Search

The lack of a validated severity scoring system for individuals with Zellweger spectrum disorders (ZSD) hampers optimal patient care and reliable research. Here, we describe the development of such severity score and its validation in a large, well-characterized cohort of ZSD individuals. We developed a severity scoring system based on the 14 organs that typically can be affected in ZSD. A standardized and validated method was used to classify additional care needs in individuals with neurodevelopmental disabilities (Capacity Profile [CAP]). Thirty ZSD patients of varying ages were scored by the severity score and the CAP. The median score was 9 (range 6-19) with a median scoring age of 16.0 years (range 2-36 years). The ZSD severity score was significantly correlated with all 5 domains of the CAP, most significantly with the sensory domain (r = 0.8971, P =

BackgroundFeedback learning is essential for behavioral development. We investigated feedback learning in relation to behavior problems after pediatric traumatic brain injury (TBI).MethodChildren aged 6–13 years diagnosed with TBI (n= 112; 1.7 years post-injury) were compared with children with traumatic control (TC) injury (n= 52). TBI severity was defined as mild TBI without risk factors for complicated TBI (mildRF−TBI,n= 24), mild TBI with ⩾1 risk factor for complicated TBI (mildRF+TBI,n= 51) and moderate/severe TBI (n= 37). The Probabilistic Learning Test was used to measure feedback learning, assessing the effects of inconsistent feedback on learning and generalization of learning from the learning context to novel contexts. The relation between feedback learning and behavioral functioning rated by parents and teachers was explored.ResultsNo evidence was found for an effect of TBI on learning from inconsistent feedback, while the moderate/severe TBI group showed impaired generalization of learning from the learning context to novel contexts (p= 0.03,d= −0.51). Furthermore, the mildRF+TBI and moderate/severe TBI groups had higher parent and teacher ratings of internalizing problems (p's⩽ 0.04,d's ⩾ 0.47) than the TC group, while the moderate/severe TBI group also had higher parent ratings of externalizing problems (p= 0.006,d= 0.58). Importantly, poorer generalization of learning predicted higher parent ratings of externalizing problems in children with TBI (p= 0.03,β= −0.21) and had diagnostic utility for the identification of children with TBI and clinically significant externalizing behavior problems (area under the curve = 0.77,p= 0.001).ConclusionsModerate/severe pediatric TBI has a negative impact on generalization of learning, which may contribute to post-injury externalizing problems.

Item does not contain fulltext 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 (

Rett syndrome is a neurodevelopmental disorder in girls, related to mutations in MECP2 gene. It has been postulated that low 5-methyltetrahydrofolate (5-MTHF) levels are present in cerebrospinal fluid. Folinic acid demonstrated clinical improvement. However, because studies have produced conflicting results, we performed a randomized, double-blind crossover, long-term, follow-up study on folinic acid. Eight Rett syndrome patients received both folinic acid and placebo, for 1 year each. Measurements included plasma folate, 5-MTHF, and clinical outcome scores like Rett Syndrome Motor Behavioral Assessment, Hand Apraxia Scale, and the parental Overall Well-Being Index. In 2 patients, low 5-MTHF levels were present. Folinic acid supplementation increased cerebrospinal fluid 5-MTHF levels, but with no objective evidence of clinical improvement. The Overall Well-Being Index showed a significant difference in favor of folinic acid, not confirmed objectively. In our double-blind randomized study, folinic acid supplementation resulted in increased 5-MTHF levels, but with no objective signs of clinical improvement.

Objective: To study the clinical spectrum of CACNA1A S218L mutation carriers with special attention to "early seizures and cerebral oedema after trivial head trauma (ESCEATHT)", a combination of symptoms which resembles the "juvenile head trauma syndrome".Patients and methods: In two patients with ESCEATHT all exons of CACNA1A were sequenced. Both patients also had hemiplegic migraine and ataxia. Subsequently, we screened the literature for S218L mutation carriers.Results: In both patients, a de novo S218L mutation in the CACNA1A gene was found. In addition, we identified 11 CACNA1A S218L carriers from the literature. Of these 13 S218L mutation carriers, 12 (92%) had ataxia or cerebellar symptoms and nine (69%) had hemiplegic migraine that could be triggered by trivial head trauma. Three mutation carriers had the complete ESCEATHT phenotype. Seven (54%) had seizures (four had early post-traumatic seizures) and five (38%) had oedema as detected by MRI/CT.Conclusions: The CACNA1A S218L mutation is associated with familial hemiplegic migraine, ataxia and/or ESCEATHT. A minority of S218L mutation carriers have the complete ESCEATHT phenotype but a high percentage of patients had one or more ESCEATHT symptoms. As the S218L mutation enhances the propensity for cortical spreading depression (CSD), we postulate a role for CSD not only in hemiplegic migraine but also in early seizures and cerebral oedema after trivial head trauma. As this combination of symptoms is part of the unexplained "juvenile head trauma syndrome", a similar molecular mechanism may underlie this disorder.

