ABSTRACT
AIM: To compare the predictive values of the General Movements Assessment (GMA) and the Standardized Infant NeuroDevelopmental Assessment (SINDA) neurological scale for atypical neurodevelopmental outcome in 3-month-old at-risk infants. METHOD: A total of 109 infants (gestational age 30 weeks; range: 24-41; 52 males) attending a non-academic outpatient clinic were assessed with the GMA and the SINDA at 3 (2-4) months corrected age. The GMA pays attention to the complexity of general movements and presence of fidgety movements. Atypical neurodevelopmental outcome at 24 months corrected age (and older) implied cerebral palsy (CP) or a Bayley Mental Development Index or Bayley Psychomotor Development Index lower than 70. RESULTS: At 24 months corrected (and older) age, 16 children had an atypical outcome, including 14 children with CP. Regarding markedly reduced general movement complexity in combination with absent or sporadic fidgety movements, the GMA predicted an atypical outcome with specificity, positive, and negative predictive values greater than 0.900, and sensitivity of 0.687 (95% confidence interval [CI] = 0.460-0.915). SINDA predicted an atypical outcome with sensitivity, specificity, and negative predictive value greater than 0.900 and a positive predictive value of 0.652 (95% CI = 0.457-0.847). Regarding absent fidgety movements only or markedly reduced general movement complexity, the GMA predicted the outcome less well than both general movement criteria. INTERPRETATION: The SINDA and GMA both predict neurodevelopmental outcome well, but SINDA is easier to learn than the GMA; being a non-video-based assessment, it allows caregiver feedback during the consultation whereas the GMA usually does not.
ABSTRACT
Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.
Subject(s)
Magnetic Resonance Imaging , White Matter , Humans , Male , Adolescent , Magnetic Resonance Imaging/methods , Brain , White Matter/pathology , Diffusion Magnetic Resonance Imaging , Neurologic ExaminationABSTRACT
AIM: To assess the reliability and predictive validity of the developmental and socio-emotional scales of the Standardized Infant NeuroDevelopmental Assessment (SINDA). METHOD: To assess reliability, two sets of three assessors forming eight assessor-pairs independently rated the developmental and socio-emotional scales of 60 infants. To evaluate predictive validity, 223 infants (gestational age 30wks [range 23-41wks]; 117 males, 106 females) attending a non-academic outpatient clinic were assessed by different assessors with SINDA's neurological, developmental, and socio-emotional scales. Atypical neurodevelopmental outcome at a corrected age of 24 months or older implied a Bayley Mental or Psychomotor Developmental Index score of less than 70 or neurological disorder (including cerebral palsy). Behavioural and emotional disorders were classified according to the International Classification of Diseases, 10th Revision. Predictive values were calculated from SINDA (2-12mo corrected age, median 7mo) and typical versus atypical outcome, and for intellectual disability only (Mental Developmental Index <70). RESULTS: Assessors highly agreed on the developmental and socio-emotional assessments (developmental scores: Spearman's rank correlation coefficient ρ=0.972; single socio-emotional behaviour items: Cohen's κ=0.783-0.896). At 24 months or older, 65 children had atypical outcome. Atypical neurological scores predicted atypical outcome (sensitivity 83%, specificity 96%); atypical developmental scores predicted intellectual disability (sensitivity 77%, specificity 92%). Atypical emotionality and atypical self-regulation were associated with behavioural and emotional disorders. INTERPRETATION: SINDA's three scales are reliable, and have a satisfactory predictive validity for atypical developmental outcome at 24 months or older in a non-academic outpatient setting. SINDA's developmental scale has promising predictive validity for intellectual disability. SINDA's socio-emotional scale is a tool for caregiver counselling. WHAT THIS PAPER ADDS: Standardized Infant NeuroDevelopmental Assessment (SINDA)'s developmental and socio-emotional scales have excellent interrater reliability. Replication of the satisfactory validity of SINDA's neurological scale for atypical outcome.
