Laurence E. Walsh

Rapid-onset dystonia-parkinsonism.

We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder “rapid-onset dystonia-parkinsonism” (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis

Background Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients. Method The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals. Results One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria. Conclusions These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.

Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial

BACKGROUND Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Distal 13q deletion syndrome and the VACTERL Association : Case report, literature review, and possible implications

We present a case of a child with del(13) (q31.1qter), VACTERL association, and penoscrotal transposition. Deletion of the distal long arm of chromosome 13 is associated with variable phenotypes. These phenotypes are divided into three clusters; each cluster represents a specific deleted segment of 13q. Individuals with deletions of a critical region at 13q32 have multiple congenital malformations that include components of the VACTERL association. Our patient had all six manifestations of VACTERL association. In addition, he had complete penoscrotal transposition, a unique malformation reported rarely in VACTERL association and only twice previously in deletion of distal 13q. We reviewed all reported cases of distal 13q deletions to date. Of these 137 patients, 15 could be classified into the VACTERL association. Ours was the only patient with distal 13q deletion and all VACTERL association features and also the only one with tracheoesophageal fistula. Neither holoprosencephaly nor the other central nervous system malformations that have been seen in individuals with distal 13q deletions were apparent in him. The patient presented here appears to be unique among individuals with distal 13q deletion. His cluster of malformations strengthens the argument that distal 13q deletion is a cause for VACTERL association, and that this causal relationship implies a syndromic form of VACTERL. In addition, this case and those ascertained from the literature suggest that penoscrotal transposition should be considered part of both the distal 13q-deletion syndrome and some forms of VACTERL association.

Rituximab for the treatment of thymoma-associated and de novo myasthenia gravis: 3 cases and review.

Objectives: Myasthenia gravis (MG) is an immune-mediated disorder associated with autoantibodies against postsynaptic nicotinic acetylcholine receptors at neuromuscular junctions. Rituximab, a monoclonal antibody specific for CD20, is used primarily to treat B-cell non-Hodgkin lymphoma. Although it has been used for treatment of a number of autoimmune diseases, there is limited experience in MG. Methods: Three patients with refractory MG (2 with concurrent thymoma) were given rituximab. Results: Symptoms stabilized and reductions in immunosuppressive medications were tolerated for extended periods, without adverse effects or infectious complications. Conclusions: These observations support the concept that rituximab may be helpful for the treatment of MG. Remissions in patients with or without thymoma are achievable with rituximab given in combination with commonly used modalities. Furthermore, rituximab is not necessarily contraindicated for the treatment of MG in patients being treated for thymoma. Controlled studies are called for to define its role in the treatment of refractory MG.

Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges.

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.

Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management.

Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.

Clinical Findings in Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease is a rare X-linked disease characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein 1 gene. Few studies report detailed clinical findings in children with genetic confirmation of mutations in the proteolipid protein 1 gene. We reviewed the records of 10 boys with Pelizaeus-Merzbacher disease and one symptomatic carrier girl. Their median age was 2½ years (range 10 months to 20 years). Nine had proteolipid protein 1 gene duplications, one had a point mutation, and one had a single codon deletion. The families of eight patients reported perinatal complications, including maternal hypertension (three patients) and meconium aspiration (three patients). All of the patients were social and interactive, but all had difficulty with expressive speech. All patients presented with nystagmus and had hypotonia that progressed to spasticity, affecting the legs more than the arms; ataxia also contributed to motor impairment. Additional problems reported regarded feeding (eight patients) and sleep (three patients). Further work is needed to clarify the variations in disease course and the relationship of genotype to phenotype. (J Child Neurol 2004;19:328-331).

Neurologic complications of pediatric liver transplantation

The neurologic complications of 24 children, ages 5 months to 18 years, following orthotopic liver transplantation at the Indiana University hospitals are reported. Biliary atresia (14 patients) was the most common cause for orthotopic liver transplantation. Three children died. Seventeen children (70%) had no neurologic deficit on follow-up 6 months or longer after transplantation. Eleven children (46%), including 4 of 16 patients (25%) who had received OKT3, had neurologic complications. Seven children (29%) had new-onset seizures; 4 of these patients had status epilepticus. Two children had intracranial hemorrhage. Seizures occurred later in children than in adults following orthotopic liver transplantation and were not associated with poor prognosis. Longer term follow-up is indicated to assess subtle, cognitive deficits following liver transplantation in children.

Is It ADEM, POLG, or Both?

OBJECTIVE To describe a child with apparent brain biopsy-confirmed acute disseminated encephalomyelitis (ADEM) but genetic confirmation of compound heterozygosity for DNA mutations of the polymerase gamma (POLG) gene. DESIGN Case report. SETTING Tertiary referral center. PATIENT A 4-year-old boy presented with ataxia and encephalopathy. RESULTS Magnetic resonance imaging demonstrated multiple focal areas of T2 prolongation. The patients family refused steroid treatment. His symptoms improved then progressed. Magnetic resonance imaging findings also progressed. A cerebrospinal fluid specimen revealed myelin basic protein and oligoclonal bands. A brain biopsy specimen demonstrated demyelination, suggesting progression of ADEM. However, polymerase chain reaction amplification and sequencing revealed 2 heterozygous mutations of the POLG gene, suggesting mitochondrial disease. The patient died 9 months after his initial presentation. CONCLUSIONS This case raises interesting questions about whether ADEM triggered severe neurologic degeneration in a patient with mitochondrial disease, whether mitochondrial disease predisposed to a pathologic immune response, or whether mitochondrial disease can mimic an autoimmune disease. Mitochondrial disease-causing mutations may help explain the poor outcome in some cases of apparent autoimmune central nervous system disease.