Item does not contain fulltext OBJECTIVE: To identify clinical, radiologic, or CSF factors that predict conversion to multiple sclerosis (MS) after a first attack of inflammatory demyelination in children. METHODS: In this nationwide retrospective multicenter study in the Netherlands, 117 children below age 16 were included. Fifty-four children presented with a monofocal clinically isolated syndrome (CIS) and 63 children with a polyfocal CIS (PCIS). RESULTS: A second MS-defining attack occurred in 43% of the CIS cases, compared to 21% of the patients with PCIS onset (p < 0.006). Basal ganglia and thalamic lesions and lesions larger than 2 cm on MRI (considered typical of ADEM) were observed during PCIS, irrespective of the presence of encephalopathy. No significant difference in developing MS was found in children with PCIS with or without encephalopathy. Elevated IgG index and presence of oligoclonal CSF bands were more often observed in children who developed MS. Both Barkhof and KIDMUS MRI criteria shared a high specificity and had a high positive predictive value for conversion to MS. In children under the age of 10, the Barkhof criteria had a higher sensitivity than the KIDMUS criteria, but still lower than in older children. CONCLUSIONS: Barkhof and KIDMUS MRI criteria share a high specificity and positive prognostic value for conversion to multiple sclerosis (MS). Sensitivity of these criteria is poor, especially in children below 10 years of age. Basal ganglia lesions can occur in patients who later develop MS. A substantial number of patients presenting with polyfocal onset and no encephalopathy remained monophasic.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is characterized by a striking and unpredictable variation in phenotypic expression. It ranges from a rapidly progressive and fatal cerebral demyelinating disease in childhood (CCALD), to the milder slowly progressive form in adulthood (AMN). X-ALD is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane located ABC half-transporter named ALDP. Mutations in ALDP result in reduced beta-oxidation of very long-chain fatty acids (VLCFA, >22 carbon atoms) in peroxisomes and elevated levels of VLCFA in plasma and tissues. Previously, it has been shown that culturing skin fibroblasts from X-ALD patients in lipoprotein-deficient medium results in reduced VLCFA levels and increased expression of the functionally redundant ALD-related protein (ALDRP). The aim of this study was to further resolve the interaction between cholesterol and VLCFA metabolism in X-ALD. Our data show that the reduction in 26:0 in X-ALD fibroblasts grown in lipoprotein-deficient culture medium (free of cholesterol) is offset by a significant increase in both the level and synthesis of 26:1. We also demonstrate that cholesterol-deprivation results in increased expression of stearoyl-CoA-desaturase (SCD) and increased desaturation of 18:0 to 18:1. Finally, there was no increase in [1-(14)C]-26:0 beta-oxidation. Taken together, we conclude that cholesterol-deprivation reduces saturated VLCFA, but increases mono-unsaturated VLCFA. These data may have implications for treatment of X-ALD patients with lovastatin.

Background: The classic rhizomelic chondrodysplasia punctata (RCDP) phenotype involves a typical facial appearance, cataracts, skeletal dysplasia causing disproportionate somatic growth failure, microcephaly, and severe psychomotor defects. Biochemical abnormalities include impaired plasmalogen biosynthesis in all forms of RCDP and accumulation of phytanic acid in RCDP type 1. A subset of patients has a milder clinical and biochemical phenotype, with less severe neurologic impairment and an incomplete deficiency in plasmalogens. The impact of plasmalogen deficiency on neurologic function is severe, causing spasticity and mental defects, but its pathomechanism is still unknown. The authors specifically focused on myelination because myelin is rich in ethanolamine plasmalogens. Objective: To define the neuroimaging characteristics of the genetic peroxisomal disorder RCDP. Methods: Twenty-one MR images of the brain and cervical spine of 11 patients were evaluated and correlated with neurologic and biochemical profiles. Results: No abnormalities on MRI were seen in the patients with a mild phenotype of RCDP, whereas delayed myelination, ventricular enlargement and increased subarachnoidal spaces, supratentorial myelin abnormalities, and cerebellar atrophy were observed in patients with the severe phenotype of both RCDP type 1 and 3. The severity of both the MRI abnormalities and the clinical phenotype is correlated with the plasmalogen level. Conclusions: The severe phenotype of rhizomelic chondrodysplasia punctata (RCDP) is accompanied by a specific pattern of both developmental and regressive MRI abnormalities. Plasmalogen levels seem to play an important role in the pathophysiology of CNS abnormalities in RCDP. Increased phytanic acid appears not to be the cause of cerebellar atrophy.

