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INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized clinically by eosinophilic hyaline intranuclear inclusions in neuronal and other somatic cells. Skin biopsies are reportedly useful in diagnosing NIID, and the genetic cause of NIID was identified as a GGC repeat expansion in NOTCH2NLC in recent years. The number of adult patients diagnosed via genetic testing has increased; however, there have been no detailed reports of pediatric NIID cases with GGC expansions in NOTCH2NLC. This is the first detailed report of a pediatric patient showing various neurological symptoms from the age of 10 and was ultimately diagnosed with NIID via skin biopsy and triplet repeat primed polymerase chain reaction analyses. CASE REPORT: This was an 18-year-old female who developed cyclic vomiting, distal dominant muscle weakness, and sustained miosis at 10 years. Nerve conduction studies revealed axonal degeneration, and her neuropathy had slowly progressed despite several rounds of high-dose methylprednisolone and intravenous immunoglobulin therapy. At 13 years, she had an acute encephalopathy-like episode. At 15 years, brain MRI revealed slightly high-intensity lesions on diffusion-weighted and T2-weighted imaging in the subcortical white matter of her frontal lobes that expanded over time. At 16 years, esophagography, upper gastrointestinal endoscopy, and esophageal manometry revealed esophageal achalasia, and per-oral endoscopic myotomy was performed. At 18 years, we diagnosed her with NIID based on the findings of skin specimen analyses and a GGC repeat expansion in NOTCH2NLC. CONCLUSION: NIID should be considered as a differential diagnosis in pediatric patients with various neurological symptoms.
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Enfermedades Neurodegenerativas , Humanos , Adulto , Niño , Femenino , Adolescente , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/patología , Imagen por Resonancia Magnética , Pruebas Genéticas , Debilidad Muscular/genéticaRESUMEN
OBJECTIVE: To clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE). METHODS: We retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups. RESULTS: The response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH3, procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3- < 20 mmol/L (1 point), Cl <100 mEq/L (1 point), Cr ≥0.35 mg/dL (1 point), glucose ≥200 mg/dL (1 point), and PCT ≥1.7 pg/mL (2 points). The scoring system had sensitivity of 84.2% and specificity of 81.0%. CONCLUSION: Incidence data and prediction scores for AESD will be useful for future intervention trials for AESD.
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Encefalopatías/diagnóstico , Encefalopatías/epidemiología , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/epidemiología , Estado Epiléptico/diagnóstico , Estado Epiléptico/epidemiología , Preescolar , Epilepsia/diagnóstico , Femenino , Hospitales/estadística & datos numéricos , Humanos , Incidencia , Lactante , Japón/epidemiología , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.
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OBJECTIVE: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome. METHODS: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant. RESULTS: We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology. SIGNIFICANCE: MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
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OBJECTIVES: To investigate the prevalence and background of children with medical complexity (CMC) and its secular trend in Japan. METHODS: CMC were defined as patients under the age of 20 years requiring medical care and devices. The patients were enrolled using the national health insurance claims data of three hospitals and two rehabilitation centers in Tottori Prefecture. The study period was divided into three periods: Period 1, 2007-2010; Period 2, 2011-2014; and Period 3, 2015-2018. RESULTS: A total of 378 CMC were enrolled. The prevalence of CMC was 1.88 per 1000 population among subjects aged <20 years in 2018, and it increased by approximately 1.9 times during the study period. The number of CMC who presented with severe motor and intellectual disabilities did not change from Period 1 to Period 3. Meanwhile, the number of CMC who had relatively preserved motor and intellectual abilities increased from 58 to 98. The proportion of CMC who required respiratory management and oxygen therapy increased by 1.3 and 1.8 times, respectively. By contrast, the proportion of CMC who need tube feeding decreased significantly between periods 1 and 3 (P < 0.05). CONCLUSIONS: The prevalence of CMC increased almost twice during the 12-year study period; however, the increase in the number of patients with relatively preserved motor and intellectual abilities was pronounced. This study showed that the need for medical care and devices differed based on the underlying disorders and severity of CMC; therefore, individualized medical, welfare, and administrative services and education about the various types of CMC must be provided.
