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Biomedical subjects

Eugen Boltshauser

Publications and source records attributed to Eugen Boltshauser.

At least 19 recordsLinked to original sources
PubMed2006

Long-term outcome of ten children with opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) in children is a rare neurological condition with opsoclonus, myoclonus, ataxia and irritability in the first 2 years of life. It can be idiopathic, parainfectious, or paraneoplastic with tumours of the neural crest. Few studies of long-term follow-up after OMS have been published. We investigated the motor, cognitive and behavioural outcome of ten patients (eight girls and two boys) seen between 1987 and 2002. We reviewed the records and reassessed the patients. A ganglioneuroma was found in one patient and a neuroblastoma in another. Tumour resection did not influence the OMS. The age at diagnosis was 10-24 months and the follow-up period 1-17 years (average 6.5 years). The interval between the first signs and symptoms and starting treatment was 2-12 weeks: treatment consisted of different immunosupressants. Remission was achieved within 5 months in seven, and relapses were present in seven of ten. At follow-up, only one child had mild ataxia. IQ testing was performed in nine with scores below 75 in four and above 85 in four. Attention deficit and visuomotor difficulties led to school problems with special needs, also in those three children with normal IQs. Only two children were attending regular schools. Behavioural problems were reported in seven, and speech difficulties were present in five. In conclusion, the long-term outcome in our patients with OMS was dominated by cognitive and behavioural problems and not by ataxia. Compared with previous reports, our patients were treated earlier. Larger studies and uniform treatment protocols are needed to demonstrate whether early and prolonged immunosupressant therapy has a favourable influence on outcome.

Adolescent↗
PubMed2006

Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit.

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.

Amino Acid Sequence↗
PubMed2006

Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome.

Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.

Animals↗
PubMed2006

Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: clinical and radiographic delineation of a pleiotropic disorder.

Enchondromas are a feature of several constitutional disorders of bone, and the classification of different nosologic entities is still provisional. Among these disorders, spondyloenchondrodysplasia (SPENCD), as outlined by Schorr et al. [1976], is defined by the presence of radiolucent spondylar and metaphyseal lesions that represent persistence of islands of chondroid tissue within bone. Careful review of radiographic findings is needed to distinguish SPENCD from the many other disorders combining enchondromas with spinal lesions. Even when strict criteria are applied, it appears that SPENCD is clinically heterogeneous, as some SPENCD patients are neurologically intact while others present with spasticity, mental retardation, and cerebral calcifications in different combinations, and it has been suggested that SPENCD should be divided in two types. We herein report ten individuals from six families with SPENCD and illustrate the radiographic changes. Seven individuals had CNS manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. We also noted that six individuals had clinical manifestations of autoimmunity (auto-immune thrombocytopenic purpura, auto-immune hemolytic anemia, auto-immune thyroiditis, and SLE) and one had been diagnosed with immune deficiency. Neurological and autoimmune manifestations were seen in different combinations within one single family. These observations suggest that SPENCD may be a single entity defined by specific radiographic features, but with remarkably pleiotropic manifestations that include CNS disease (spasticity, mental retardation, and calcifications), as well as immune dysregulation ranging from autoimmunity to immunodeficiency. The notion of recessive inheritance hitherto assumed is challenged by the observation of two apparently dominant pedigrees.

Abnormalities, Multiple↗
PubMed2006

Facial nerve palsy-an unusual complication after evacuation of a subdural haematoma or hygroma in children.

OBJECTIVE: This paper reports and discusses on the possible etiology of postoperative contralateral facial nerve palsy after uneventful evacuation of a subdural haematoma or hygroma after mild head trauma in two children with pre-existing middle cranial fossa subarachnoid cysts. RESULTS: Two 14- and 15-year-old boys had prolonged headaches after mild head injuries. CT showed a right-sided middle cranial fossa arachnoid cyst in each patient. In one patient, an ipsilateral subdural haematoma was identified, and in the other, bilateral hygromas were identified. Exacerbation of symptoms required emergency evacuation of the subdural haematoma in the first child, and bilateral external drainage of the hygroma in the other child. In both children the late postoperative period was complicated by peripheral facial nerve palsies contralateral to the arachnoid cyst. CONCLUSION: Facial nerve palsy may be a complication of hygroma or haematoma drainage. The etiology is not clear; traction of the facial nerve due to displacement of the brainstem may be the most likely explanation.

Adolescent↗
PubMed2006

Optic nerve sheath meningiomas in patients with neurofibromatosis type 2.