We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.

Een pasgeborene wordt beschreven met een bijzondere oorzaak van cholestatische icterus waarvan de uitgebreide differentiaaldiagnose wordt besproken. De patient bleek te lijden aan een ziekte behorend tot het Zellweger-spectrum, een erfelijke stoornis in de biogenese van peroxisomen, resulterend in gegeneraliseerde deficienties van peroxisomale enzymen. Peroxisomen zijn betrokken bij vele metabole processen. Patienten met gegeneraliseerde peroxisomale enzymdeficienties hebben een achterstand in cognitieve en motore ontwikkeling, leverfunctiestoornissen, retinopathie en sensorineurale doofheid. Verschijnselen van de leveraandoening kunnen in de neonatale periode op de voorgrond staan. De patient had leververschijnselen en neurologische verschijnselen bij presentatie en overleed op de leeftijd van 6 maanden ten gevolge van respiratoire insufficientie.

Ocular manifestations in inborn errors of metabolism occur in many diseases and may be associated with any part of all eye components. In a minority of diseases it is possible to attribute the eye symptoms to a single hereditary pathogenetic mechanism. More often the aetiological relationship of the ocular defects to the metabolic disease is unknown. Diverse pathogenetic mechanisms may act via a common pathological pathway inducing ocular damage. The occurrence of eye abnormalities in metabolic disorders suggests that they are associated with direct toxic actions, errors of synthetic pathways or deficient energy metabolism. In this review, metabolic disorders with major abnormalities in the cornea, lens, retina and optic nerve are presented. In all cases, an appropriate combined approach by the ophthalmologist, paediatrician/neurologist, geneticist and clinical biochemist is the only way to diagnostic success.

Failure to thrive is een veelvoorkomende klacht bij kinderen. In slechts 5% wordt een organische oorzaak gevonden en zelden is dit een neurologische. Twee patienten, een meisje van 8 maanden en een jongen van 20 maanden, presenteerden zich met langdurig braken en een failure to thrive. Het meisje was alert, opvallend vrolijk en had een pendelnystagmus. Deze symptomen zijn karakteristiek voor het diencefaalsyndroom, een hypothalamische dysfunctie veroorzaakt door een tumor in de hypofyse-/hypothalamusregio, meestal een glioom. De mri-scan van het cerebrum van het meisje toonde een opticusglioom. De jongen presenteerde zich in eerste instantie met alleen een failure to thrive, later ontwikkelde hij een fotofobie. De mri-scan van het cerebrum liet een infratentorieel ependymoom zien. Beide tumoren worden kort besproken. Hersentumoren bij kinderen geven vaak aspecifieke symptomen als geirriteerdheid, veranderd gedrag, braken (vooral in de ochtend) anorexie en een failure to thrive. Van de zuigelingen met een hersentumor had 13% als eerste symptoom een failure to thrive. Bij deze klachten mag een neurologische anamnese en onderzoek niet ontbreken. Ook bij subtiele neurologische afwijkingen moet beeldvormend onderzoek worden verricht in de vorm van een ct- of mri-scan van de hersenen.

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.Spaapen LJ, Bakker JA, Velter C, Loots W, Rubio-Gonzalbo ME, Forget PP, Dorland L, De Koning TJ, Poll-The BT, Ploos van Amstel HK, Bekhof J, Blau N, Duran M.Department of Biochemical Genetics, Stichting Klinische Genetica Zuid-Oost Nederland, Maastricht. leo.spaapen@gen.unimaas.nlFour neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 micromol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH4) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH4 loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH4 load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH4 biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1-4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH4.

Objectives. The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency. Methods. The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced. Results. Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations. Conclusions. Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.

Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There are two types. an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or AHC-GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, I nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic variability of the isolated GKD was remarkable. The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.

Congenital hepatic fibrosis is a rare disorder of intrahepatic bile ducts with the persistence of embryological bile duct structures in ductal plate configuration. Three siblings aged 18, 17 and 14 years old were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme phosphomannose isomerase. The clinical symptoms were recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly. The biochemical abnormalities included elevated serum transferases during attacks, clotting factor deficiencies and persistent hypoalbuminemia. In the youngest patient protein-losing enteropathy was present. Liver biopsies of the three patients taken when they were 1, 3 and 14 years old showed an excess of bile duct structures in ductal plate configuration with mild fibrosis in the portal triads. In one patient the liver biopsy was repeated after 18 years and showed only a mild progression of fibrosis in the portal triads. Duodenal biopsies taken in infancy in two of the three patients did not show any abnormalities. Recognition of phosphomannose isomerase deficiency in association with congenital hepatic fibrosis and protein-losing enteropathy is important, because some of the clinical symptoms are potentially treatable by oral mannose therapy.