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Atención a la Salud/tendencias , Niños con Discapacidad/estadística & datos numéricos , Personas con Discapacidades Mentales/estadística & datos numéricos , Adolescente , Niño , Preescolar , Atención a la Salud/economía , Atención a la Salud/métodos , Equipos y Suministros/provisión & distribución , Femenino , Humanos , Japón/epidemiología , Estudios Longitudinales , Masculino , Prevalencia , Adulto JovenRESUMEN
A 12-year-old girl presented with talipes equinus of both legs, attenuation of upper and lower limb tendon reflexes, thermal hyperalgesia, and reduction of vibratory sensation. On clinical examination, muscle twitches of fingers of both hands, as well as the abductor halluces and the dorsal interossei muscles of the right foot were observed. Nerve conduction velocity was significantly declined in the upper and lower extremities. Needle electromyography (EMG) was not performed; however, ultrasonography revealed repetitive, semi-regular muscle twitches lasting 0.2-0.4s, concomitant with muscle discharges on surface EMG in the right foot muscles. These findings were compatible with contraction fasciculation in muscles under chronic reinnervation. Nerve and muscle biopsies were suggestive of chronic motor, sensory, and autonomic neuropathy. This is the first case of pediatric peripheral neuropathy where muscle fasciculation was noninvasively identified by simultaneous surface EMG and ultrasonography.
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Electromiografía , Fasciculación/diagnóstico , Fasciculación/fisiopatología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Ultrasonografía , Niño , Fasciculación/patología , Fasciculación/terapia , Femenino , Humanos , Extremidad Inferior/diagnóstico por imagen , Extremidad Inferior/fisiopatología , Músculo Esquelético/patología , Conducción Nerviosa , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/fisiopatología , Enfermedades Neuromusculares/terapia , Extremidad Superior/diagnóstico por imagen , Extremidad Superior/fisiopatología , Vómitos/diagnóstico , Vómitos/patología , Vómitos/fisiopatología , Vómitos/terapiaRESUMEN
An 11-year-old boy with Lesch-Nyhan syndrome (LNS) had persistently injured himself by biting his lips and buccal mucosa since infancy. Risperidone was only partially effective in suppressing this behavior. Oral administration of S-adenosylmethionine (SAMe), involving increasing the dose from 400 mg to 1 g, resulted in the amelioration of self-injurious behavior and anxiety as well as marked improvement in his self-esteem, performance at school, and friendships. No adverse effects were noted. SAMe may have a favorable effect on symptoms of LNS by activating monoaminergic pathways and/or increasing the adenosine pool in the salvage pathway of guanosine monophosphate synthesis. Defects in these pathways have been essentially implicated in the neurological pathophysiology of LNS.
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Síndrome de Lesch-Nyhan/terapia , S-Adenosilmetionina/uso terapéutico , Conducta Autodestructiva/tratamiento farmacológico , Niño , Humanos , Hipoxantina Fosforribosiltransferasa/genética , Síndrome de Lesch-Nyhan/complicaciones , Masculino , Calidad de Vida , Conducta Autodestructiva/etiologíaRESUMEN
There are no published reports of patients harboring microdeletions involving the 7p22.1 region. Although 7p22.1 microdeletions are rare, some reports have shown microduplications encompassing this region. In this study, we report five patients with overlapping deletions of the 7p22.1 region. The patients exhibited clinical similarities including non-specific developmental delay, short stature, microcephaly, and other distinctive features. The shortest region of overlap within the 7p22.1 region includes five genes, FBXL18, ACTB, FSCN1, RNF216, and ZNF815P. Of these genes, only ACTB is known to be associated with an autosomal dominant trait. Dominant negative mutations in ACTB are responsible for Baraitser-Winter syndrome 1. We analyzed ACTB expression in immortalized lymphocytes derived from one of the patients and found that it was reduced to approximately half that observed in controls. This indicates that ACTB expression is linearly correlated with the gene copy number. We suggest that haploinsufficiency of ACTB may be responsible for the clinical features of patients with 7p22.1 microdeletions.