Subject(s)
Diagnostic Techniques, Neurological/standards , Neurodevelopmental Disorders/diagnosis , Psychiatric Status Rating Scales/standards , Self-Control , Affective Symptoms/diagnosis , Child Behavior Disorders/diagnosis , Emotional Regulation , Female , Humans , Infant , Intellectual Disability/diagnosis , Male , Predictive Value of Tests , Psychometrics/standards , Reproducibility of ResultsABSTRACT
Children with motor development disorders benefit greatly from early interventions. An early diagnosis in pediatric preventive care (U2-U5) can be improved by automated screening. Current approaches to automated motion analysis, however, are expensive, require lots of technical support, and cannot be used in broad clinical application. Here we present an inexpensive, marker-free video analysis tool (KineMAT) for infants, which digitizes 3D movements of the entire body over time allowing automated analysis in the future.Three-minute video sequences of spontaneously moving infants were recorded with a commercially available depth-imaging camera and aligned with a virtual infant body model (SMIL model). The virtual image generated allows any measurements to be carried out in 3D with high precision. We demonstrate seven infants with different diagnoses. A selection of possible movement parameters was quantified and aligned with diagnosis-specific movement characteristics.KineMAT and the SMIL model allow reliable, three-dimensional measurements of spontaneous activity in infants with a very low error rate. Based on machine-learning algorithms, KineMAT can be trained to automatically recognize pathological spontaneous motor skills. It is inexpensive and easy to use and can be developed into a screening tool for preventive care for children.
Subject(s)
Developmental Disabilities/diagnosis , Movement , Algorithms , Child , Early Diagnosis , Germany , Humans , InfantABSTRACT
AIM: To assess reliability and predictive validity of the neurological scale of the Standardized Infant NeuroDevelopmental Assessment (SINDA), a recently developed assessment for infants aged 6 weeks to 12 months. METHOD: To assess reliability, three assessors independently rated video-recorded neurological assessments of 24 infants twice. Item difficulty and discrimination were determined. To evaluate predictive validity, 181 infants (median gestational age 30wks [range 22-41wks]; 92 males, 89 females) attending a non-academic outpatient clinic were assessed with SINDA's neurological scale (28 dichotomized items). Atypical neurodevelopmental outcome at 24 months or older corrected age implied a Bayley Mental Developmental Index or Psychomotor Developmental Index lower than 70 or a diagnosis of cerebral palsy (CP). Predictive values were calculated from SINDA (2-12mo corrected age, median 3mo) and typical versus atypical outcome. RESULTS: Intraclass correlation coefficients of intrarater and interrater agreement of the neurological score varied between 0.923 and 0.965. Item difficulty and discrimination were satisfactory. At 24 months or older, 56 children (31%) had an atypical outcome (29 had CP). Atypical neurological scores (below 25th centile, ≤21) predicted atypical outcome and CP with sensitivities of 89% and 100%, and specificities of 94% and 81% respectively. INTERPRETATION: SINDA's neurological scale is reliable and in a non-academic outpatient setting has a satisfactory predictive validity for atypical developmental outcome, including CP, at 24 months or older. WHAT THIS PAPER ADDS: The Standardized Infant NeuroDevelopmental Assessment's neurological scale has a good to excellent reliability. The scale has promising predictive validity for cerebral palsy. The scale has promising predictive validity for other types of atypical developmental outcome.