OBJECTIVE: To determine the prevalence of optic nerve sheath meningiomas (ONSMs) in patients with neurofibromatosis type 2 (NF2). METHODS: An observational retrospective case series of 30 consecutive patients with NF2 referred to an academic ophthalmology unit from November 1, 1991, through August 31, 2003. Twenty-six patients were followed up for a mean of 93 months (range, 3-150 months). One individual was lost to follow-up, and 3 had been referred recently. Diagnosis of ONSM was made based on typical neuroradiologic and clinical features in 7 patients and on histologic criteria in 1. RESULTS: Eight of 30 patients harbored unilateral (n = 6) or bilateral (n = 2) ONSMs. Six ONSMs were diagnosed at initial examination, and 4 during follow-up. CONCLUSIONS: There is a strong association between ONSMs and NF2 that parallels the well-known association of optic nerve gliomas with NF1. Physicians should be aware of the possibility that patients with ONSMs may also have NF2.

Adolescent↗
PubMed2006

Clinical and biochemical spectrum of D-bifunctional protein deficiency.

OBJECTIVE: D-bifunctional protein deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation. Although case reports and small series of patients have been published, these do not give a complete and balanced picture of the clinical and biochemical spectrum associated with this disorder. METHODS: To improve early recognition, diagnosis, prognosis, and management of this disorder and to provide markers for life expectancy, we performed extensive biochemical studies in a large cohort of D-bifunctional protein-deficient patients and sent out questionnaires about clinical signs and symptoms to the responsible physicians. RESULTS: Virtually all children presented with neonatal hypotonia and seizures and died within the first 2 years of life without achieving any developmental milestones. However, within our cohort, 12 patients survived beyond the age of 2 years, and detailed information on 5 patients with prolonged survival (> or =7.5 years) is provided. INTERPRETATION: Biochemical analyses showed that there is a clear correlation between several biochemical parameters and survival of the patient, with C26:0 beta-oxidation activity in cultured skin fibroblasts being the best predictive marker for life expectancy. Remarkably, three patients were identified without biochemical abnormalities in plasma, stressing that D-bifunctional protein deficiency cannot be excluded when all peroxisomal parameters in plasma are normal.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2006

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.

OBJECTIVE: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. METHODS: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. RESULTS: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. INTERPRETATION: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2.

PURPOSE: To evaluate ophthalmologic findings and long-term course in patients with neurofibromatosis type 2 (NF2). DESIGN: Retrospective observational case series. METHODS SETTING: Single-center institutional practice. STUDY POPULATION: Thirty referred patients with NF2 were enrolled from 1991 to 2003 and underwent at least one thorough neuroophthalmologic examination. Follow-up of 23 patients ranged from 4.3 to 12.5 years. MAIN OUTCOME MEASURES: Visual function, structural ocular abnormalities, onset and type of presenting NF2-related symptoms, and number of central nervous system tumors. RESULTS: Initial symptoms for patients with early-onset NF2 mostly comprised ophthalmologic symptoms (n = 7) and lower motor neuron extremity weakness (n = 6), as opposed to eighth nerve impairment (n = 11) in late disease onset. NF2-specific ocular findings were noted in 83% of all patients (94% childhood onset; 67% adult onset): 67% had cataracts, 40% epiretinal membranes, 3% hamartoma, 13% disk gliomas, and 27% optic nerve sheath meningiomas. Only 14% in the childhood-onset group-as opposed to 78% in the adult-onset group-sustained visual acuity of 1.0 in both eyes at final examination. Significantly more patients with early onset of symptoms developed multiple central nervous system tumors (P = .004) and showed a higher amount of NF2-specific findings (P = .015). CONCLUSIONS: Initial manifestations of NF2 differ between children and adults. NF2-specific ophthalmologic findings can help establish the diagnosis. Symptom onset at a young age is clearly a risk factor for marked disease progression. These patients should be carefully followed because survival rates have increased, and vision becomes increasingly important as the disease progresses.

Adolescent↗
PubMed2006

Quality of life and psychological adjustment in children and adolescents with neurofibromatosis type 1.

OBJECTIVE: To assess quality of life (QoL) and psychological adjustment in children and adolescents with neurofibromatosis type 1 (NF1). STUDY DESIGN: Forty-six patients with NF1 were investigated between the ages of 7 and 16 years (mean, 11.6 years), with children and parents used as informants. TNO-AZL Questionnaire for Children's Health-Related Quality of Life and Child Behavior Checklist scores were compared with healthy reference groups. Predictive values of sociodemographic variables, illness-related variables, and family-related variables for quality of life and psychological adjustment were assessed. RESULTS: Most dimensions of QoL in NF1 children and adolescents were different from reference values. Deviations in the NF1 group were an impairment of motor, cognitive, and social functioning and a reduction of positive and negative emotions. Also, psychological adjustment in patients with NF1 was significantly impaired compared with normal subjects. Illness-related variables had a negative impact on the emotional domain of QoL. Good family relationships positively affected both QoL and psychological adjustment. CONCLUSIONS: QoL and psychological adjustment are impaired in children and adolescents with NF1. Illness-related variables and the quality of family relationships are important predictors.

