A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.

We present a young boy whose mild ataxia and abnormal eye movements repeatedly deteriorated with fever, making him unable to sit or walk during fever episodes. SNP-array analysis identified a 202 kb deletion in chromosome 13q33.1 containing the fibroblast growth factor (FGF)14 gene, which is associated with spinocerebellar ataxia (SCA) 27. This 13q deletion was also present in the proband's mother and grandmother. The mother was unable to perform tandem gait walking and had abnormal eye movements but had never sought medical attention. The grandmother predominantly had a postural tremor. FGF14 regulates brain sodium channels, especially in the cerebellum. Sodium channels can be fever sensitive. This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis.

[A boy with acute cerebellar ataxia without opsoclonus caused by neuroblastoma]. / Een jongen met acute cerebellaire ataxie zonder opsoclonus, door een neuroblastoom.

A 2-year-old boy presented with acute cerebellar ataxia without opsoclonus. The ataxia was assumed to be post-viral. After a period of years a neuroblastoma was detected. Treatment with a curative intent was successful and consisted of metaiodobenzylguanidine I 131, chemotherapy, tumour resection, chemotherapy again and follow-up treatment with isotretinoin after irradiation. In the literature, 5 other children have been described with acute cerebellar ataxia without opsoclonus in whom neuroblastoma was detected eventually. The mean age of these children at initial presentation was 26 months. The mean time between initial presentation and diagnosis ofneuroblastoma or ganglioneuroblastoma was 12 months. Urine concentrations of catecholamine metabolites were normal in 5 of the 6 total children; concentrations were elevated in 1 child. The tumour was located paravertebrally in 5 of the 6 children. Ataxia resolved following resection of the neuroblastoma in all patients. Each child with prolonged or recurrent acute cerebellar ataxia should be extensively investigated for the presence of neuroblastoma, even in the absence of opsoclonus.

[Three infants with constipation and muscular weakness: infantile botulism]. / 3 zuigelingen met obstipatie en hypotonie: infantiel botulisme.

Two previously healthy infants, a boy of 10 weeks and a girl of 4 months presented with apathy and muscle weakness. A third previously healthy child, a girl of 6 weeks old was admitted with respiratory insufficiency. None of the three had had a bowel movement for a number of days. After extensive investigations which revealed few abnormalities Clostridium botulinum toxin was obtained in serum from all three children. Type-B-toxin was shown in the faeces of the older girl and boy; both recovered quickly. The other girl had type-A toxin; she died. Two of the three children were given honey to comfort them. Infantile botulism must be considered in every infant with symptoms of constipation and hypotonia. The diagnosis can quickly be confirmed by electromyography with repetitive 50-Hz-stimulation. Honey is a well-known source of the C. botulinum spore and should not be given to children under the age of 12 months. These three children are the first cases to be described in the Netherlands.

[The attending physician and the certificate of natural death in children]. / De behandelend arts en de verklaring van natuurlijke dood bij kinderen.

Three children died in the paediatric intensive-care unit or emergency department. The case of a 3.5-year-old girl who died after a pneumococcal infection was considered a natural death. An 8-year-old boy suddenly collapsed and died despite resuscitation. The attending physician considered this an unnatural death. The district medical examiner, after consulting the district attorney, required an autopsy, but the cause of death could not be ascertained and the next of kin were to be examined for cardiac rhythm disorders. A 2-year-old boy died after a fall out of a window. The district medical examiner and the district attorney concluded that there was sufficient explanation for this unnatural death and that autopsy was not necessary. The attending physician has several important tasks around the time of and after death in which he or she is subject to a number of legal regulations. Knowledge of these regulations is mandatory for good medical practice.

Craniopagus: the Suriname-Amsterdam conjunction.

OBJECTS: A case of a Suriname female occipito-parietal to occipito-parieto-temporal craniopagus twins is described. The girls were transferred to the VU University Medical Center (VUmc) in Amsterdam, the Netherlands, for further diagnostics and to analyze whether surgical separation was feasible and ethically justifiable. The multifactorial aspects of different treatment options are discussed. METHODS: The twins underwent multiple investigations by a multidisciplinary team. Advanced imaging techniques with 3D-CT scan, MRI and MRA scans, image fusion techniques and, most importantly, cerebral angiography with balloon occlusion tests were performed. CONCLUSIONS: Because of a shared venous ring, with preferential drainage to the left child, and which endovascular balloon occlusion showed could not be separated, surgical separation of the twins with a fair chance of survival without additional neurological damage and with prospects of a good quality of life was regarded as impossible. In accordance with the parents' wishes, the twins were not separated and offered optimal integral conservative treatment.