CONFIABILIDAD Y VALIDEZ PREDICTIVA DE LA ESCALA NEUROLÓGICA DE LA EVALUACIÓN DEL NEURODESARROLLO INFANTIL ESTANDARIZADA: OBJETIVO: Evaluar la confiabilidad y la validez predictiva de la escala neurológica de la Evaluación del Neurodesarrollo Infantil Estandarizada (SINDA), una evaluación desarrollada recientemente para bebés de 6 semanas a 12 meses. MÉTODO: Para evaluar la confiabilidad, tres evaluadores evaluaron dos veces, de forma independiente, las evaluaciones neurológicas grabadas en videos de 24 recién nacidos. Se determinaron la dificultad del ítem y la discriminación. Para evaluar la validez predictiva, se evaluaron 181 neonatos (mediana de edad gestacional de 30 semanas [rango 22-41 semanas], 92 varones, 89 mujeres) que asisten a una clínica ambulatoria no académica con la escala neurológica de SINDA (28 ítems dicotomizados). El resultado del desarrollo neurológico atípico a los 24 meses o mayor edad corregida implicaba un índice de desarrollo mental o índice de desarrollo psicomotor Bayley inferior a 70 o un diagnóstico de parálisis cerebral (PC). Los valores predictivos se calcularon a partir de SINDA (edad corregida 2-12mo, mediana 3meses) y resultado típico versus a atípico. RESULTADOS: Los coeficientes de correlación intraclase de la concordancia intra e inter codificador del puntaje neurológico variaron entre 0.923 y 0.965. La dificultad del item y la discriminación fueron satisfactorias. A los 24 meses o más, 56 niños (31%) tuvieron un resultado atípico (29 tuvieron PC). Las puntuaciones neurológicas atípicas (por debajo del percentil 25, ≤21) predijeron un resultado atípico y PC con sensibilidades del 89% y del 100%, y especificidades del 94% y del 81%, respectivamente. INTERPRETACIÓN: La escala neurológica de SINDA es confiable y en un entorno ambulatorio no académico tiene una validez predictiva satisfactoria para la detección del desarrollo atípico, incluido la PC, a los 24 meses o más.
CONFIABILIDADE E VALIDADE PREDITIVA DA ESCALA NEUROLÓGICA DE AVALIAÇÃO PADRONIZADA NEURODESENVOLVIMENTAL INFANTIL: OBJETIVO: Avaliar a confiabilidade e validade preditiva da escala neurológica Avaliação Padronizada Neurodesenvolvimental Infantil (SINDA), uma avaliação desenvolvida recentemente para lactentes de 6 semanas a 12 meses de idade. MÉTODO: Para avaliar a confiabilidade, por duas vezes três avaliadores pontuaram independentemente avaliações neurológicas de 24 lactentes registradas em vídeo. Para avaliar a validade preditiva, 181 lactentes (idade gestacional mediana de 30 semanas[variação de 22 a 41 semanas]); 92 do sexo masculino; 89 do sexo feminino) que frequentavam uma clínica não acadêmica foram avaliados com a escala neurológica da SINDA (28 itens dicotomizados). O neurodesenvolvimento atípico na idade de 24 meses de idade corrigida ou mais tarde foi determinado por índice desenvolvimental mental da Bayley ou Item desenvolvimental psicomotor menor do que 70 ou diagnóstico de paralisia cerebral (PC). Os valores preditivos foram calculados para o SINDA (2-12 meses de idade corrigida, mediana de 3 m) e resultado típico versus atípico. RESULTADOS: Os coeficientes de correlação intraclasse de concordância intra ou inter-examinadores do escore neurológico variaram de 0,923 a 0,965. A dificuldade e discriminação do item foram satisfatórias. Aos 24 meses de idade ou mais, 56 crianças (31%) tiveram resultado atípico (29 tinham PC). Os escores neurológicos atípicos (abaixo do percentil 25, ≤21) foram preditivos de resultado atípico e PC com sensibilidades de 89% e 100%, e especificidades de 94% e 81%, respectivamente. INTERPRETAÇÃO: A escala neurológica SINDA é confiável e em um ambiente não acadêmico tem validade preditiva satisfatória para resultado atípico do desenvolvimento, incluindo PC, aos 24 meses de idade ou mais.
Subject(s)
Diagnostic Techniques, Neurological/standards , Neurodevelopmental Disorders/diagnosis , Severity of Illness Index , Female , Humans , Infant , Longitudinal Studies , Male , Reproducibility of ResultsABSTRACT
Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.
