 88% were quadriplegic and 82% non-ambulatory. Mean cup/disc ratio was 0.45±0.22; 50% patients had large cup. Multivariate logistic regression models showed that disc pallor was associated with non-ambulatory status (OR: 21.7; p=0.003) and quadriplegia (OR: 12.8; p=0.03). Large cup was associated with age at examination (OR 1.15; p=0.03). Cup/disc ratio showed positive correlation with age at examination (Pearsons r=0.39; p=0.003). There was no significant association of ONH parameters with gestational age. CONCLUSION Clinically observed ONH changes (pallor, cupping and hypoplasia) are common in CP. Presence of ONH pallor serves as an indicator for poor motor outcome in patients who develop CP from perinatal causes and should prompt early referral for rehabilitation.