[Intracranial hemorrhages in infants: child abuse or a congenital coagulation disorder?]. / Intracraniële bloeding bij de zuigeling: kindermishandeling of toch een aangeboren stollingsstoornis?

In children with head injuries the severity of the neurological symptoms should concord with the patient's history and signs of neurotrauma on examination. Discrepancies between the (hetero)anamnesis and physical examination on the one hand and neurological findings on the other may indicate child abuse. The presence of both old and new intracranial haemorrhages in the absence of proportional trauma is generally considered as evidence for child abuse. However, these symptoms may also be the first manifestation of a congenital coagulation disorder. Three children, two girls aged 8 and 5 months and a boy aged 6 months were presented with alarming neurological symptoms due to intracranial haemorrhages without external signs of head trauma. The first girl had 'shaken baby' syndrome while the other 2 had congenital coagulation disorders (haemophilia B and factor V deficiency, respectively). All three recovered, the last two with remaining one-sided neurological deficits. Child abuse and congenital coagulation disorders may present with similar neurological symptoms and radiological findings. In these patients coagulation tests are mandatory and--if abnormal--enable early substitution of deficits and prevent inappropriate suspicion or accusation of caretakers.

[Children with stumbling gait due to acute spinal cord compression]. / Kinderen met een wankel looppatroon door acute ruggenmergcompressie.

Three previously healthy children, two girls aged 2 and almost 5 years and a boy aged 20 months, developed a progressively stumbling gait within days. In two this occurred after a period of weeks during which they complained of, or seemed to have back pain. In all three cases acute spinal cord compression by a malignant tumour was diagnosed. Histological examination revealed Ewing sarcoma, granulocytic sarcoma and T-cell lymphoma. Surgical decompression led to complete neurological recovery. Although rare, acute spinal cord compression during childhood is a medical emergency because of the risk of neurological morbidity. Back pain, weakness and a stumbling gait usually are the first symptoms. Sensory symptoms and sphincter dysfunction may develop later. Early recognition is essential, as prognosis depends on neurological findings and duration of symptoms when treatment is started.

Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-->A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Cerebral cavernous hemangiomas in childhood. Clinical presentation and therapeutic considerations.

Cerebral cavernous hemangiomas (CCH) are relatively rare vascular hamartomas. Since the introduction of MRI there has been an increase in the number of case reports of CCH in the medical literature. CCH are often asymptomatic; they may, however, cause epilepsy or neurological deficits due to their space-occupying effects or hemorrhagic sequelae. The tendency of CCH to bleed has been well recognized, though gross hemorrhage is infrequent owing to the relatively low blood pressure and small blood flow in CCH. MRI findings of a CCH are characteristic and can differentiate the lesions from other vascular abnormalities. To date, there has been no consensus on indications for surgical intervention. Three cases are presented, which together demonstrate by their different presentation, clinical course and MRI findings that each patient with a CCH requires an individually tailored management. Presentation, clinical course and accessibility for operation are the factors that determine whether a surgical or a conservative approach should be adopted.

Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities.

A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed hydrocephalus due to aqueduct stenosis, generalized cerebral cortical agyric or pachygyric polymicrogyria, diffuse cerebral hemispheric white matter abnormalities, and malformations of posterior fossa structures. In 4 patients with muscle-eye-brain disease, MRI showed cortical dysplasia, but less severe than in WWS. The cerebral white matter either was normal or contained multiple focal abnormalities. Malformations of posterior fossa structures were present. Eight patients, classified as having classic merosin-deficient CMD (MD-CMD), had diffuse cerebral hemispheric white matter abnormalities, no other abnormalities. One patient with MD-CMD had only a few, focal white matter abnormalities. Three CMD patients had occipital agyria, otherwise normal gyration, multifocal or more diffuse cerebral white matter changes, and variable hypoplasia of pons and vermis. Two of the 3 patients had negative muscle merosin staining. The conclusion of the study is that MRI is an important adjunct in the classification of CMD patients. CMD with occipital agyria can be regarded as a newly recognized, separate CMD subtype.

