Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy.

OBJECTIVE: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS: Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

Prednisone 10 days on/10 days off in patients with Duchenne muscular dystrophy.

Corticosteroids are effective in improving motor function in Duchenne muscular dystrophy (DMD) patients within 6 months-2 years of treatment initiation, but there is as yet no consensus on which treatment scheme is the best. We retrospectively analyzed data of 35 DMD patients who were treated with prednisone 0.75 mg/kg per day intermittently 10 days on/10 days off. Prednisone was started during the ambulant phase at age 3.5-9.7 years (median 6.5 years). The median period of treatment was 27 months (range 3-123 months). The median age at which ambulation was lost was 10.8 years (mean 10.9 years; 95% confidence interval 10.0-11.8 years). Nine patients (26%) had excessive weight gain. Eight boys (21%) had a bone fracture, which was when four of these eight children lost the ability to walk. Treatment was stopped in two obese patients, two hyperactive boys and one patient following a fracture. Our data suggest that prednisone 10 on/10 off has relatively few side effects and extends the ambulant phase by 1 year compared to historical controls.

Cerebral white matter abnormalities in 6p25 deletion syndrome.

Submicroscopic deletion of the terminal part of the short arm of chromosome 6, including 6p25, leads to developmental retardation, hearing impairment, ocular dysgenesis, and dysmorphic features. We diagnosed 3 patients referred because of white matter abnormalities of unknown origin. MR imaging showed multifocal areas of abnormal signal and enlarged perivascular spaces in the cerebral white matter that were stable during follow-up. Multifocal white matter abnormalities are most commonly seen in static, nonmetabolic encephalopathies, including chromosomal abnormalities.

GLUT-1 deficiency without epilepsy--an exceptional case.

The GLUT-1 deficiency is a metabolic disorder caused by a defect in glucose transport across the blood-brain barrier as a result of a defect in the glucose-transport protein. Patients present with epileptic seizures, delayed development, ataxia and hypotonia, and in many cases acquired microcephaly. In most patients, treatment with a ketogenic diet proved to be successful in controlling the epilepsy. We report a 9-year-old boy with retardation and ataxia, but without epilepsy, caused by GLUT-1 deficiency, proven biochemically and by DNA analysis. Treatment with a medium-chain triglyceride ketogenic diet had a beneficial effect.

Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children.

Rhombencephalosynapsis is a rare congenital abnormality characterised by dorsal fusion of the cerebellar hemispheres, agenesis or hypogenesis of the vermis, fusion of dentate nuclei and superior cerebellar peduncles. We describe 9 children, aged 1.5 to 6 years, with rhombencephalosynapsis. Isolated rhombencephalosynapsis was found in 2 patients, hydrocephalus in 3 children and another 3 children had ventriculomegaly. Additional supratentorial abnormalities were documented in 5 patients. Clinical findings ranged from mild truncal ataxia and normal cognitive abilities to severe cerebral palsy and mental retardation. No correlation between clinical findings and magnetic resonance imaging could be established so far.

An open, nonrandomized clinical comparative study evaluating the effect of epilepsy on learning.

Children with epilepsy, as a group, have a greater risk for developing learning problems as comorbid disorders. It is unknown which factors contribute to the development of such learning problems; therefore, our current knowledge does not allow the prediction of educational delay in an individual child with epilepsy. This study aimed at excluding as many factors as possible that could interfere with the analysis of the impact of epilepsy on learning. From patients referred to us in 1997 (N = 123), children were included with mild global learning impairment, defined as educational delay between 6 months and 1 year and no other apparent reason for learning impairment except for epilepsy (ie, excluding children with dyslexia, attention-deficit hyperactivity disorder, or mental handicap). A total of 44 patients fulfilled this criterion: 31 also had epilepsy (experimental group); the remaining 13 patients with similar mild learning impairment but without epilepsy were used as controls. In the experimental group two subgroups were distinguished on the basis of onset of learning impairment: in group A (n = 17) the learning problems are not unexpected as they were preceded by mild developmental delay; in group B (n = 14) the problems are unexpected and had a sudden onset. The two experimental groups differed from the control group on a number of variables, such as gender and the incidence of perinatal complications. More differences have been found between the two experimental groups: group B is selected from a larger group: all children with mild global learning impairment with sudden onset. In this group considerably more children with epilepsy have been found compared to the children with developmental delay; moreover the epilepsy is more often characterized in these children as "unexpected," that is, there was no previous established diagnosis of epilepsy, the symptoms were mostly unclear and behavioral in make-up (attentional lapses, etc); the electroencephalogram plays a much greater role in the diagnosis in this group, especially in demonstrating seizures; finally, the children in this group more frequently have neuropsychologic impairment. Children with epilepsy can have mild global learning difficulties, especially in the period after the onset of seizures. This group can be divided in a group with "trait-dependent learning difficulties," that is learning difficulties based on developmental delay, and a group with "state-dependent learning difficulties." The focus in our study was on this latter group, consisting of children with sudden and unexpected decline of results in school. The crucial finding in this group is the relatively frequent demonstration of difficult-to-detect seizures, demonstrating that an uncontrolled epilepsy can cause a decline in school results even when the seizures are of short duration and have subtle symptoms.