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Actinas/genética , Discapacidades del Desarrollo/genética , Enanismo/genética , Microcefalia/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Actinas/biosíntesis , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Discapacidades del Desarrollo/fisiopatología , Enanismo/fisiopatología , Femenino , Expresión Génica/genética , Haploinsuficiencia/genética , Humanos , Lactante , Recién Nacido , Linfocitos/metabolismo , Linfocitos/patología , Masculino , Microcefalia/fisiopatología , FenotipoRESUMEN
BACKGROUND: Rett syndrome is characterized by psychomotor regression during early childhood, autistic-like behaviors, and aberrant breathing patterns. Dysfunction of the serotonergic system has been postulated to play a role in the pathophysiology of these symptoms. PATIENT DESCRIPTION: We present an 11-year-old girl with Rett syndrome who exhibited marked respiratory symptoms, including frequent apneic events during sleep. She had been treated for these respiratory symptoms using noninvasive positive pressure ventilation since age six years. Treatment with serotonin 1A receptor agonist was initiated at age eight years, whereas treatment using a selective serotonin reuptake inhibitor began at age nine years. Noninvasive positive pressure ventilation therapy was effective in reducing symptoms of sleep apnea, and administration of serotonergic agents resulted in amelioration of sleep apneic events even in the absence of noninvasive positive pressure ventilation. In addition, improvements in hand stereotypy and social skills were observed after initiation of serotonin-based therapy. DISCUSSION: The respiratory difficulties our patient experienced during non-rapid eye movement (REM) sleep are characteristic of post-sigh central apnea. Exaggerated activity of expiratory neurons during such apneic events has been observed in mouse models of Rett syndrome. We suggest that prescribed serotonergic agents might serve to inhibit such activity, attenuating the imbalance between inspiratory and expiratory neurons. These agents might also be useful in the treatment of autistic-like behaviors caused by impaired serotonergic transmission in the brain.
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Respiración/efectos de los fármacos , Síndrome de Rett/terapia , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Síndromes de la Apnea del Sueño/tratamiento farmacológico , Niño , Femenino , Humanos , Síndrome de Rett/fisiopatología , Sueño/efectos de los fármacos , Sueño/fisiología , Síndromes de la Apnea del Sueño/fisiopatologíaRESUMEN
OBJECTIVE: Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. METHODS: This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. RESULTS: High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. INTERPRETATION: Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.
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BACKGROUND: Dystonia due to spinal lesions in adult patients is characterized by the provocation and/or amelioration of the spasm by somatosensory stimulation with a sensory trick. PATIENT DESCRIPTION: An infant with brachytelephalangic chondrodysplasia punctata developed flaccid tetraplegia due to cervical cord compression resulting from congenital atlantoaxial dislocation. Episodic, tonic extension of the extremities, neck, and trunk had appeared daily since age two years and was often provoked by tactile stimulation. Although decompression surgery was performed at age three years, progressive spinal deformity resulted in the aggravation of episodic dystonia thereafter, lasting for hours. Foot dorsiflexion and wearing a truncal brace for scoliosis inhibited these spasms. Intrathecal baclofen bolus injection transiently ameliorated the paroxysmal dystonia and detrusor-sphincter dyssynergia in the lower urinary tract. CONCLUSION: Paroxysmal dystonia is unusual in children with spinal cord lesions; however, it should be recognized for appropriate individualized clinical management.
