Search

Abstract: The FOXG1 syndrome is emerging as a relative new entity in paediatric neurology. We report a boy with acquired microcephaly, mental retardation and a thin genu of the corpus callosum. The combination of these findings led to mutation analysis of FOXG1. The patient was found to be heterozygous for a novel mutation in FOXG1, c.506dup (p.Lys170GInfsX285), which occurred de novo. This frameshift mutation disturbs the three functional domains of the FOXG1 gene. Hypo- or agenesis of the anterior corpus callosum in combination with acquired microcephaly and neurologic impairment can be an important clue for identifying patients with a mutation in FOXG1. [Copyright &y& Elsevier]

Abstract: Background: Primary coenzyme Q10 (CoQ10) deficiencies are heterogeneous autosomal recessive disorders. CoQ2 mutations have been identified only rarely in patients. All affected individuals presented with nephrotic syndrome in the first year of life. Methods: An infant is studied with myoclonic seizures and hypertrophic cardiomyopathy in the first months of life and developed a nephrotic syndrome in a later stage. Results: At three weeks of age, the index patient developed myoclonic seizures. In addition, he had hypertrophic cardiomyopathy and increased CSF lactate. A skeletal muscle biopsy performed at two months of age disclosed normal activities of the oxidative phosphorylation complexes. The child was supplemented with CoQ10 (5 mg/kg/day). At the age of four months, brain MR images showed bilateral increased signal intensities in putamen and cerebral cortex. After that age, he developed massive proteinuria. The daily dose of CoQ10 was increased to 30 mg/kg. Renal biopsy showed focal segmental glomerulosclerosis. Biochemical analyses of a kidney biopsy sample revealed a severely decreased activity of succinate cytochrome c reductase [complex II + III] suggesting ubiquinone depletion. Incorporation of labelled precursors necessary for CoQ10 synthesis was significantly decreased in cultured skin fibroblasts. His condition deteriorated and he died at the age of five months. A novel homozygous mutation c.326G > A (p.Ser109Asn) was found in COQ2. Conclusions: In contrast to previously reported patients with CoQ2 the proband presented with early myoclonic epilepsy, hypertrophic cardiomyopathy and only in a later stage developed a nephrotic syndrome. The phenotype of this patient enlarges the phenotypical spectrum of the multisystem infantile variant. [Copyright &y& Elsevier]

Abstract: Aims: Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction. Results: At 31/2 months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh’s encephalopathy. Conclusion: The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions. [Copyright &y& Elsevier]

Abstract: We systematically reviewed the files of 51 infants presenting with infantile spasms and hypsarrhythmia in order to study the initial treatment strategies and the long term outcome. 80% of the infants were classified as symptomatic. In the nine participating centres, different treatment protocols were used, but the large majority of the children received vigabatrin as first line treatment. Second line options included hormonal treatment, topiramate and valproate. The time to reach cessation of infantile spasms was significantly shorter in the cryptogenic group than in the symptomatic group (50% at 13 days versus 66 days respectively) and was irrespective of the treatment used. The late follow up data (>2 years) showed that 60% of the children had epilepsy and that 75% of the children had a delay in their psychomotor development. Again, outcome in the cryptogenic group was better than in the symptomatic group, but also in the cryptogenic group, 50% of the children had a clear developmental delay, even if spasms were controlled early in the course of the disease. Our retrospective study illustrates that not only the underlying brain dysfunction is the major determinant for later outcome in infantile spasms (symptomatic group) but also even a short period of infantile spasms can be responsible for later developmental delay (cryptogenic group). [Copyright &y& Elsevier]

Abstract: Background: In the heterogeneous group of mitochondrial disorders, patients with the same genotype can show different phenotypes and the same phenotype can be caused by different genotypes. We describe a family with the m.14709T>C mutation and a clinical presentation of hydrops fetalis, in contrast to previous reports in which patients presented with myopathy and/or diabetes mellitus. Aim: To identify a mutation in the mtDNA of a family with a heterogeneous clinical presentation. Methods: Both biochemical and molecular analyses were performed. Results: Biochemical results showed a decreased complex I and IV activity in muscle tissue of the patients. A mosaic-staining pattern for complex I in the patients’ fibroblasts was revealed using immunocytochemistry. Molecular analyses identified the m.14709T>C mutation in the mitochondrial encoded tRNAGlu gene. Conclusion: We report 2 siblings with the m.14709T>C mutation in the mitochondrial tRNAGlu gene. The first patient showed hydrops fetalis, a new presentation within the clinical spectrum of this mutation, and the other a known presentation namely mild myopathy. [Copyright &y& Elsevier]