Subject(s)
Heredodegenerative Disorders, Nervous System/enzymology , Heredodegenerative Disorders, Nervous System/genetics , Ribonuclease H/genetics , Amino Acid Sequence , Base Sequence , DNA/genetics , Encephalitis, Viral/congenital , Female , Humans , Male , Models, Molecular , Molecular Sequence Data , Mutation , Protein Structure, Quaternary , Protein Subunits , Ribonuclease H/chemistry , Ribonuclease H/metabolism , SyndromeABSTRACT
5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Malformations of Cortical Development/genetics , Brain/pathology , Child, Preschool , Comparative Genomic Hybridization , Facies , Humans , MEF2 Transcription Factors/genetics , Magnetic Resonance Imaging , Male , Malformations of Cortical Development/diagnosisABSTRACT
We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary alpha-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.
Subject(s)
Aldehyde Dehydrogenase/genetics , Mutation/genetics , Pyridoxine/metabolism , Seizures/genetics , Animals , Bacterial Proteins/metabolism , CHO Cells , Child , Child, Preschool , Cricetinae , Cricetulus , Exons/genetics , Heterozygote , Homozygote , Humans , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Pipecolic Acids/metabolism , Proline/metabolism , Pyridoxal Phosphate/metabolismABSTRACT
INTRODUCTION: Neurological soft signs (NSS) are minor deviations from the norm in motor performance that are commonly assessed using neurological examinations. NSS may be of clinical relevance for evaluating the developmental status of adolescents. Here we investigate whether quantitative force plate measures may add relevant information to observer-based neurological examinations. METHODS: Male adolescent athletes (n = 141) aged 13-16 years from three European sites underwent a neurological examination including 28 tests grouped into six functional clusters. The performance of tests and functional clusters was rated as optimal/non-optimal resulting in NSS+/NSS- groups and a continuous total NSS score. Participants performed a postural control task on a Balance Tracking System measured as path length, root mean square and sway area. ANCOVAs were applied to test for group differences in postural control between the NSS+ and NSS- group, and between optimal/non-optimal performance on a cluster- and test-level. Moreover, we tested for correlations between the total NSS score and postural control variables. RESULTS: There was no significant overall difference between the NSS+ and NSS- group in postural control. However, non-optimal performing participants in the diadochokinesis test swayed significantly more in the medial-lateral direction than optimal performing participants. Moreover, a lower total NSS score was associated with reduced postural control in the medial-lateral direction. CONCLUSION: Our findings demonstrate that NSS are related to postural control in adolescent athletes. Thus, force plate measures may add a quantitative, objective measurement of postural control to observer-based qualitative assessments, and thus, may complement clinical testing.
Subject(s)
Athletes , Postural Balance , Humans , Male , Adolescent , Neurologic ExaminationABSTRACT
BACKGROUND: General Movement Assessment (GMA) is a powerful tool to predict Cerebral Palsy (CP). Yet, GMA requires substantial training challenging its broad implementation in clinical routine. This inspired a world-wide quest for automated GMA. AIMS: To test whether a low-cost, marker-less system for three-dimensional motion capture from RGB depth sequences using a whole body infant model may serve as the basis for automated GMA. STUDY DESIGN: Clinical case study at an academic neurodevelopmental outpatient clinic. SUBJECTS: Twenty-nine high risk infants were assessed at their clinical follow-up at 2-4 month corrected age (CA). Their neurodevelopmental outcome was assessed regularly up to 12-31 months CA. OUTCOME MEASURES: GMA according to Hadders-Algra by a masked GMA-expert of conventional and computed 3D body model ("SMIL motion") videos of the same GMs. Agreement between both GMAs was tested using dichotomous and graded scaling with Kappa and intraclass correlations, respectively. Sensitivity and specificity to predict CP at ≥12 months CA were assessed. RESULTS: Agreement of the two GMA ratings was moderate-good for GM-complexity (κ = 0.58; ICC = 0.874 [95%CI 0.730; 0.941]) and substantial-good for fidgety movements (FMs; Kappa = 0.78, ICC = 0.926 [95%CI 0.843; 0.965]). Five children were diagnosed with CP (four bilateral, one unilateral CP). The GMs of the child with unilateral CP were twice rated as mildly abnormal with FMs. GM-complexity and somewhat less FMs, of both conventional and SMIL motion videos predicted bilateral CP comparably to published literature. CONCLUSIONS: Our computed infant 3D full body model is an attractive starting point for automated GMA in infants at risk of CP.
