Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.

Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid. We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation. This analysis confirms our finding that Refsum disease is caused by a deficiency of PhyH.

Continuous intrathecal baclofen therapy in children with cerebral palsy - when does improvement emerge?

AIM: The aim of the study was to explore the timing of effects of intrathecal baclofen therapy in children with cerebral palsy. METHODS: Thirty five children with severe disabilities with cerebral palsy who started continuous intrathecal baclofen therapy (CITB) were followed for 18 months. Pain, number of awakenings during night, spasticity, GMFM-66 scores and PEDI scores were recorded the day before pump implantation and after 6 and 18 months of treatment respectively. RESULTS: Introduction of CITB was associated with changes across all ICF dimensions. Reduced pain and improved sleep occurred within 6 months of treatment. Social function improved within 6 months and continued to improve until 18 months of CITB. Mobility also improved, but with a latency. CONCLUSION: There seems to be a sequence of changes after introduction of continuous intrathecal baclofen in a child with cerebral palsy that may guide the multidisciplinary team in their timing of therapy during post-surgical follow-up.

Therapy in a subtropical climate for children with cerebral palsy. Evidence of physical and psychosocial effects?

AIM: To assess a possible therapeutic effect in children and adolescents with cerebral palsy of a habilitation programme in a warm sunny climate. METHODS: Fifty-seven children and adolescents with cerebral palsy, all integrated with normal functioning children through mainstream schooling, received an individualized four-week habilitation programme at a habilitation centre in Lanzarote in the Canary Islands. They were clinically assessed before and after treatment, and again after three and six months. The clinical tests included gross motor function measure (GMFM) and the paediatric evaluation of disability inventory (PEDI). Mental health and self-esteem were assessed by using the youth self report (YSR), the child behaviour checklist (CBCL) and the Harter's self-perception profile. We also used focus-group interviews on all 57 parents by the end of the treatment period. RESULTS: The study revealed some improvements in the level of physical performance. The most striking finding, however, was the lasting effect on behavioural and emotional parameters and the children's self-esteem. CONCLUSION: Training in a warm climate may explain some of this positive effect. However, based on the focus-group interviews and its quantitative findings a more plausible explanation may be the interaction in a social setting with others in a similar situation.

The subcellular localization of phytanic acid oxidase in rat liver.

Peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's syndrome, rhizomelic chondrodysplasia) show a series of enzymatic defects related to peroxisomal dysfunctions. Accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) has been found in several of these patients, caused by a defect in the alpha-oxidation mechanism of this acid. The fact that the alpha-oxidation of phytanic acid is defective in the peroxisomal disorders as well as in classical Refsum's disease makes it likely that this oxidation normally takes place in the peroxisomes. A series of experiments preformed to localize the phytanic acid oxidase in subcellular fractions of rat liver show, however, that the alpha-oxidation of phytanic acid is a mitochondrial process. Free phytanic acid is the substrate, and the only cofactors necessary are ATP and Mg2+.

Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

BACKGROUND: Neurotrophic factors are essential regulators of neuronal maturation including synaptic synthesis. Among those, Brain derived neurotrophic factor (BDNF) has been in particular focus in the understanding of autism spectrum disorders (ASD). PURPOSE: The aim of our study was to investigate whether BNDF could be used as diagnostic/biological marker for ASD. For this purpose we examined the plasma levels of BDNF and the precursors pro- BDNF in patients with ASD and compared it with non-autistic controls; determined whether there was a correlation between the BDNF and proBDNF levels and clinical severity. We also investigated the coding region of BDNF identify for well-variations which could be associated to ASD. METHODS: The 65 ASD patients (51 boys) were enrolled from a recent completed epidemiological survey covering two counties (Oppland and Hedmark) in Norway. The mean age of the total number of children who participated in this study was 11,7 years. 30 non-autistic children were included as controls, 14 boys and 16 girls. The mean age was 11.3 years. Exclusion criteria for control group were individuals suffering from either neurological, endocrine, or immune insuffiency. RESULTS AND CONCLUSIONS: Patients with ASD were characterized by moderately but significantly elevated plasma levels of BDNF compared to matched controls. No differences were observed in the proBDNF level between patients and controls. Within the ASD group, children with intellectual disability demonstrated increased BDNF, but not proBDNF levels, while the presence of ADHD had no impact on circulating proBDNF or BDNF. No further associations between plasma proBDNF or BDNF and other clinical demographics were observed.

Refsum disease, peroxisomes and phytanic acid oxidation: a review.

