Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy.

Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG). Next generation sequencing revealed novel biallelic homozygous mutations in SPEG in both cases. Patient 1 showed the c.1627_1628insA (p.Thr544Aspfs*48) mutation and patient 2 the c.9586C>T (p.Arg3196*) mutation. The clinical phenotype was distinctive in the two patients since patient 2 developed a dilated cardiomyopathy with milder myopathy features, while patient 1 showed only myopathic features without cardiac involvement. These findings expand the genotype-phenotype correlations after the initial report. Additionally, we describe whole body muscle MRI of patient 2 and we argue on the different SPEG isoforms in skeletal muscle and heart as the possible explanation leading to variable phenotypes of SPEG mutations.

Encefalitis subaguda por anticuerpos anti receptor de N-metil-D-aspartato: Serie de 13 casos pediátricos / Subacute anti-N-methyl-D-aspartate receptor encephalitis: A serie of 13 paediatric cases

Introducción: La encefalitis subaguda por anticuerpos anti-receptor N-metil-Daspartato (NMDA) es un cuadro autoinmune reconocido el año 2007 como entidad clínica y descrito primero en mujeres jóvenes con teratoma ovárico. El año 2009 se describe primera serie pediátrica no relacionada con tumores. Objetivo: Mostrar características clínicas, tratamiento y pronóstico de 13 pacientes con encefalitis por anticuerpos anti receptor NMDA en Chile. Pacientes y método: Se describen 13 niños, 9 varones, de edades comprendidas entre 1-16 años, estudiados entre 2009-2016 en 7 hospitales y diagnosticados entre 2009-2016. Los pacientes fueron estudiados con resonancia magnética cerebral, electroencefalograma y estudio de líquido cefalorraquídeo, citoquímico, bandas oligoclonales y panel viral (anticuerpos y PCR). Todos fueron estudiados para detección de anticuerpos anti receptor NMDA en suero y líquido cefalorraquídeo (LCR) y pesquisa de tumores por imágenes. Resultados: Trece de 13 niños iniciaron la enfermedad con síntomas psiquiátricos y 11/13 tuvieron crisis epilépticas. Posteriormente todos presentaron agitación psicomotora, distonías y discinesias bucolinguales; 11/13 pérdida de lenguaje y 6/13 trastornos autonómicos. Todos ellos tuvieron anticuerpos anti receptor NMDA positivo. El LCR fue normal en 12/13 niños, hubo bandas oligoclonales positivas en 6/10 pacientes, la resonancia cerebral fue normal en todos los niños, el EEG estuvo alterado en 12/13 niños y la SPECT resultó anormal en 6/6 niños. Doce de 13 niños recibieron metilprednisolona en bolos 30 mg/kg/3-5 días y 6 recibieron inmunoglobulina 2 g/kg. Doce de 13 niños se recuperaron de 2 a 4 meses después de iniciada la enfermedad. Un niño tuvo recidiva un año después y se recuperó rápidamente. Conclusiones: La encefalitis subaguda por anticuerpos anti-receptor NMDA debe sospecharse en niños con alteraciones psiquiátricas y movimientos anormales. Los estudios funcionales (EEG y SPECT) son valiosos para apoyar el diagnóstico. La detección precoz de esta encefalitis permite la recuperación más rápida de los pacientes.