Early clinical signs and symptoms in occult spinal dysraphism: a retrospective case study of 47 patients.

Since occult spinal dysraphism can lead to irreversible neurological complications, early diagnosis and treatment are necessary. We retrospectively studied the presenting clinical signs and symptoms in all 47 cases of occult spinal dysraphism identified in two university hospitals in The Netherlands since 1965. Dermal sinus had been diagnosed in 12, lipomyelomeningocele in nine, and diastematomyelia in eight patients. Thirty-three patients had symptoms due to tethering of the spinal cord, leading to a clinical suspicion of occult spinal dysraphism in only eight cases. Twenty-eight patients had cutaneous back lesions that led to further investigation in eight cases. Nineteen patients had a small backmass leading to further examination in 13 cases. Three patients with dermal sinus presented with meningitis caused by an unusual aetiological agent. This study stresses the importance of identification of neurological dysfunction due to tethered cord syndrome, cutaneous back lesions, a small backmass and meningitis caused by an unusual aetiological agent for the early diagnosis of occult spinal dysraphism.

Mild closed head injury in children compared to traumatic fractured bone; neurobehavioural sequelae in daily life 2 years after the accident.

UNLABELLED: Two years after an accident resulting in either a mild head injury or a fractured bone, two groups of 22 children each, aged 4-14 years, were examined for the existence of any neurobehavioural symptoms by means of a standardized questionnaire filled out by their caretakers. Selection of the children was based on reports of the Accident and Emergency Department in 1 year. Significantly more symptoms were reported after mild head injury. The main symptoms reported were headache, dizziness, fatigue and memory problems. The total number of symptoms in the children with mild head injury exceeded four times this in the group of children with a fractured bone. CONCLUSION: Even 2 years after a mild head injury there are still residual symptoms in daily life.

Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.

The simultaneous occurrence of familial neurofibromatosis type 1 (NF1) and an overgrowth syndrome resembling Weaver syndrome was observed in two related cases (a mother and her son). NF1 was confirmed by molecular genetic analysis showing a large deletion at 17q11.2, encompassing the entire NF1 gene. The other symptoms in the two cases were similar to the features reported in Weaver syndrome. Although the combination of NF1 and an overgrowth syndrome resembling Weaver syndrome in this family may be fortuitous, we favour the hypothesis that the deletion of the entire gene has caused this combined phenotype. Possible pathogenetic mechanisms are discussed. The observation suggests a relation between NF1 with an extraordinarily large gene deletion and a Weaver(-like) syndrome. This warrants investigation for deletions in the 17q11.2 region in Weaver(-like) syndrome patients.

[Neurofibromatosis type 1: a survey of 195 patients]. / Neurofibromatosis type 1: een overzicht van 196 patiënten.

OBJECTIVE: To analyse symptoms and complications in patients with neurofibromatosis type 1 (NF1). All patients were examined in a multidisciplinary outpatient neurofibromatosis clinic during a period of 10 years. DESIGN: Retrospective. SETTING: Academic Medical Center, University Hospital Amsterdam, the Netherlands. METHOD: All data on 450 persons visiting the neurofibromatosis clinic were stored in a database. Data were collected on the results of dermatological, neurological, ophthalmological and general examinations and on family history. For this study the follow-up data of 196 patients with a definite diagnosis of 'NF1' were analysed. RESULTS: In childhood diagnosis NF1 is predominantly based on specific dermatological symptoms such as > 6 café-au-lait (CAL) spots and freckling and on the presence of characteristic ophthalmological signs as two or more Lisch nodules. In this study the frequencies of these symptoms were 98% (CAL). 92% (freckles), and 93% (Lisch nodules) respectively. The frequencies of well-known complications of this disorder are comparable with the literature findings. In this study we found optic pathway glioma (OPG) in 10%, macrocephaly in 36%, hydrocephalus in 5%, retardation in 14%, brain tumours in 5%, kyphoscoliosis in 13%. renal artery stenosis in 0.5% and neurofibrosarcoma in 0.5% of NF1 patients. In children the degree of severity of this disorder is less than in adults, demonstrating the progressive character of the disease. CONCLUSION: The diagnosis of 'NF1' can usually be made by dermatological and ophthalmological examination. In case of a definite diagnosis in childhood regular follow-up is recommended since severe complications, such as OPG and kyphoscoliosis, may occur specifically in childhood and adolescence. For adult patients determination of the degree of severity is essential for the decision whether or not they need regular follow-up; they should have their blood pressure measured annually.