Two male relatives with Fabry disease presented striking differences in clinical symptoms and age of onset. The propositus had retarded statural growth and skeletal dysplasia while his nephew suffered mainly from aggravating acroparesthesia and celiac disease. Fabry disease is an X-linked inborn error of glycosphingolipid metabolism resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A) enzyme. The alpha-Gal A gene is located at Xq22.1. Efforts to establish genotype-phenotype correlations have been limited because most patients have private mutations. In previous clinical studies performed in families with Fabry disease, marked differences in phenotype are described between affected relatives. This family also demonstrates the difficulty in predicting the clinical phenotype in patients and relatives with the same alpha-Gal A mutation. Furthermore, in the absence of a family history, the diagnosis may be easily missed.

Serine deficiency disorders comprise a new group of inborn errors of serine metabolism. Patients affected with these disorders present with major neurological symptoms including congenital microcephaly, seizures, psychomotor retardation or polyneuropathy. The diagnosis of serine deficiency is based on the detection of low concentrations of the amino acids serine and glycine in fasted plasma and cerebrospinal fluid (CSF). Amino acid analysis of cerebrospinal fluid is preferable over plasma analysis, because the deficiencies are more pronounced in CSF. Because of the interference of amino acids absorbed from the diet, diagnostic procedures have to be performed in the fasted state. Although the disorders are probably rare and not many cases have been reported, recognition of serine deficiency is important, given the fact that the disorders are potentially treatable. The clinical symptoms respond well to amino acid replacement therapy. So far, three serine deficiency disorders have been reported; 3-phosphoglycerate dehydrogenase deficiency, 3-phosphoserine phosphatase deficiency and a still unexplained serine deficiency disorder. In this paper, we will discuss the various serine deficiency disorders, their biochemical abnormalities and the results of amino acid replacement therapy.

The branched-chain fatty acid phytanic acid is a constituent of the diet, present in diary products, meat and fish. Degradation of this fatty acid in the human body is preceded by activation to phytanoyl-CoA and starts with one cycle of alpha-oxidation. Intermediates in this pathway are 2-hydroxy-phytanoyl-CoA and pristanal; the product is pristanic acid. After activation, pristanic acid is degraded by peroxisomal beta-oxidation. Several disorders have been described in which phytanic acid accumulates, in some cases in combination with pristanic acid. In classical Refsum disease, the enzyme that converts phytanoyl-CoA into 2-hydroxyphytanoyl-CoA--phytanoyl-CoA hydroxylase--is deficient, resulting in highly elevated levels of phytanic acid in blood and tissues. Also in rhizomelic chondrodysplasia punctata, phytanic acid accumulates, owing to a deficiency in the peroxisomal import of proteins with a peroxisomal targeting sequence type 2. In patients affected with generalized peroxisomal disorders, degradation of both phytanic acid and pristanic acid is impaired owing to absence of functional peroxisomes. In bifunctional protein deficiency, the disturbed oxidation of pristanic acid results in elevated levels of this fatty acid and a secondary elevation of phytanic acid. In addition, several variant peroxisomal disorders with unknown aetiology have been described in which phytanic acid and/or pristanic acid accumulate. This review describes the discovery of phytanic acid and pristanic acid and the initial attempts to elucidate the origins and fates of these fatty acids. The current knowledge on the alpha-oxidation and beta-oxidation of these branched-chain fatty acids is summarized. The disorders in which phytanic acid and/or pristanic acid accumulate are described and some remarks are made on the pathogenic mechanisms of elevated levels of phytanic acid and pristanic acid.