Subject(s)
Cerebral Palsy/diagnosis , Diagnosis, Computer-Assisted/methods , Imaging, Three-Dimensional/methods , Video Recording , Female , Humans , Infant , Male , Motor Activity , Neurologic Examination , Sensitivity and Specificity , Supine PositionABSTRACT
OBJECTIVE: Craniopharyngiomas in children are typically present in combination with heterogeneous clinical and neuroradiological findings. It has remained highly challenging to choose the optimal treatment strategy with regard to local tumor control and clinical outcome. Here, we analyze different treatment methods and evaluate the results. METHODS: We performed a detailed retrospective evaluation of 32 children <18 years old treated for craniopharyngioma between 1990 and 2008 at the University Hospital Freiburg. Three patient groups could be identified: children treated with microsurgical resection (n=17), with stereotactic cyst drainage and radiotherapy (n=7), and with various combined approaches (n=8). RESULTS: Six of seven children treated with stereotactic cyst punction and radiation are still alive. All of them are in an age-appropriate neuropsychological condition. Two of seven patients in this group have tumor recurrences. Fourteen of the 17 children treated with microsurgical resection show tumor recurrences (p=0.02). Fifteen are alive, and ten out of 17 show an age-appropriate neuropsychological development. The 8.5 years freedom from progression differed from 24% in the resection group to 71% in the cohort treated with stereotactic cyst drainage and radiotherapy (p=0.05). In the third group treated with various approaches, three of eight patients were treated for cystic recurrence. The average follow-up is 5.5 years. CONCLUSIONS: Based on our nonrandomized retrospective monocentric analysis, patients treated with less invasive stereotactic and radiotherapeutical methods have a more favorable long-term clinical outcome compared to children treated with a more radical microsurgical approach. Due to the possible implications of these results, further prospective trials should be encouraged.
Subject(s)
Brain Neoplasms/surgery , Craniopharyngioma/surgery , Neurosurgical Procedures/methods , Adolescent , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Child , Child, Preschool , Cohort Studies , Craniopharyngioma/pathology , Craniopharyngioma/radiotherapy , Cysts/radiotherapy , Cysts/surgery , Female , Follow-Up Studies , Humans , Infant , Male , Microsurgery/methods , Neoplasm Recurrence, Local , Radiotherapy/methods , Retrospective Studies , Stereotaxic Techniques , Treatment OutcomeABSTRACT
Osteoarticular infections in the newborn period are rare. A serious complication is paralysis of the affected extremity resulting from either pain or direct involvement of the nerve. We report a newborn with combined osteomyelitis and suppurative arthritis caused by Streptococcus pyogenes presenting with right brachial plexus palsy.