A Croatian case of the Schinzel-Giedion syndrome.

The Schinzel-Giedion syndrome is an infrequently described malformation syndrome, mainly characterized by a profound mental deficiency, a typical face including a midface hypoplasia, urogenital abnormalities, and minor radiographic features. Death prior to two year of age is the rule. A boy with typical features of the syndrome is described. He died at the age of 21 months. This is the first case of this syndrome reported from Croatia. The recurrence in only one of the 20 families, does not firmly sustain an autosomal recessive pattern of inheritance, although this still remains possible.

Supernumerary ring chromosome 20 characterized by fluorescence in situ hybridization.

We report on a boy with mild dysmorphic features and developmental delay, in whom karyotyping showed an additional minute ring chromosome in 60% of metaphases. Fluorescence in situ hybridization (FISH) with a centromere specific probe demonstrated that the ring chromosome contained the centromeric region of chromosome 20. The ring was highlighted completely using a chromosome 20 painting probe. A cosmid probe for 20p 12-13 gave a positive signal and hybridization with an all-telomere probe showed on signal, suggesting a breakpoint in the 20p telomere. The results suggested that only a small part of 20q was involved in this ring. The ring was also detected in 18% of nuclei of a buccal smear. The phenotypic similarities of symptoms in the proband to patients with a (partial) trisomy 20p and the dissimilarities to symptoms in patients with (partial) trisomy 20q were in agreement with the FISH results.

Operculum syndrome: unusual feature of herpes simplex encephalitis.

Herpes simplex encephalitis in adults and young patients carries a high mortality and morbidity. Its presentation may be nonspecific, sometimes hampering early diagnosis. Two young children are reported with herpes simplex encephalitis in whom the operculum syndrome was an outstanding feature. This syndrome is caused by focal, bilateral cortical damage to the anterior opercular regions resulting in anarthria and impairment of mastication and swallowing. After initiation of treatment with acyclovir in the early stage of the disease, the outcomes in both patients were characterized by good general recovery with persistence of deficits of speech, mastication, and swallowing, more pronounced in the patient who was comatose during the illness. Early recognition of the operculum syndrome as a presenting feature of herpes simplex encephalitis may expedite the diagnosis and thereby improve the prognosis.

Molybdenum-cofactor deficiency: an easily missed cause of neonatal convulsions.

Intractable seizures in the neonatal period may be caused by molybdenum-cofactor deficiency, an inborn error which combines the deficiencies of sulphite oxidase and xanthine dehydrogenase. The neurological symptoms of molybdenum cofactor and isolated sulphite oxidase deficiencies are identical. Two new cases are reported, and the literature on neonatal convulsions due to molybdenum-cofactor and sulphite deficiencies is reviewed. Because of the high incidence of neonatal convulsions a search for this deficiency is advocated in each case of unexplained refractory neonatal convulsions. Diagnosis may be missed or delayed on standard metabolic screening for several reasons discussed. By simply using a sulphite strip test in a fresh urine sample an indication for the defect can be obtained. Antenatal diagnosis can be performed by assay of sulphite oxidase activity in a chorionic villus sample.

[Value of an electroencephalogram in a patient with transient neurological symptoms]. / Het nut van een elektro-encefalogram bij een patiënt met voorbijgaande uitvalsverschijnselen.

A seven year old boy had several episodes of dysfunction of the left hemisphere. The only sign on physical examination was a very slight facial asymmetry on the right side. The CT scan with and without contrast enhancement was normal. Because of a marked asymmetry of the EEG, duplex scan examination of the carotid arteries was carried out; it showed a flow disturbance of the left carotid artery. Angiography showed a narrowing of the supraclinoidal portion of the internal carotid artery which was considered to be due to angiitis. As the boy was known to have bronchitis and eczema and the blood tests showed a marked increase of eosinophil cells, he was treated with corticosteroids. At follow-up after three months the EEG and the duplex scan were normal. There had been no TIAs since the start of the treatment.