Adaptation, Psychological↗
PubMed2006

Proven startle-provoked epileptic seizures in childhood: semiologic and electrophysiologic variability.

PURPOSE: To delineate further the clinical and electrophysiologic features of proven startle-provoked epileptic seizures (SPESs) in children. METHODS: Clinical, neuroradiologic, and neurophysiologic data of 22 consecutive patients with SPESs were analyzed. Eighty-nine SPESs were documented by video-EEG and evaluated with respect to semiology and ictal and interictal EEG findings. RESULTS: Mean age was 68 months (10-178 months). Most children had severe mental retardation (86%). Neuroimaging demonstrated diffuse cerebral abnormalities in 15 of 19. Somatosensory evoked potentials revealed cortical abnormalities in 10 of 13 children. The underlying causes were heterogeneous. Only two patients were normally developed. Seizure frequency was usually high (>10/day). Two children had less frequent SPESs (two per month; two per week). Seizures were easily precipitated by sudden sound (n=15), unexpected touch (n=3), or both (n=4). The most common semiologic findings (50%) were generalized tonic seizures or those characterized by a predominant tonic phase, followed in frequency by myoclonic seizures (36%), which were generalized in seven, and unilateral in one. Generalized clonic seizures were observed in one. A complex seizure spread was documented in two children. The most common ictal EEG finding (60%) was a diffuse electrodecremental pattern (DEP). Generalized spike/polyspike waves were found in five and focal discharges in four. CONCLUSIONS: Our results imply that startle epilepsy is not a uniform epileptic entity. We were able to demonstrate a number of distinct patterns of SPESs, characterized by clinical, semiologic, and electrophysiologic features. Considering the high diversity of SPES patients, a common underlying pathophysiologic mechanism seems unlikely.

Acoustic Stimulation↗
PubMed2005

Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2gene.

UNLABELLED: A boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. Hypertrophic cardiomyopathy progressed relentlessly, leading to death at age 16 years shortly before planned heart transplantation. During the course of the disease, his mother developed severe dilated cardiomyopathy and died of its complications at 46 years of age. The combination of myopathy and cardiomyopathy, the biochemical and electron microscopy findings in a muscle biopsy, and the pedigree suggested Danon disease (MIM 300257), an X-linked lysosomal storage disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP2). The diagnosis was confirmed by the identification of a novel mutation, G138A, in the LAMP2gene, leading to the premature stop codon W46X. CONCLUSION: Early diagnosis of Danon disease is important for genetic counselling and timely cardiac transplantation, the only effective therapeutic option.

Adolescent↗
PubMed2005

Distinguishing the four genetic causes of Jouberts syndrome-related disorders.

Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34.3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.

Abnormalities, Multiple↗
PubMed2005

Disruption of cerebellar development: potential complication of extreme prematurity.

BACKGROUND AND PURPOSE: Infants with very low birth weight are at high risk for cerebral lesions. Although supratentorial brain damage is a common radiologic finding, posterior fossa pathologies are rare. We studied the morphology of cerebellar involvement in a large series of 28 premature infants born before the 30th week of gestation to define typical patterns and identify possible risk factors for this pathology. METHODS: Cranial sonograms were obtained in the early neonatal period. MR imaging was performed between the 2nd month and the 6th year of life. Morphologic patterns of cerebellar involvement were evaluated. RESULTS: Three morphologic patterns of cerebellar involvement were recognized: (1) symmetric volume reduction of the cerebellar hemispheres, which were floating immediately beneath the tentorium, and a small vermis with preserved shape; (2) symmetrical reduction in hemispheric volume with an enlarged, balloon-shaped fourth ventricle and a small, deformed vermis; and (3) normal overall cerebellar shape with extensive reduction of its dimensions. A small brain stem with flattened anterior curvature of the pons and loss of supratentorial white matter was present in all patients. CONCLUSION: Symmetric cerebellar volume reduction was found as a consequence of extreme prematurity. Selective vulnerability of the developing cerebellum in the window of 24-30 weeks of gestation, combined with several additive perinatal risk factors (eg, hemosiderin deposits) seems to lead to destruction of immature structures and developmental arrest. Therefore, the resulting condition is the consequence of disrupted cerebellar development.

Cerebellum↗
PubMed2005

Diffusion tensor imaging in progressive multifocal leukoencephalopathy: early predictor for demyelination?

Progressive multifocal leukoencephalopathy is a severe demyelinating disease of the central nervous system caused by a JC papovavirus infection. Prognosis is poor with fatal outcome within 1 year in 90% of patients. Our case report shows that diffusion tensor imaging can give early and specific information about disease status and extent in a 15-year-old girl with progressive multifocal leukoencephalopathy associated with congenital human immunodeficiency virus (HIV) infection.

Adolescent↗