Subject(s)
Arthritis, Infectious , Brachial Plexus Neuropathies , Osteomyelitis , Shoulder , Streptococcal Infections , Streptococcus pyogenes , Anti-Bacterial Agents/therapeutic use , Humans , Infant, Newborn , Male , Penicillin G/therapeutic use , Shoulder/diagnostic imaging , Shoulder/pathology , Shoulder/physiopathologyABSTRACT
BACKGROUND: Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset encephalopathy with variable phenotype, including neurologic manifestations such as dystonia, spasticity, epileptic seizures, progressive microcephaly, and severe developmental delay. The aim of our study was the characterization of epilepsy, one of the most frequent and severe AGS manifestations, in molecularly confirmed patients. METHODS: We reviewed the medical records, EEG, and CT/MRI findings in 16 patients aged 1-22 years that carried AGS1-5 mutations. RESULTS: Epilepsy manifested in 12 (75%) patients and took a refractory course in 9 (56%). 4 (25%) patients presented with seizures in the first four weeks and 11 (69%) altogether in the first year of life. Spasms were reported in 3 (19%) patients, focal seizures in 4 (25%), myoclonic in 5 (31%), symmetric or asymmetric tonic in 11 (69%), generalized tonic-clonic in 3 (19%) and status epilepticus in 4 (25%). EEG recordings initially showed a slow and disorganized background, followed by a regional intermittent theta/delta slow, while obvious multifocal or generalized epileptic discharges were only observed at follow-up. None of these EEG features were specific of AGS. There was no discernible correlation between the genotype and epilepsy onset, seizure types and epilepsy evolution. Epilepsy severity did not correspond to neuroimaging pathology. DISCUSSION: Epilepsy constitutes a cardinal feature of AGS, characterized by early onset, predominantly tonic semiology and a refractory course. The early discrimination of epileptic seizures from paroxysmal dystonia poses a challenge for neuropaediatricians, considering the initially inconspicuous or non-specific EEG findings. This study underlines the necessity of a more systematic serial evaluation of AGS patients using long-term video-EEG recordings.
Subject(s)
Autoimmune Diseases of the Nervous System/physiopathology , Epilepsy/physiopathology , Nervous System Malformations/physiopathology , Adolescent , Adult , Age of Onset , Autoimmune Diseases of the Nervous System/complications , Autoimmune Diseases of the Nervous System/genetics , Child , Child, Preschool , Epilepsy/etiology , Epilepsy/genetics , Follow-Up Studies , Humans , Infant , Nervous System Malformations/complications , Nervous System Malformations/genetics , Phenotype , Retrospective Studies , Severity of Illness Index , Young AdultABSTRACT
PURPOSE: Observations of multiple ocular malformations together with heterozygosity for galactosaemia in siblings and homozygosity in one child are highly unusual. In these case histories, a series of investigations in one family are reported. METHODS: Members of a family of two brothers and one sister and their children were pre- and post-surgically examined over several years. Blood examination was carried out in a laboratory specializing in investigation into genetic diseases (Dr Podskarbi, Munich). RESULTS: Two brothers and one sister suffered from cataract-induced visual deterioration at 38, 34 and 35 years of age, respectively. All three siblings reported having had bilateral poor vision since early childhood. The three siblings' parents had no congenital ocular malformations, nor was there any parental consanguinity. One child, the 10-year-old son of the 35-year-old sister, exhibited classic galactosaemia and normal ocular findings. This sister's other child was healthy. All three siblings presented congenital lens luxation, axial myopia, cataract and iridodonesis. In addition, the 34-year-old brother showed unilateral right corectopia and left coloboma adjacent to the optic disc. The 38-year-old brother revealed myopic fundus changes, but no coloboma. The three siblings experienced a distinct increase in visual acuity after cataract surgery. Both eyes of the patients were partially or distinctly amblyopic, respectively. We assume an autosomal-recessive transmission. Molecular genetic examination of the 10-year-old child with classic galactosaemia showed homozygosity for the mutation Q188R with a complete galactose-1-phosphate-uridyltransferase (GALT) deficiency. Because of his galactose-free diet, the child showed normal values for galactose-1-phosphate. The 35-year-old mother showed compound heterozygosity for Q188R and G1391A (D2/G). The 10-year-old boy's father also revealed heterozygosity for galactosaemia caused by GALT deficiency. The two children of the 38-year-old brother were heterozygous for G1391A. They did not show any clinical abnormality. None of the family members had clinical signs of Marfan's syndrome or homocysteinuria. The three siblings' parents were not consanguineous. CONCLUSIONS: Patients with worsening cataracts occurring at a pre-senile age should be examined for galactosaemia. We describe for the first time the molecular genetic findings in congenital ectopia lentis et pupillae. Early treatment in conjunction with a galactose-free diet is mandatory in patients with galactosaemia. Members of a family with heterozygosity for galactosaemia should be advised to attend a human genetic consultation.