Introduction: Subacute anti-NMDA receptor encephalitis was recognised in 2007 as a clinical entity, and was first described in young women with ovarian teratoma. The first paediatric series unrelated with tumours was reported in 2009. Objective: To present the clinical features, treatment, and prognosis of 13 patients with anti-NMDA receptor encephalitis in Chile. Patients and method: A description is presented of 13 children, 9 males, aged between 1 and 16 years, diagnosed between 2009 and 2016 in 7 hospitals. All patients were evaluated with cerebral magnetic resonance and electroencephalogram. Cytochemical, oligoclonal bands and virus studies (PCR and antibodies) were performed in cerebrospinal fluid. All patients were evaluated in search of anti NMDA receptor in serum and cerebrospinal fluid. Tumor imaging studies were performed in all children. Results: All children began the disease with psychiatric symptoms, and 11/13 had seizures. All of them subsequently presented with psychomotor agitation, dystonia, and bucolingual dyskinesias, with 11/13 loss of language and 6/13 autonomic disorders. All of them (13/13) had positive anti-NMDA receptor antibodies. CSF was normal in 12/13 children, positive oligoclonal bands in 6/10 patients, normal brain resonance in 13/13 children, EEG changes in 11/13 children, and abnormal SPECT in 6/6 children. A methylprednisolone bolus of 30 mg/kg was given for 3-5 days to 12/13 children, and 6 received immunoglobulin 2 g/kg. The large majority (12/13) of children recovered 1-4 months after disease onset. One child had a recurrence one year later, and recovered quickly. Conclusions: Subacute encephalitis due to NMDA anti-receptor antibodies should be suspected in children with psychiatric disorders and abnormal movements. Functional studies, such as EEG and SPECT are valuable diagnostic support. Early detection of this encephalitis leads to a faster recovery of patients.

[Subacute anti-N-methyl-D-aspartate receptor encephalitis. A serie of 13 paediatric cases]. / Encefalitis subaguda por anticuerpos anti receptor de N-metil-D-aspartato. Serie de 13 casos pediátricos.

INTRODUCTION: Subacute anti-NMDA receptor encephalitis was recognised in 2007 as a clinical entity, and was first described in young women with ovarian teratoma. The first paediatric series unrelated with tumours was reported in 2009. OBJECTIVE: To present the clinical features, treatment, and prognosis of 13 patients with anti-NMDA receptor encephalitis in Chile. PATIENTS AND METHOD: A description is presented of 13 children, 9 males, aged between 1 and 16 years, diagnosed between 2009 and 2016 in 7 hospitals. All patients were evaluated with cerebral magnetic resonance and electroencephalogram. Cytochemical, oligoclonal bands and virus studies (PCR and antibodies) were performed in cerebrospinal fluid. All patients were evaluated in search of anti NMDA receptor in serum and cerebrospinal fluid. Tumor imaging studies were performed in all children. RESULTS: All children began the disease with psychiatric symptoms, and 11/13 had seizures. All of them subsequently presented with psychomotor agitation, dystonia, and bucolingual dyskinesias, with 11/13 loss of language and 6/13 autonomic disorders. All of them (13/13) had positive anti-NMDA receptor antibodies. CSF was normal in 12/13 children, positive oligoclonal bands in 6/10 patients, normal brain resonance in 13/13 children, EEG changes in 11/13 children, and abnormal SPECT in 6/6 children. A methylprednisolone bolus of 30mg/kg was given for 3-5 days to 12/13 children, and 6 received immunoglobulin 2g/kg. The large majority (12/13) of children recovered 1-4 months after disease onset. One child had a recurrence one year later, and recovered quickly. CONCLUSIONS: Subacute encephalitis due to NMDA anti-receptor antibodies should be suspected in children with psychiatric disorders and abnormal movements. Functional studies, such as EEG and SPECT are valuable diagnostic support. Early detection of this encephalitis leads to a faster recovery of patients.

Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene.

BACKGROUND: Mitochondrial DNA depletion syndrome is an autosomal recessive disorder characterized by decreased mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the beta-subunit of the adenosine diphosphate-forming succinyl coenzyme A synthetase ligase. OBJECTIVE: To highlight the variability in the clinical spectrum of TK2-related mitochondrial DNA depletion syndrome. DESIGN: Review of patients and the literature. SETTING: Tertiary care university. PATIENTS: Four patients with mitochondrial DNA depletion syndrome and mutations in the TK2 gene. MAIN OUTCOME MEASURES: Definition of clinical variability. RESULTS: Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. CONCLUSION: The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3-like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.