We present a new derivatization procedure for the simultaneous gas chromatographic–mass spectrometric analysis of free fatty acids and 3-hydroxyfatty acids in plasma. Derivatization of target compounds involved trifluoroacetylation of hydroxyl groups and tert-butyldimethylsilylation of the carboxyl groups. This new derivatization procedure had the advantage of allowing the complete baseline separation of free fatty acids and 3-hydroxyfatty acids while the superior gas chromatographic and mass spectrometric properties of tert-butyldimethylsilyl derivatives remained unchanged, permitting a sensitive analysis of the target compounds. Thirty-nine plasma samples from control subjects and patients with known defects of mitochondrial fatty acid β-oxidation were analyzed. A characteristic increase of long-chain 3-hydroxyfatty acids was observed for all of the long-chain 3-hydroxyacyl-CoA dehydrogenase-deficient and mitochondrial trifunctional protein-deficient plasma samples. For medium-chain acyl-CoA dehydrogenase deficiency and very-long-chain acyl-CoA dehydrogenase deficiency, decenoic and tetradecenoic acids, respectively, were the main abnormal fatty acids, whereas the multiple acyl-CoA dehydrogenase-deficient patients showed variable increases of these unusual intermediates. The results showed that this selective and sensitive method is a powerful tool in the diagnosis and monitoring of mitochondrial fatty acid β-oxidation disorders.

Three siblings suffered from an unusual disorder of cyclic vomiting and congenital hepatic fibrosis. Serum transferrin isoelectric focusing showed increased asialo- and disialotransferrin isoforms as seen in the carbohydrate-deficient glycoprotein (CDG) syndrome type I. Phosphomannomutase, which is deficient in most patients with type I CDG syndrome, was found to be normal in all three patients. Structural analysis of serum transferrin revealed nonglycosylated, hypoglycosylated, and normoglycosylated transferrin molecules. These findings suggested a defect in the early glycosylation pathway. Phosphomannose isomerase was found to be deficient and the defect was present in leucocytes, fibroblasts, and liver tissue. Phosphomannose isomerase deficiency appears to be a novel glycosylation disorder, which is biochemically indistinguishable from CDG syndrome type I. However, the clinical presentation is entirely different.

Previous studies have suggested that tyrosinaemia type I may be associated with reduced glutathione availability due to conjugation of tyrosinaemia-associated reactive intermediates with glutathione. In the present study, the glutathione/ glutathione S-transferase system of two tyrosinaemia patients and three healthy controls were characterized by administering the racemic sedative drug bromisoval, a probe drug for assessing glutathione conjugation activity in vivo. Furthermore, concentrations of glutathione and glutathione S-transferase class alpha (GSTA) isoenzymes as well as the glutathione S-transferase class mu phenotype were assessed in the blood of six tyrosinaemia patients. The excretion of bromisoval mercapturates in healthy children was comparable to that observed in healthy adults. Tyrosinaemia patients were found to have a very high urinary recovery of bromisoval mercapturates (> or = 60% of the dose compared to about 30% for healthy, age-matched children and adults), which could be attributed mainly to a higher urinary excretion of the mercapturate derived from S-bromisoval. Healthy children and adults predominantly excrete the (R)-bromisoval mercapturate. The differences in amount excreted as well as in stereoselectivity of the urinary excretion of bromisoval mercapturates in tyrosinaemia patients are possibly related to an increased activity of specific glutathione S-transferase isoenzymes. Plasma glutathione and blood cell glutathione disulphide concentrations in tyrosinaemia patients were normal. Low blood cell glutathione concentrations were in general found only in two patients with a poor clinical condition. These results indicate that, in contrast to previous suggestions, reduced glutathione availability is not a generalized problem in (stabilized) tyrosinaemia patients.

We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.

Several patients have been described recently who suffer from a non-rhizomelic type of chondrodysplasia punctata (CDP), but who show all the biochemical abnormalities characteristic of the rhizomelic form of chondrodysplasia punctata (RCDP), a peroxisomal disorder. We have used protease protection experiments and microinjection of reporter-protein-encoding expression plasmids to show that peroxisomal thiolase fails to be imported into peroxisomes in cells from non-rhizomelic CDP patients, as has already been found in cells from classical RCDP patients. Furthermore, complementation analysis after somatic cell fusion indicates that the non-rhizomelic CDP patients are impaired in the same gene as classical RCDP patients. We conclude that defects in a single gene can give rise to both clinical phenotypes.

Most of the mutations causing deficiency of the pyruvate dehydrogenase (PDH) complex are in the X-linked E ^ gene. We have developed a rapid screening method for the detection of mutations in this gene using reverse transcription of total RNA, polymerase chain reaction amplification of the whole coding region of the gene and single-strand conformation polymorphism (SSCP) analysis. With this method, we studied eight patients with a PDH complex deficiency, using cultured fibroblasts. In all patients, aberrant SSCP patterns were found and, after sequencing of the corresponding fragments, we were able to identify six new mutations and two mutations already described previously. The mutations are point mutations leading to amino acid substitutions (5) and direct repeat insertions (3). The presence of the mutations was confirmed in genomic fibroblast DNA* The 4 female patients were shown to carry both a normal and a mutated Exa gene. © 1996 Wiley^Liss, Inc, k e y w o r d s : Pyruvate dehydrogenase Eta, RT-PCR, SSCP, Mutation analysis