Abstract Biallelic mutations in the RTTN gene have been reported in association with microcephaly, short stature, developmental delay and malformations of cortical development. RTTN mutations have previously shown to link aberrant ciliary function with abnormal development and organization of the human cerebral cortex. We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia.Methods: We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment.Results: Increased cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC, or GCSH. Biochemical analysis identified persistently increased cerebrospinal fluid levels of glycine and methylmalonic acid and increased urinary methylmalonic acid and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked cobalamin (HCFC1), c.344C>T, p. Ala115Val. In addition, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin deficiency also identified increased cerebrospinal fluid glycine levels.Conclusions: This boy had X-linked cobalamin deficiency (HCFC1) with increased cerebrospinal fluid glycine and methylmalonic acid and increased cerebrospinal fluid to plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and increased glycine. [ABSTRACT FROM AUTHOR]

Studies in yeast have shown that a deficiency in Atp12p prevents assembly of the extrinsic domain (F1) of complex V and renders cells unable to make ATP through oxidative phosphorylation. De Meirleir et al. (De Meirleir, L., Seneca, S., Lissens, W., De Clercq, 1., Eyskens, F., Gerlo, E., Smet, J., and Van Coster, R. (2004) J. Med. Genet. 41, 120-124) have reported that a homozygous missense mutation in the gene for human Atp12p (HuAtp12p), which replaces Trp-94 with Arg, was linked to the death of a 14-month-old patient. We have investigated the impact of the pathogenic W94R mutation on Atp12p structure/function. Plasmid-borne wild type human Atp12p rescues the respiratory defect of a yeast ATP12 deletion mutant (Δatp12). The W94R mutation alters the protein at the most highly conserved position in the Pfam sequence and renders HuAtp12p insoluble in the background of Δatp12. In contrast, the yeast protein harboring the corresponding mutation, ScAtp12p(W103R), is soluble in the background of Δatp12 but not in the background of Δatp12Δfmc1, a strain that also lacks Fmc1p. Fmc1p is a yeast mitochondrial protein not found in higher eukaryotes. Tryptophan 94 (human) or 103 (yeast) is located in a positively charged region of Atp12p, and hence its mutation to arginine does not alter significantly the electrostatic properties of the protein. Instead, we provide evidence that the primary effect of the substitution is on the dynamic properties of Atp12p. [ABSTRACT FROM AUTHOR]

The properties of water diffusion in human brain tissue can be characterized by diffusion tensors computed from diffusion weighted magnetic resonance images. Since these properties are strongly determined by the structural and geometrical characteristics of the tissue, the maturation process of white matter and gray matter tissue can be expected to be reflected in these images and derived tensor quantities.The purpose of this work was therefore to study the development of pediatric brain in terms of changes occurring in the observed diffusion behavior. Echo planar diffusion tensor imaging was performed on 22 (10 females and 12 males) full term newborn and infant patients, diagnosed in retrospect as neurologically healthy. The subjects were subdivided in three age categories. A number of quantities based on the diffusion images were calculated for each tissue type and age category, and the ability of these quantities to provide sensitive and consistent information about the tissue differences and evolution was evaluated.The results clearly illustrate that the rotationally invariant quantities (e.g., the highest diffusivity, anisotropy ratio and volume ratio) are superior to the rotationally variant ones (e.g., ADCs measured along the three axes of the magnet) often used in the clinic. On the basis of the anisotropy ratio and the volume ratio indices, a correlation between the white matter maturation and the evolution of the diffusion anisotropy could be established. The same quantities did not exhibit any age dependence for the gray matter tissues. [Copyright &y& Elsevier]