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Artrogriposis/complicaciones , Baclofeno/uso terapéutico , Condrodisplasia Punctata/complicaciones , Distonía/tratamiento farmacológico , Distonía/etiología , Neuropatía Hereditaria Motora y Sensorial/complicaciones , Relajantes Musculares Centrales/uso terapéutico , Artrogriposis/etiología , Preescolar , Condrodisplasia Punctata/diagnóstico por imagen , Distonía/diagnóstico por imagen , Neuropatía Hereditaria Motora y Sensorial/etiología , Humanos , Inyecciones Espinales , Imagen por Resonancia Magnética , MasculinoRESUMEN
Objective: This study aimed to investigate the effectiveness of vigabatrin (VGB) for intractable generalized epilepsy in infants and young children. Methods: We retrospectively examined the data of 12 patients who received VGB at our department. There were eight patients with West syndrome, two with early-infantile epileptic encephalopathy, one with symptomatic generalized epilepsy, and one with early myoclonic encephalopathy. Results: All patients had drug-resistant epilepsy and received at least three antiepileptic drugs (range, 3-10 ; median, 5) before receiving VGB. These drugs included valproate (11 patients), nitrazepam (six patients), adrenocorticotropic hormone (ACTH ; five patients), clonazepam (four patients), and zonisamide (four patients). VGB was effective in only one case of symptomatic West syndrome associated with tuberous sclerosis. In two cases of cryptogenic West syndrome, VGB showed transient effects. Conclusions: VGB showed poor effectiveness for intractable generalized epilepsy in infancy and early childhood, except for West syndrome associated with tuberous sclerosis. Therefore, it is important to carefully select the cases for VGB administration.
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Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/tratamiento farmacológico , Vigabatrin/uso terapéutico , Preescolar , Epilepsia Refractaria/fisiopatología , Electroencefalografía , Humanos , Lactante , Recién Nacido , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Various conjugated cholesterol metabolites are excreted in urine of the patients with metabolic abnormalities and hepatobiliary diseases. We aimed to examine the usefulness of precursor ion scan and neutral loss scan for the characterization of conjugated cholesterol metabolites in urine. METHODS: A mixture of authentic standards of conjugated cholesterol metabolites was used for investigating the performance of the present method. The urine of patients with Niemann-Pick diseases type C and 3ß-hydroxysteroid dehydrogenase deficiency were analysed by precursor ion scan of m/z 97, 74, and 124. RESULTS: A precursor ion scan of m/z 97 was effective for identifying conjugates with ester sulphates on hydroxyl groups whereas ester sulphates on phenolic alcohols were signalled by a neutral loss scan of 80 Da. Monosaccharide-conjugated cholesterol metabolites were signalled by a precursor ion scan of m/z 113. Although precursor ion scan of m/z 74 and 124 was effective for finding glycine- and taurine-conjugated metabolites, high intensity of product ions (m/z 74 and 124) disturbed measurement of other multiply conjugated metabolites. The urine samples contained many conjugated cholesterol metabolites, and there were several disease-specific intense peaks. We found several unknown intense peaks with three known peaks in urine of the Niemann-Pick type C patient. In the patient with 3ß-hydroxysteroid dehydrogenase deficiency, intense peaks that were tentatively identified as 5-cholenoic acid sulphates and their glycine and taurine conjugates were present. CONCLUSION: The method should lead to the discovery of new urinary biomarkers for these disturbances of cholesterol catabolism and transport.