Congenital supratentorial arachnoidal and giant cysts in children: a clinical study with arguments for a conservative approach.

Little is known about the natural course of arachnoidal cysts (AC) and the incidence of complications. This poses a problem in selection of patients for surgical interventions. The present authors report on 19 children with supratentorial AC of varying location and size. The mean follow-up time is 6 years. The evolution of presenting symptoms, the developmental course, the occurrence of complications, the surgical intervention performed and its outcome are described. Associated neurological disorders cannot always be attributed to the cyst. If surgery is being considered, a causal relationship between the symptom and the cyst should be plausible.

Severe irreversible optic neuritis following Mantoux tuberculin skin test in a child with multiple sclerosis--a case report.

A 12-year-old girl was diagnosed as suffering from multiple sclerosis. At age 14, just after recovery from an exacerbation of MS with left-sided optic neuritis, she underwent a Mantoux tuberculin skin test. Within 30 minutes she developed complete irreversible optic neuropathy of the left eye. This case illustrates the urge for caution to perform vaccinations and tuberculin skin tests not only during progressive disease activity of MS, but also in the reconvalescent phase after an acute exacerbation.

Deficiency of the voltage-dependent anion channel: a novel cause of mitochondriopathy.

A patient with a deficient voltage-dependent anion channel (VDAC) is reported, presenting clinically with psychomotor retardation and minor dysmorphic features. Biochemical studies on muscle mitochondria showed impaired rates of pyruvate oxidation and ATP production; however, no specific deficient activity of one of the mitochondrial enzymes was involved. Western blotting experiments indicated an almost complete VDAC deficiency in skeletal muscle. The only moderately decreased VDAC content in the patient's fibroblasts might indicate that VDAC is expressed in a tissue-specific manner. The deficiency is likely caused by a mutation in the HVDAC1 gene or by a distributed posttranslational modification. This is the first described deficiency of a component of the outer mitochondrial membrane associated with the pyruvate oxidation pathway. Defects in this membrane should be considered as a possible cause of otherwise unexplained mitochondrial disorders.

A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder that is characterized by dysmyelination of the central nervous system resulting from mutations in the proteolipid protein (PLP) gene. Mutations causing either overexpression or expression of a truncated form of PLP result in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. It has therefore been hypothesized that absence of the protein should result in a less severe phenotype. However, until now, only one patient has been described with a complete deletion of the PLP gene. We report a Dutch family with a relatively mild form of PMD, in which the disease cosegregates with a (G-to-A) mutation in the initiation codon of the PLP gene. This mutation should cause the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD.

Leukoencephalopathy with swelling in children and adolescents: MRI patterns and differential diagnosis.

In children, several neurological disorders are characterised by spongiform leukoencephalopathy. MRI of the brain typically shows white matter swelling, but does not enable differentiation of the various underlying disorders. The aim of this article is optimisation of the diagnostic value of MRI in leukoencephalopathy accompanied by swelling. MRI-based inclusion criteria were met by 20 patients in our database. The images were analysed using a detailed scoring list. In 13 of the 20 patients the clinical diagnosis was known (11 definite and 2 probable diagnoses). Characteristic MRI abnormalities could be defined in these patients. Of the 7 patients without a diagnosis, 5 had identical MRI abnormalities: diffuse hemisphere swelling and typical cysts in frontoparietal subcortical white matter and the tips of the temporal lobes. The clinical picture was also similar in these patients, suggesting a similar disease.

Molecular basis of phenotypic variation in patients with argininemia.

Argininemia is an autosomal recessive disorder caused by a deficiency in the liver-type arginase enzyme. Clinical manifestations include progressive spastic diplegia and mental retardation. While the quality of life can severely deteriorate in most such patients, some do show remarkable improvement in neurological symptoms while on controlled diets. We examined the thesis that differences in clinical responses to dietary treatment are based on molecular heterogeneity in mutant arginase alleles. Genomic DNAs from 11 patients with argininemia were examined using the polymerase chain reaction, cloning, and sequencing. Nine mutations representing 21/22 mutant alleles were identified in 11 patients with argininemia, and four of these mutations were expressed in vitro to determine the severity of enzymatic defects. We found that these mutations accounted for 64% of the mutant alleles in our patients. Based on findings in vitro expression tests, the mutations can be considered either severe or moderate. Patients with at least one moderate mutant allele responded well to dietary treatment; concentrations of plasma arginine were controlled within 300 microM. In contrast, patients with two severely mutated alleles did not respond to dietary treatment and plasma arginine was over 400 microM. Argininemia is heterogeneous at the molecular level. The degree of clinical improvement during dietary treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment correlated with types of molecular defects in the arginase genes.

