Francois Dominique Jacob

Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature.

Rett syndrome is a severe neurodegenerative disorder characterized by acquired microcephaly, communication dysfunction, psychomotor regression, seizures and stereotypical hand movements. Mutations in methyl CpG binding protein 2 (MECP2) are identified in most patients with classic Rett syndrome. Genetic studies in patients with a Rett variant have expanded the spectrum of underlying genetic etiologies. Recently, a deletion encompassing several genes in the long arm of chromosome 14 has been associated with the congenital Rett-syndrome phenotype. Using array-based comparative genomic hybridization, we identified a 3-year-old female with a Rett-like syndrome carrying a de novo single-gene deletion of FOXG1. Her presentation included intellectual disability, epilepsy and a Rett-like phenotype. The variant features included microcephaly at birth and prominent synophrys. Our results confirm that congenital Rett syndrome can be caused by copy-number variation in FOXG1 and expand the clinical phenotypic spectrum of FOXG1 defect in humans.

Clinical Characteristics of Pediatric Myasthenia: A Surveillance Study

OBJECTIVE: To evaluate the incidence, clinical features, diagnostic, and treatment trends of pediatric myasthenia in Canada. METHODS: Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data. Inclusion criteria were any child <18 years old with ≥1 of the following: (1) fluctuating ptosis or extraocular weakness, (2) skeletal muscle weakness or fatigue, and (3) any of the following supportive tests: clinical response to acetylcholinesterase inhibitor, positive antibodies, abnormal slow repetitive nerve stimulation, or single-fiber electromyography. RESULTS: In 2 years of surveillance, 57 confirmed cases were reported. There were 34 generalized and 18 ocular reports of juvenile myasthenia gravis plus 5 congenital myasthenic syndrome cases. There were 14 incident cases in 2010 and 6 in 2011. Age of onset ranged from “birth” to 17 years for the generalized form compared with 18 months to 11 years for the ocular subtype. Positive acetylcholine receptor titers were found in 22 (67%) of 33 generalized cases and 8 (44%) of 18 ocular patients. Of patients started on pyridostigmine, improvement was noted in 33 (100%) of 33 generalized cases and 15 (88%) of 17 ocular cases. CONCLUSIONS: This study represents the largest descriptive series of pediatric myasthenia in North America and provides valuable information about clinical characteristics. A high index of suspicion is important for this treatable disease. Children generally respond promptly to readily available therapies.

Fetal Hippocampal Development: Analysis by Magnetic Resonance Imaging Volumetry

The hippocampal formation plays an important role in learning and memory; however, data on its development in utero in humans are limited. This study was performed to evaluate hippocampal development in healthy fetuses using 3D reconstructed MRI. A cohort of 20 healthy pregnant women underwent prenatal MRI at a median GA of 24.9 wk (range, 21.3–31.9 wk); six of the women also had a second fetal MRI performed at a 6-wk interval. Routine 2D ultrafast T2-weighted images were used to reconstruct a 3D volume image, which was then used to manually segment the right and left hippocampi. Total hippocampal volume was calculated for each subject and compared against GA. There was a linear increase in total hippocampal volume with increasing GA (p < 0.001). For subjects scanned twice, there was an increase in hippocampal size on the second fetal MRI (p = 0.0004). This represents the first volumetric study of fetal hippocampal development in vivo. This normative volumetric data will be helpful for future comparison studies of suspected developmental abnormalities of hippocampal structure and function.

An unusual presentation of copper metabolism disorder and a possible connection with Niemann-Pick type C.

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency—dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.

Acquired monocular nystagmus as the initial presenting sign of a chiasmal glioma.

A 15-month-old male presented with a one-day history of acute onset, continuous oscillating movement of his right eye. He had received his one-year immunizations four days prior and had a four-day history of a febrile viral respiratory tract infection. Pregnancy was unremarkable. He had severe iron deficiency anemia (MCV 66, Hb 65) and was developmentally delayed, as he was unable to stand independently and was non-verbal. His head circumference was 49 cm (95th percentile) and his weight was at the 25th percentile. On physical examination, continuous horizontal large amplitude pendular nystagmus of the right eye at a frequency of 3-4 Hz was observed. No nystagmus was observed in the left eye, even on funduscopic examination. The child could fixate targets in all four quadrants with both eyes independently, and could fixate and track small objects with both eyes independently suggesting no significant visual field defect or visual loss. Dilated funduscopic examination was normal, extra ocular movements were full, pupils were equal and reactive and there was no relative afferent pupillary defect. The remainder of the neurological examination was normal. There was no head bobbing or anomalous head position and no stigmata of neurofibromatosis type 1. Magnetic resonance imaging of the brain (Figure) demonstrated a 2 cm x 1.6 cm x 1.2 cm suprasellar enhancing mass involving the optic chiasm, hypothalamus, mamillary bodies and superior pituitary stalk. There was no extension into the pituitary fossa or the optic nerves and no ventricular enlargement. A biopsy of the mass was

Pontocerebellar hypoplasia type 3 with severe vitamin A deficiency.

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders. It is characterized by hypoplasia and atrophy of the cerebellar cortex, dentate nuclei, pontine nuclei, and inferior olives. We present an 18-month-old infant with pontocerebellar hypoplasia type 3 and severe vitamin A deficiency. This case emphasizes the significance of vitamin A in the proper formation of the hindbrain. The authors conclude that vitamin A screening should be considered in maternal and newborn metabolic screening.

Rearrangement of Chromosome 14q with Associated White Matter Disease

We report the case of a 29-month-old boy with spasticity and periventricular white matter changes on magnetic resonance imaging in whom a complex rearrangement consisting of a de novo duplication of 14q32.31q32.33 and deletion of 14q32.33 was identified by array-based comparative genomic hybridization. Our case replicates some of the previous features associated with chromosome 14q duplication and deletion while expanding its clinical spectrum with pyramidal tract dysfunction signs and neuroimaging features. Genomic lesions should be considered in cases of leukodystrophies, and genome-wide studies such as array-based comparative genomic hybridization could be considered in the assessment of undefined white matter disorders.

Recurrent Diplopia in a Pediatric Patient with Bickerstaff Brainstem Encephalitis

Introduction. Acute complete external ophthalmoplegia is a rare finding in clinical practice that is associated with diseases affecting the neuromuscular junction, the oculomotor nerves, or the brainstem. Ophthalmoplegia has been reported with acute ataxia in Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE). Up to 95% of these cases are associated with anti-GQ1b antibodies. Only a small number of cases of anti-GQ1b negative MFS have been documented in pediatric patients. This is the first case reporting a recurrence of ocular symptoms in an anti-GQ1b antibody negative patient with BBE. Case Presentation. An 8-year-old Caucasian boy presented with complete external ophthalmoplegia without ptosis, cerebellar ataxia, and a disturbance of consciousness. He had recently recovered from a confirmed Campylobacter jejuni infection. On subsequent laboratory testing he was anti-GQ1b antibody negative. He had a recurrence of diplopia at four-week follow-up. Conclusions. This patients recurrence of diplopia was treated with a five-week course of oral corticosteroids which did not worsen his condition, and this may be a therapeutic option for similar patients. We will discuss the symptoms and treatment of reported pediatric cases of anti-GQ1b antibody negative cases of MFS and the variation between cases representing a spectrum of illness.

Lingual Dyskinesia and Tics: A Novel Presentation of Copper-Metabolism Disorder

Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue. Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease; however, the diagnosis of non-Wilson, non–Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics. We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia. His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable. Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.