Refsum disease was first recognized as a distinct disease entity by Sigvald Refsum in the 1940s. The discovery of markedly elevated levels of the branched-chain fatty acid phytanic acid in certain patients marked Refsum disease as a disorder of lipid metabolism. Although it was immediately recognized that the accumulation of phytanic acid is due to its deficient breakdown in Refsum disease patients, the true enzymatic defect remained mysterious until recently. A major breakthrough in this respect was the resolution of the mechanism of phytanic acid alpha-oxidation in humans. In this review we describe the many aspects of Refsum disease from the clinical signs and symptoms to the enzyme and molecular defect plus the recent identification of genetic heterogeneity in Refsum disease.

Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I.

Glutaric aciduria type I is an uncommon inborn error of metabolism. It is a serious disease, often with a fatal outcome. This study reports the presence of bilateral temporal fluid collections, probably bilateral arachnoid cysts, in association with glutaric aciduria type I. The CT and, when available, MR studies from five patients with this disorder were reviewed. Four of the patients had findings consistent with bilateral arachnoid cysts of the temporal fossa. This is a rare occurrence, with only 11 such cases reported in the literature. The observed association between temporal fluid collections and glutaric aciduria type I suggests that patients with bilateral arachnoid cysts should be investigated for this metabolic disorder.

Clinical and biochemical heterogeneity in conditions with phytanic acid accumulation.

Phytanic acid accumulation has for more than 20 years been used as a diagnostic criterion of Refsum's disease. Recently, however, phytanic acid has also been found in peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's syndrome, rhizomelic chondrodysplasia punctata). The 17 patients with Refsum's disease in the present study had serum phytanic acid values differing from 73 to less than 0.5 mg/dl (normal). alpha-Oxidation of phytanic acid in skin fibroblast cultures showed a defective capacity in all, with only small differences in residual activity. Phytanic acid determinations in serum from 3 of the 7 patients with peroxisomal disorders showed slightly elevated levels in 2. The alpha-oxidation capacity in the fibroblasts was defective in all, with a residual activity similar to that of Refsum's disease. An assay of the alpha-oxidation capacity may be useful in the diagnosis of both Refsum's disease and the peroxisomal disorders. The distinction between Refsum's disease and the peroxisomal disorders can easily be done on a clinical basis.

Evidence that Alpers-Huttenlocher syndrome could be a mitochondrial disease.

We report an 11-year-old boy with a slight developmental delay and epilepsy. After he was placed on valproate, he developed hepatic failure and increasing neurologic symptoms, including epilepsia partialis continua, and died. Autopsy findings in liver and cerebrum were consistent with progressive neuronal degeneration of childhood with liver disease, also called Alpers-Huttenlocher syndrome. Ragged red fibers and cytochrome c oxidase negative fibers were present in muscle. These results suggest that Alpers-Huttenlocher syndrome, at least in some patients, is a mitochondrial disease.

Childhood autism: the need for physical investigations.

In this paper the results of an extensive medical investigation of 25 children with childhood autism are presented and compared with those found in a group of non-autistic individuals matched for sex, age and intellectual level, all referred for developmental deviancy of unknown etiology. The examination included a psychiatric assessment and a neurological examination in addition to neurophysiological, chromosomal, metabolic and neuroimaging evaluation. In the clinical examination macrocephaly was found only among the autistic individuals, while the frequency of pathological cerebral CT and clinical parameters such as tendon reflexes and mobility problems was significantly greater in the control group. All the other pathological findings were found to occur with the same frequency in the two groups. Except for research purposes this study did not lend support to those who argue for extensive medical examinations for all children with autism. Based on the present findings, ordinary procedures for assessment of developmentally delayed children should be followed. This should include a systematic clinical neuropaediatric examination, an assessment of vision and hearing and a chromosome study, including that for fragile X.

Rett syndrome: geographic variation in prevalence in Norway.

The prevalence of Rett syndrome is reported for three Norwegian counties (Rogaland, Ostfold and Nordland). The total number of females between 3 and 19 years of age in these counties was 96,920, and among these 21 females with Rett syndrome were identified, yielding a prevalence rate for Rett syndrome of 2.17 per 10,000 girls. One reason for this comparatively high prevalence rate might be that the full spectrum of Rett syndrome variants was included. The quality of the health care system and the awareness of Rett syndrome and its variants among Norwegians physicians also make it unlikely that many case were missed. However, the high total prevalence was caused by a statistically significant larger number of girls with Rett syndrome in Rogaland than in the other two counties. Sixteen of the girls were identified in Rogaland county, which gives a prevalence rate for this county of 3.77 per 10,000 girls. The prevalence rates in the two other counties were 1.05 and 0.77 per 10,000 girls. The geographical distribution of girls with Rett syndrome in Rogaland is probably due to genetic clustering. Geographical mobility in Norway is limited and many families have lived in the same geographical area for generations. An explanation based on genetic clustering is also supported by the fact that several of the girls with Rett syndrome in Rogaland county are known to be related.