Ca2+ homeostasis in Brody's disease. A study in skeletal muscle and cultured muscle cells and the effects of dantrolene an verapamil.

Brody's disease, i.e., sarcoplasmic reticulum (SR) Ca(2+)-dependent Mg(2+)-ATPase (Ca(2+)-ATPase) deficiency, is a rare inherited disorder of skeletal muscle function. Pseudo-myotonia is the most important clinical feature. SR Ca(2+)-ATPase and Ca2+ homeostasis are examined in m. quadriceps and/or cultured muscle cells of controls and 10 patients suffering from Brody's disease. In both m. quadriceps and cultured muscle cells of patients, the SR Ca(2+)-ATPase activity is decreased by approximately 50%. However, the concentration of SR Ca(2+)-ATPase and SERCA1 are normal. SERCA1 accounts for 83 and 100% of total SR Ca(2+)-ATPase in m. quadriceps and cultured muscle cells, respectively. This implies a reduction of the molecular activity of SERCA1 in Brody's disease. The cytosolic Ca2+ concentration ([Ca2+]i) at rest and the increase of [Ca2+]i after addition of acetylcholine are the same in cultured muscle cells of controls and patients. The half-life of the maximal response, however, is raised three times in the pathological muscle cells. Addition of dantrolene or verapamil after the maximal response accelerates the restoration of the [Ca2+]i in these muscle cells. The differences in Ca2+ handling disappear by administration of dantrolene or verapamil concomitantly with acetylcholine. The reduced Ca2+ re-uptake from the cytosol presumably due to structural modification(s) of SERCA1 may explain the pseudo-myotonia in Brody's disease. Single cell measurements suggest a beneficial effect of dantrolene or verapamil in treating patients suffering from Brody's disease.

MR of the caudal regression syndrome: embryologic implications.

PURPOSE: To evaluate the spectrum of developmental anomalies observed in patients with the caudal regression syndrome and relate them to the pathogenesis of this syndrome. METHODS: Nineteen children with caudal regression were investigated with MR. RESULTS: The level of vertebral agenesis varied from T-11 to S-5. In 9 of the 19 children the characteristic high-ending wedge-shaped cord terminus was observed. A separation of the anterior and posterior spinal roots of the cauda equina was observed in 9 patients. Four patients had a tethered spinal cord, in 1 in combination with a wedge-shaped cord terminus. CONCLUSIONS: The pathogenesis of the caudal regression syndrome can be divided into two kinds: there is usually a disturbance of the primary neurulation process; in other cases there is a derailment of the process of degeneration and differentiation of an initially normally developed primary and secondary neural tube. MR aids understanding of the morphology and pathogenesis of congenital malformations involved (including the associated anomalies of the genitourinary and gastrointestinal systems), but other studies are still necessary to determine the exact mechanism of this syndrome.

A case of macrocephaly, hydrocephalus, megacerebellum, white matter abnormalities and Rosenthal fibres.

The authors report the case of a young boy with macrocephaly, cerebellar symptoms and signs of raised intracranial pressure. Magnetic resonance imaging showed obstruction of the aqueduct, ventricular enlargement of the cerebellum and areas of increased signal intensity in the cerebellar and frontal white matter. A stereotactic biopsy of the cerebellum showed many Rosenthal fibres and glial proliferation. Although the histopathological and neuroradiological findings were suggestive of Alexander's disease, the initial presentation and clinical course were unusual for this diagnosis. The authors suggest that a separate form of Alexander's disease should be distinguished with predominant clinical, neuroradiological and neuropathological cerebellar involvement. This form also seems to have a better life-expectancy.

Presumed intraocular lymphoma in a 60-year-old man with AIDS.

A 60-year-old man with AIDS and active pulmonary tuberculosis presented with a rapidly growing chorioretinal tumor. Tuberculostatics had no effect on the tumor but radiation resulted in a quick decrease in its size. It is therefore believed to be a lymphoma. No biopsy was performed. An intraocular lymphoma in a patient with AIDS has not yet been described.