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Hiperplasia Suprarrenal Congénita/orina , Colesterol/orina , Metabolómica/normas , Enfermedad de Niemann-Pick Tipo C/orina , Espectrometría de Masa por Ionización de Electrospray/normas , Espectrometría de Masas en Tándem/normas , Hiperplasia Suprarrenal Congénita/diagnóstico , Biomarcadores/orina , Colesterol/metabolismo , Cromatografía Liquida/métodos , Cromatografía Liquida/normas , Femenino , Humanos , Lactante , Masculino , Metabolómica/métodos , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
BACKGROUND: Early predictors of status epilepticus (SE)-associated mortality and morbidity have not been systematically studied in children, considerably impeding the identification of patients at risk. OBJECTIVES: To determine reliable early predictors of SE-associated mortality and morbidity and identify the etiology of SE-associated sequelae in Japanese children. METHODS: We conducted a prospective multicenter study of clinical findings and initial laboratory data acquired at SE onset, and assessed outcomes at the last follow-up examination. In-hospital death during the acute period and neurological sequelae were classified as poor outcomes. RESULTS: Of the 201 children who experienced their first SE episode, 16 exhibited poor outcome that was most commonly associated with acute encephalopathy. Univariate analysis revealed that the following were associated with poor outcomes: young age (⩽24 months); seizure duration >90 min; seizure intractability (failure of the second anticonvulsive drug); biphasic seizures; abnormal blood glucose levels (<61 or >250 mg/dL); serum aspartate aminotransferase (AST) ⩾56 U/L; and C-reactive protein (CRP) levels >2.00 mg/dL. Multivariate analysis revealed that young age, seizure intractability, abnormal blood glucose levels, and elevated AST and CRP levels were statistically significant. CONCLUSIONS: Young age and seizure intractability were highly predictive of poor outcomes in pediatric SE. Moreover, abnormal blood glucose levels and elevated AST and CRP levels were predictors that might be closely associated with the etiology, especially acute encephalopathy and severe bacterial infection (sepsis and meningitis) in Japanese children.
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Estado Epiléptico/mortalidad , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Japón/epidemiología , Masculino , Pronóstico , Estudios Prospectivos , Estado Epiléptico/fisiopatologíaRESUMEN
A 2-year-old boy had glaucoma, bilateral facial haemangioma and widespread blue nevi on the trunk and extremities since birth. Dilated medullary veins were detected in the left cerebral periventricular white matter on magnetic resonance imaging (MRI). Macrocephaly and delayed psychomotor development were observed during late infancy, and susceptibility-weighted angiography revealed an extensive developmental venous anomaly with multiple caput medusae throughout bilateral hemispheres, accompanied by periventricular hyperintense alterations on MRI and progressive diffuse atrophy of the cerebral mantle with left-sided predominance. Hypoperfusion in the left cerebral and cerebellar hemisphere was also uncovered. No meningeal haemangioma was observed. This patient may represent a novel subgroup of phakomatosis cases that can be regarded as a variant of Sturge-Weber syndrome.
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Corteza Cerebral/patología , Síndrome de Sturge-Weber/patología , Atrofia/patología , Cerebelo/patología , Venas Cerebrales/patología , Preescolar , Hemangioma/patología , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.
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Trastorno Autístico/genética , Deleción Cromosómica , Mapeo Cromosómico , Discapacidades del Desarrollo/genética , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Proteínas de la Membrana/genética , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Síndrome WAGR/diagnóstico , Síndrome WAGR/genética , Proteínas WT1/genética , Preescolar , Hibridación Genómica Comparativa , Femenino , Estudios de Asociación Genética , Haploinsuficiencia , Humanos , Hibridación Fluorescente in Situ , Masculino , Factor de Transcripción PAX6 , Índice de Severidad de la EnfermedadRESUMEN
We developed a sensitive, reliable, and accurate LC/ESI-MS/MS method for measurement of 3ß-sulfooxy-7ß-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine and taurine amides in urine. This atypical C24 bile acid has been reported previously to be present in the urine of patients with Niemann-Pick Type C (NPC) disease. In the method, targeted analytes are concentrated at the front edge of a trapping column, Shim-pack MAYI-C8, which permits elimination of contaminating molecules in the urinary matrix. The trapped analytes are then eluted, separated on a YMC-Pack Pro C18, and quantified with MS/MS using selected reaction monitoring. The method could detect (as amount injected) 2pg of nonamidated 3ß-sulfooxy-7ß-N-acetylglucosaminyl-5-cholen-24-oic acid, 2pg of its glycine-amide, and 0.6pg of its taurine-amide, and is linear up to 300pg. The method was then used to measure the three analytes in the urine of NPC patients (N=2), 3ß-hydroxysteroid dehydrogenase deficiency patients (N=2), and healthy volunteers (N=8). Measurable concentrations of all three analytes were present in all subjects. The urinary concentration of the sum of all three analytes was four hundred times greater in the 3month NPC patient and 40times greater in the adult patient than that of healthy volunteers. The markedly elevated urinary concentration of 3ß-sulfooxy-7ß-N-acetylglucosaminyl-5-cholen-24-oic acid and its amides in NPC patients suggests that these compounds may be valuable biomarkers for detection of NPC disease.