Rett variants: a suggested model for inclusion criteria.

A model for the clinical delineation of atypical cases of Rett syndrome is presented. It is based on the presence, at age > or = 10 years, of combined clusters of at least 3 of 6 primary criteria and at least 5 of 11 supportive manifestations appearing through childhood with advancing age. The model was applied to 16 mentally retarded females, aged 11-47 years (median: 23) who were considered to manifest atypical variants of the syndrome (8 formes frustes, 6 late regression, 2 congenital variants). Two of the 16 patients had an early seizure history as the initial abnormality. In parallel, the number of supportive manifestations in a series of 41 females over 10 years of age with classic Rett syndrome are given. The differentiating power was tested on 8 patients with a chromosome-verified Angelman syndrome. It is concluded that the model applied here has the capacity to identify and distinguish Rett syndrome variants of different types, to sift out other developmental disorders in routine clinical work, and to have potential as a useful research tool.

Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity.

A boy with delayed psychomotor development, attention deficit disorder, and therapy-resistant epilepsy was treated with valproate. The patient died of liver failure after 4 months of valproate treatment. Postmortem investigation of cultured fibroblasts suggested medium chain acyl-CoA dehydrogenase deficiency, an unexpected finding since the boy had not presented typical manifestations of this disease. Because medium chain acyl-CoA dehydrogenase is an important enzyme in the beta-oxidation of fatty acids, our patient probably had a genetically reduced tolerance to valproate. This drug should be omitted in the treatment of seizures in patients with possible medium chain acyl-CoA dehydrogenase deficiency.

Disorders related to the metabolism of phytanic acid.

The phytanic acid found in man stems from exogenous sources, mainly as minor parts of fish and animal fats. Free phytol, which is easily converted to phytanic acid in mammals, is present in fats of vegetable origin. Healthy individuals are able to degrade the small amounts of phytanic acid and phytol which are ingested. Accumulation of phytanic acid has been considered diagnostic for Refsum's disease, and a prerequisite for this diagnosis. However, a few patients with proven Refsum's disease have eliminated their phytanic acid stores by dietary means. Two healthy mothers of patients with Refsum's disease have been reported, in whom serum phytanic acid was considerably increased. Furthermore, phytanic acid has recently been found in patients with several socalled peroxisomal disorders (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, hyperpipecolic acidemia, rhizomelic chondrodysplasia punctata, Leber disease). Skin fibroblasts both from patients with classical Refsum's disease and from those with the peroxisomal disorders have a defect in the alpha-oxidation of phytanic acid, with a residual enzyme activity less than 10% of normal. The presence of this defect in the patients with peroxisomal disease makes it tempting to suggest that alpha-oxidation of phytanic acid normally takes place in the peroxisomes. Subcellular studies in rat liver show, however, unequivocally that the alpha-oxidation of phytanic acid is located to the mitochondria. Thus, patients with the peroxisomal syndromes must probably have a defect also in the mitochondria, in addition to the many peroxisomal deficiencies.

[Refsum's disease. Epidemiologic, clinical and biological correlation. 6 cases]. / La maladie de Refsum. Corrélations épidémiologiques, cliniques et biologiques. Six cas.

Nine patients with symptoms and signs of Refsum's disease are reported. In 6 a systemic accumulation of phytanic acid was demonstrated, together with low phytanic acid oxidase activity in skin fibroblasts in 5 of them. In 3, no disorder of phytanic acid metabolism was demonstrated. In 3, the diagnosis was made during the pre-clinical period. The disease seems more frequent in Northern France, which agrees with the hypothesis of a genetic mutation which would have taken place in Scandinavia some centuries ago and was subsequently spread by the Vikings. The effects of a dietary treatment on serum phytanic acid levels and clinical disorders are reported. The general condition of the patients improved remarkably but only partially. The diet is unpalatable and in some patients the level of serum phytanic acid increased, due to the mobilization of body fat. Patients with very high levels of phytanic acid might be initially treated by plasmapheresis. For the same reason, the diet should supply enough calories to keep body weight unchanged, and body weight loss whatever its cause should be avoided.