The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established. The screening was performed by analysis of exons 2-14 of the FAH gene by using the polymerase chain reaction (PCR) and of the mRNA by reverse transcription/PCR. Nine different mutations were identified, of which six are novel. Three mutations involve consensus sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and IVS 12 + 5 (g-a). Two missense mutations (C193R and G369V) and three nonsense mutations (R237X, E357X and E364X) were found. One silent mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. Analysis of the effect of the respective mutations on the FAH mRNA showed a strong reduction of FAH mRNA levels in association with the nonsense mutations, and normal levels with the missense mutations. The splice consensus mutations give deletions of complete or small parts of exon sequences from the FAH mRNA. Data suggest a founder effect for several of the mutations, with a frequency for both the IVS 6-1 (g-t) and IVS 12 + 5 (g-a) mutations of approximately 30% in the HT 1 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.

Poll-The stressed the age-dependence of clinical presentation, as summarized in Table 1. Most symptoms are not specific for peroxisomal disorders but combinations of symptoms may be. Atypical CDP has the biochemical abnormalities of classical RCDP, but there is no shortening of the limbs (Poll-The et al 1991; Smeitink et al 1992). Many other neurological disorders, chromosomal aberrations and several malformation syndromes share symptoms with peroxisomal disorders. When laboratory tests such as plasma VLCFA are performed routinely in all doubtful cases, peroxisomal function may be normal in more than 80%. A karyotype is always very useful. Zellweger syndrome and infantile Refsum disease have been mistaken for Down syndrome. Dysmorphic features due to chromosomal aberrations remain constant, whereas in metabolic diseases they become more severe as the disease progresses (J.F. Gaddisseux). The clinical picture of neuronal ceroid lipofuscinosis may appear similar to a peroxisomal disorder and is comparatively common; diagnosis of the former is by electron microscopy of a rectal biopsy for inclusion bodies (B.T. Poll-The, P. Augoustides, J. Leroy).

We reviewed our data on patients in whom plasma pipecolic acid was analysed. Mild to moderate elevations of pipecolic acid were frequently found in non-peroxisomal disorders and this should be taken into account when interpreting the laboratory data.

Rett syndrome is characterized by the development of stereotypic hand movements and seizures, which are often difficult to treat. Previous studies have shown conflicting results during add-on folinic acid. Here, the authors reevaluate the response to folinic acid in terms of epilepsy control and electroencephalography features. They performed a randomized, placebo-controlled, double-blind crossover trial, with a follow-up of more than 2 years. Twelve girls with Rett syndrome participated, comparable in clinical stage and disease severity. The Rett syndrome patients were given either folinic acid or placebo, for 1 year each. Only 3 girls benefited to some extent: 2 had a reduction and/or decrease in seizures, and all 3 showed some decreased epileptiform activity on electroencephalography during the addition of folinic acid. Despite this, antiepileptic drugs were adjusted. Because the effect of added folinic acid was limited and did not prevent antiepileptic drug increase, the authors do not recommend adding on folinic acid in Rett syndrome girls with epilepsy.

Biotinidase deficiency (McKusick 253260) leads to a progressive deficiency of the vitamin biotin, an essential cofactor for the carboxylation reactions of pyruvate, propionyl-CoA, 3-methylcrotonyl-CoA and acetyl-CoA. This disease usually presents with neurological symptoms such as hypotonia, convulsions and ataxia, while skin rash and alopecia usually appear later. If treatment is delayed, irreversible brain damage such as optic atrophy and neurosensory hearing loss may result. The neurological dysfunction appears to be more severe than that observed in holocarboxylase synthetase (HCS) deficiency, propionic acidaemia or isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency

Peroxisomes are the metabolic sites of a variety of substrates that are poorly oxidized in mitochondria. Impairment of one or more peroxisomal functions results in serious disease. Most of the peroxisomal disorders present with severe neurological abnormalities like psychomotor retardation, hypotonia, seizures, hearing deficiencies and ocular involvement (see Wanders et al (1988) for a review). In plasma from patients with peroxisomal disorders very long-chain fatty acids (VLCFA), pipecolic acid (PIPA), bile acids, and pristanic (PrA) and phytanic (PhA) acids accumulate in varying degree. Little is known about the pathogenesis of neurological symptoms encountered in peroxisomal disorders