Subject(s)
Eye Abnormalities/genetics , Galactosemias/genetics , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/genetics , Adult , Cataract/complications , Cataract/genetics , Eye Abnormalities/complications , Family Health , Female , Galactosemias/complications , Humans , Lens Subluxation/complications , Lens Subluxation/genetics , Male , Myopia/complications , Myopia/genetics , Pedigree , Point Mutation , Pupil Disorders/complications , Pupil Disorders/genetics , SiblingsABSTRACT
The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ibß (GP1BB) but also the SEPT5 gene, located 5' to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIbß and SEPT5 proteins in the patient's platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealed impaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleeding episodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect.
Subject(s)
Bernard-Soulier Syndrome/therapy , Bone Marrow Transplantation , Cell Cycle Proteins/genetics , Factor IX/genetics , Septins/genetics , Bernard-Soulier Syndrome/genetics , Bernard-Soulier Syndrome/pathology , Bernard-Soulier Syndrome/physiopathology , Blood Platelets/metabolism , Blood Platelets/pathology , Child, Preschool , Disease-Free Survival , Exocytosis/genetics , Homozygote , Humans , Immune Tolerance , Male , Malformations of Cortical Development , Microscopy, Electron, Transmission , Neurons/metabolism , Neurons/pathology , Secretory Pathway/genetics , Secretory Vesicles/metabolism , Sequence Deletion/geneticsABSTRACT
BACKGROUND: National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome. METHODS: In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated. RESULTS: Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two. CONCLUSIONS: Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.
Subject(s)
Infant, Newborn, Diseases/diagnosis , Metabolism, Inborn Errors/diagnosis , Neonatal Screening/methods , Outcome Assessment, Health Care , Technology Assessment, Biomedical , Female , Germany/epidemiology , Humans , Infant, Newborn , Infant, Newborn, Diseases/epidemiology , Male , Metabolism, Inborn Errors/epidemiology , Phenylketonurias/diagnosis , Phenylketonurias/epidemiology , Tandem Mass Spectrometry/methodsABSTRACT
Epidemiological surveys have indicated that there has been a notable increase in the prevalence of both asthma and other allergic symptoms in children and young adults. Since it seems unlikely that genetic factors would contribute to the rising trend, environmental factors might play a major part in the development of childhood asthma. In a prospective birth-cohort study, we assessed the relevance of different exposures such as mite and cat allergen exposure, environmental tobacco smoke (ETS) exposure, early infectious diseases and vaccinations for the development of childhood asthma up to the age of 10 years. Data up to 7 years of age have been evaluated. Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children (72%). Assessments included repeated measurements of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months and 3 years of age and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial responsiveness was determined in 645 children. At age 7, the prevalence of wheezing in the past 12 months was 10% (94 out of 938), and 6.1% (57 out of 939) parents reported a doctor's diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness. However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. During the first 3 years of life, intra-uterine tobacco and consistent ETS exposure have an adjuvant effect on allergic sensitisation that is transient and restricted to children with a genetic predisposition for allergy. Children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88). Children with repeated episodes (> or =2) of runny nose before the age of 1 year were less likely to develop asthma by the age of 7 years (OR = 0.52; 95% CI = 0.29-0.92). Our data do not support the hypothesis that exposure to environmental allergens directly causes asthma in childhood but that induction of specific IgE responses and the development of childhood asthma are determined by independent factors. Indoor allergen avoidance is recommended as first line treatment in secondary and tertiary prevention; however, conclusions should be drawn with caution about the possible effect of primary preventative measures. Since allergic asthma seems to be a Th2-disease, immunomodulating factors such as early childhood infections, LPS-exposure or other factors influencing gene-environment interaction and individual susceptibility seem to be relevant for the development of childhood asthma.