Automated spectral EEG analyses of premature infants during the first three days of life correlated with developmental outcomes at 24 months.

BACKGROUND: Spectral EEG analysis using automated quantification of total absolute band power (tABP) for long-term brain monitoring is reliable. We hypothesised that tABP during the first critical days of life could be a useful tool for predicting later developmental outcomes. OBJECTIVE: To determine whether measuring EEG background activity in premature infants with automated tABP quantification during the first 3 days of life correlated with their developmental outcomes at 24 months. METHODS: Preterm infants (group 1, gestational age, GA 24-28 weeks and group 2, GA 28-31 weeks) were continuously monitored by EEG for 3 days after birth. Their developmental outcomes were assessed using the Bayley-II and Peabody-2 developmental tests at 24 months. Their respective indices were calculated. Normal (index ≥85) and abnormal (index <85) outcomes were correlated with the tABP. RESULTS: In group 1, the tABP was significantly lower in the abnormal infants than in the normal infants. The specificity and negative predictive value were also high for all of the tests that were applied in this group. In group 2, there was no correlation between the tABP and developmental outcome. CONCLUSION: This study found that extremely premature infants with poor developmental outcomes had significantly lower tABP values in their first days of life compared to infants from the same group with normal outcomes. This method may be useful in predicting later outcomes in extremely premature infants and has the advantage of being automated.

Phenotype of adult Refsum disease due to a defect in peroxin 7.

The biochemical hallmark of adult Refsum disease (ARD) is an isolated deficiency in the breakdown of phytanic acid. This usually results from a PHYH gene defect, although some cases have been found to carry a PEX7 defect. We describe the phenotype of such a patient, indistinguishable from that of classic ARD. Hence, we propose the subdivision of ARD into type 1 and type 2, depending on which gene is defective.

Evidence against alpha-hydroxyphytanic acid as an intermediate in the metabolism of phytanic acid.

It was established 20 years ago that phytanic acid is degraded by an initial alpha-oxidation, and that alpha-hydroxyphytanic acid is an intermediate in the reaction. Patients with Refsum's disease, as well as those with the so-called peroxisomal disorders, have an enzymatic defect in this alpha-oxidation. The present work shows that when cultured skin fibroblasts from both groups of patients as well as from healthy controls are incubated with (1-14C)phytanic acid, the only radioactive compounds which can be detected are 14CO2 and unmetabolised phytanic acid. The degradation of (1-14C)alpha-hydroxyphytanic acid to 14CO2 takes place in the mitochondrial fraction of rat liver. Unlabelled alpha-hydroxyphytanic acid added to rat liver homogenate or mitochondria and (1-14C)phytanic acid reduced considerably the production of 14CO2. However, 14C-labelling of the alpha-hydroxyphytanic acid pool did not occur. Thus, we have been unable to confirm the previous demonstration of alpha-hydroxyphytanic acid as an intermediate in the degradation of phytanic acid.

[Peroxisomal disorders. A new group of metabolic diseases]. / Peroksysomale sykdommer. En ny gruppe metabolske sykdommer.

Peroxisomes play an essential role in a number of different metabolic reactions, and the last few years have seen an enormous increase in our knowledge about peroxisomes and peroxisomal disorders. These disorders are caused by impairment of one or more peroxisomal functions. This article briefly reviews the clinical and biochemical aspects of peroxisomal disorders.

[Mitochondrial diseases--more common than we realize?]. / Mitokondrielle sykdommer--hyppigere enn vi tror?

The last two decades have revealed a novel group of inborn errors with defects on the pathways of aerobic energy substrates into the mitochondria or the capacity to generate reducing potential from these substrates, as well as those that block the oxidative phosphorylation pathway itself. The mitochondrial diseases are clinically heterogenous disorders that can affect multiple organ systems, mainly the skeletal muscle and nervous system (mitochondrial encephalomyopathies). There are a few distinctive syndromes such as Leigh's syndrome, Alper's syndrome, Kearns-Sayre's syndrome, myoclonus epilepsy with "ragged-red fibres" (MERRF), and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes). The last year our department has evaluated ten children with mitochondrial disorders. Among these are two siblings with Leigh's syndrome and cytochrome c-oxidase defect. The first child, a girl, developed the first symptoms at the age of four months and died 13 months old. The younger brother showed the same clinical picture as his sister. However, the clinical neurological picture was stabilized when he was 18 months old, and he is still alive at six years of age and slightly psychomotorically retarded.