A series of in vivo experiments is described in which [1-13C]phytanic acid was given as an oral substrate to a healthy subject and two patients showing an impairment in phytanic acid degradation, one with Refsum's disease and one with chondrodysplasia punctata. After intake of the substrate by the control in a dose of 20 mg/kg body weight, the production of 13CO2 was measured in exhaled breath air and the concomitant formation of labeled 2-hydroxyphytanic acid and of pristanic acid was demonstrated by plasma analysis. After application of a substrate dose of 1 mg/kg body weight to the control, no substantial amounts of 13CO2 were measured, whereas time-dependent analysis of labeled 2-hydroxyphytanic acid in plasma yielded a concentration curve superimposed upon the baseline value (0.2 mumol/L) of the unlabeled substance. Phytanic acid accumulated in plasma from the Refsum's disease patient [649 mumol/L, controls1 y (n = 100):10 mumol/L], whereas the pristanic acid concentration was within the control range [1.4 mumol/L, controls1 y (n = 100):3 mumol/L]. Low amounts of 2-hydroxyphytanic acid were found normally present [0.04 mumol/L, controls1 y (n = 11):0.2 mumol/L], and formation of labeled 2-hydroxyphytanic acid could not be demonstrated after ingestion of [1-13C]phytanic acid in a dose of 1 mg/kg body weight. In addition to phytanic acid accumulation (232 mumol/L), the chondrodysplasia punctata patient showed an elevated 2-hydroxyphytanic acid plasma concentration (0.4 mumol/L), whereas the plasma pristanic acid level was in the control range (0.7 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

A stable isotope dilution method was developed for the measurement of 2-hydroxyphytanic acid and 2-oxophytanic acid in plasma. In plasma from healthy individuals and from patients with Refsum's disease, 2-hydroxyphytanic acid was found at levels less than 0.2 mumol/l, whereas the acid accumulated in plasma from patients with rhizomelic chondrodysplasia punctata, generalized peroxisomal dysfunction, and a single peroxisomal beta-oxidation enzyme deficiency. In plasma from both healthy controls and patients with peroxisomal disorders, 2-oxophytanic acid was undetectable. Four different groups of diseases were characterized with a defective phytanic acid alpha-oxidation and/or pristanic acid beta-oxidation: 1) Refsum's disease, with a defect at phytanic acid alpha-hydroxylation; 2) rhizomelic chondrodysplasia punctata, with a defect at 2-hydroxyphytanic acid decarboxylation; 3) generalized peroxisomal disorders, with defects at 2-hydroxyphytanic acid decarboxylation and at pristanic acid beta-oxidation; 4) single peroxisomal beta-oxidation enzyme deficiencies, with a defect at pristanic acid beta-oxidation, resulting in an impaired phytanic acid alpha-oxidation by inhibition. The results indicate that 2-hydroxyphytanic acid decarboxylation and pristanic acid beta-oxidation take place in peroxisomes.

The concentration of pristanic acid was measured in plasma from a patient with an isolated peroxisomal very long chain fatty acid (VLCFA) acyl-CoA oxidase deficiency, a defect in peroxisomal beta-oxidation resulting in accumulation of VLCFA in plasma and tissues. Although peroxisomes are believed to be involved in pristanic acid beta-oxidation, the pristanic acid level in the patient's plasma was within the control range. This finding provides evidence for the existence of a pristanyl-CoA oxidase distinct from the specific trihydroxycholestanoyl-CoA and VLCFA acyl-CoA oxidases.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

The data from 5 clinics concerning 8 infants, who had developed severe lactic acidosis and hyperglutamic acidaemia were reviewed. Blood-lactate levels were up to 15 mmol/l (reference level:2) and plasma-glutamate levels up to 1632 pmol/l (reference level: 14-78), and there was no concomitant hyperglutaminaemia (levels up to 1032 micromol/l (reference level: 333-809)). A positive correlation between the amount of calcium levulinate administered and the degree of hyperglutamic acidaemia was found. Replacement of the calcium levulinate by another calcium salt caused a reversal of the biochemical abnormalities of the patients. Two of the infants had a 22q11 microdeletion. This development of severe acidosis in infants who had been given a calcium supplement in the form of calcium levulinate may be related to genetic predisposition. The paradoxal hyperketonaemia and generalized aminoaciduria in 4 other patients suggested disturbed function ofthe mitochondrial respiratory chain. The hypothesis of the occurrence of an underlying defect of the mitochondrial respiratory chain was tested in the muscle tissue of one 22q11 patient, but this showed no abnormalities. Excessive accumulation of glutamate because of dysfunction ofglutamine synthetase, which forms glutamate from glutamine seems unlikely because of the relatively low values of plasma glutamate compared to the glutamine plasma levels. Calcium levulinate should no longer be used in neonates as it may lead to lactic acidosis.