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Enfermedad de Niemann-Pick Tipo C/orina , Saponinas/orina , Adolescente , Adulto , Biomarcadores/orina , Estudios de Casos y Controles , Femenino , Humanos , Lactante , Masculino , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Niemann-Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Currently, there are no effective treatments for NPC, although miglustat has shown some effectiveness in stabilizing neurological status in juvenile-onset NPC patients. Recent studies have demonstrated the efficacy of hydroxypropyl-ß-cyclodextrin (HPB-CD) in NPC mice. Herein, we describe the effects of HPB-CD in two patients with NPC. The two patients received HPB-CD infusions twice (Patient 2) or thrice (Patient 1) weekly, starting with a dose of 80 mg/kg per dose that was increased gradually to 2g/kg per dose (Patient 2) or 2.5 g/kg per dose (Patient 1). Although HPB-CD did not improve the neurological deficits in either patient, it was partially effective in improving hepatosplenomegaly and central nervous system dysfunction, especially during the first 6 months of treatment. No adverse effects were observed over the course of treatment, although Patient 1 exhibited transient cloudiness of the lungs with fever after 2 years. For more effective treatment of NPC patients with HPB-CD, it is necessary to improve drug delivery into the central nervous system.
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Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , beta-Ciclodextrinas/uso terapéutico , 2-Hidroxipropil-beta-Ciclodextrina , Adolescente , Preescolar , Femenino , HumanosRESUMEN
BACKGROUND: Duplications involving the methyl-CpG-binding protein 2 gene (MECP2) locus at Xq28 have been frequently identified in male patients who exhibit a phenotype unique from that of Rett syndrome, which is mainly characterized by severe mental retardation, recurrent infections, and epilepsy. This combination of features is recognized as MECP2 duplication syndrome. METHODS: Genomic copy number was investigated for patients with unexplained mental retardation, and phenotypic features of the patients having interstitial duplications including MECP2 were analyzed. RESULTS: Three male and one female patients with MECP2 duplication were identified. The phenotypic features of all the four patients were compatible with MECP2 duplication syndrome. The X-chromosome inactivation (XCI) pattern was analyzed in the female patient, identifying a skewed XCI that activated the X-chromosome containing the MECP2 duplication. Her mother possessed the same MECP2 duplication and a random XCI pattern but exhibited no phenotypic features, indicating a nonsymptomatic carrier. The brain magnetic resonance imaging revealed periventricular cystic lesions in all four patients, including the female patient. CONCLUSION: This study suggested clinical implications of the MECP2 duplication syndrome not only in the male but also in female patients with unexplained mental retardation.
Asunto(s)
Duplicación de Gen/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Inactivación del Cromosoma X/genética , Adolescente , Encéfalo/patología , Preescolar , Mapeo Cromosómico , Femenino , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Fenotipo , Adulto JovenRESUMEN
We report a patient harboring a novel homozygous mutation of c.604T>G (p.F202V) in POMT2. He showed delayed psychomotor development but acquired the ability to walk at the age of 3 years and 10 months. His brain MRI was normal. No ocular abnormalities were seen. Biopsied skeletal muscle revealed markedly decreased but still detectable glycosylated forms of alpha-dystroglycan (alpha-DG). Our results indicate that mutations in POMT2 can cause a wide spectrum of clinical phenotypes as observed in other genes associated with alpha-dystroglycanopathy. Presence of small amounts of partly glycosylated alpha-DG may have a role in reducing the clinical symptoms of alpha-dystroglycanopathy.