SUMMARY: Serial diffusion-weighted (DWI) and diffusion tensor imaging (DTI) were performed in a patient with neonatal onset nonketotic hyperglycinemia (NKH). At 3 weeks areas that are normally myelinated at this time showed increased T2-signal intensity and restricted diffusion, consistent with vacuolating myelinopathy. At 3 months, these areas had increased in the topographic pattern of normal myelination, whereas fractional anisotropy was compatible with axonal sparing. At 17 months, diffusion restriction had disappeared, likely because of coalescence of myelin vacuoles. A decrease of fractional anisotropy was observed in the previously myelinated areas indicative of axonal loss. We conclude that DWI and DTI can be used to identify and characterize white matter tract abnormalities in patients with NKH.

Item does not contain fulltext

Four myopathic patients with complex I deficiency followed diets containing 55 energy per cent (En%) as fat or 25 En% as fat, both for three weeks. Maximal workload and muscle force were not different on either diet. Exercise endurance time, oxygen consumption and lactate levels were also not different, but one patient had diminished endurance time on 25 En% as fat. Our observations do not support the use of increasing the fat in the diet of patients with mitochondrial complex I deficiency.

Contains fulltext : 58762.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS). METHODS: The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations. RESULTS: Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation. CONCLUSIONS: MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.

Objective. Infantile Pompe’s disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies.Methods. A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected.Results. The course of Pompe’s disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe’s disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid α-glucosidase activity is severely deficient.Conclusions. Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies of infantile Pompe’s disease. Mutation analysis and measurement of the α-glucosidase activity should be part of the enrollment program.

We reviewed our data on patients in whom plasma pipecolic acid was analysed. Mild to moderate elevations of pipecolic acid were frequently found in non-peroxisomal disorders and this should be taken into account when interpreting the laboratory data.

Veel patienten met klassieke galactosemie vertonen, ondanks een streng galactosearm dieet, complicaties. In 1992 is een registratie van Nederlandse galactosemiepatienten opgezet met het doel de evaluatie en de behandeling van patienten te standaardiseren. Door middel van statusonderzoek onderzochten wij de klinische en biochemische situatie en het genotype van 34 van de 36 Nederlandse galactosemiepatienten geboren tussen 1992 en 1997.

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.

Phytanic acid and pristanic acid are branched-chain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Here we show that both phytanic acid and pristanic acid activate the peroxisome proliferator-activated receptor alpha (PPARalpha) in a concentration-dependent manner. Activation is observed via the ligand-binding domain of PPARalpha as well as via a PPAR response element (PPRE). Via the PPRE significant induction is found with both phytanic acid and pristanic acid at concentrations of 3 and 1 microM, respectively. The trans-activation of PPARdelta and PPARgamma by these two ligands is negligible. Besides PPARalpha, phytanic acid also trans-activates all three retinoic X receptor subtypes in a concentration-dependent manner. In primary human fibroblasts, deficient in phytanic acid alpha-oxidation, trans-activation through PPARalpha by phytanic acid is observed. This clearly demonstrates that phytanic acid itself, and not only its metabolite, pristanic acid, is a true physiological ligand for PPARalpha. Because induction of PPARalpha occurs at ligand concentrations comparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands for PPARalpha. These results demonstrate that both pristanic acid and phytanic acid are naturally occurring ligands for PPARalpha, which are present at physiological concentrations.

Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome. Cases have been reported worldwide, the majority from France and The Netherlands. From infancy the patients suffer fever attacks that recur every 2-8 weeks, often precipitated by immunizations, infections or emotional stress. Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. Laboratory evaluation during fever shows granulocytosis and elevated acute phase reactants. DPF is caused by a deficiency of the enzyme mevalonate kinase (MK). Besides DPF, the spectrum of MK deficiency includes a severe phenotype, mevalonic aciduria (MA). MA patients have less residual MK activity, leading to substantially higher urinary mevalonic acid excretion than in DPF. Mevalonic aciduria is characterized by mental retardation and dysmorphic features in addition to the clinical features of DPF. At the genomic level, several mutations of varying severity have been identified. The DPF phenotype is caused by one particular mild missense mutation. Most patients are compound heterozygotes for this mutation and a more severe mutation. The mechanism by which MK deficiency leads to fever is not understood. The vast majority of DPF patients have persistently elevated serum IgD and can be classified as having hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Conversely, most HIDS patients have MK deficiency and hence DPF, but the two disorders do not overlap entirely.