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Abstract: Peroxisomal disorders are an important group of neurometabolic diseases. The clinical presentation is varied in terms of age of onset, severity, and different neurological symptoms. The clinical course spans from death in infancy, rapid functional decline, slow decline on long-term followup, to apparent stable course. Leukoencephalopathy and developmental anomalies are characteristic findings on cerebral MR imaging. From a diagnostic point of view the disorders can be clinically subdivided into four broad categories: (1) the Zellweger spectrum disorders and the peroxisomal ß-oxidation disorders, (2) the rhizomelic chondrodysplasia punctata spectrum disorders, (3) the X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex and (4) the remaining disorders. This article discusses the role of MRI findings in the clinical approach of peroxisomal disorders with neurological disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease. [Copyright &y& Elsevier]

Abstract: Introduction: Epilepsy is very frequent in Rett syndrome (RTT) patients and often difficult to treat. Because most cases of RTT are caused by mutations in the MECP2 gene it is reasonable to assume that convulsions are based on common pathogenetic mechanisms and thus should have a similar response to antiepileptic drugs. Purpose: To find the optimal treatment for epilepsy in RTT. Methods: We performed a retrospective study on 110 female patients with confirmed MECP2 mutations. Results: The median age was 10 years, 58% had a history of epilepsy and 55% received antiepileptic drugs (AEDs). Only sulthiame, carbamazepine and valproate were administered in an adequate frequency to allow statistical analysis. The best anticonvulsive results were seen in the RTT group that was treated with carbamazepine. Sulthiame was slightly less effective while valproate was significantly less effective. The rate of side effects was equivalent in all groups. In conclusion, carbamazepine should be recommended as first choice AED in RTT. If carbamazepine is not effective or not well tolerated sulthiame ought to be taken as second choice AED. [Copyright &y& Elsevier]

Abstract: X-linked adrenoleukodystrophy (X-ALD) is a clinically heterogeneous disorder ranging from the severe childhood cerebral form to asymptomatic persons. The overall incidence is 1:16,800 including hemizygotes as well as heterozygotes. The principal molecular defect is due to inborn mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein (ALDP), a transporter in the peroxisome membrane. ALDP is involved in the transport of substrates from the cytoplasm into the peroxisomal lumen. ALDP defects lead to characteristic accumulation of saturated very long-chain fatty acids, the diagnostic disease marker. The pathogenesis is unclear. Different molecular mechanisms seem to induce inflammatory demyelination, neurodegeneration and adrenocortical insufficiency involving the primary ABCD1 defect, environmental factors and modifier genes. Important information has been derived from the X-ALD mouse models; species differences however complicate the interpretation of results. So far, bone marrow transplantation is the only effective long-term treatment for childhood cerebral X-ALD, however, only when performed at an early-stage of disease. Urgently needed novel therapeutic strategies are under consideration ranging from dietary approaches to gene therapy. [Copyright &y& Elsevier]

Pediatric patients with multiple sclerosis (MS) frequently do not meet MRI criteria for diagnosis because of lack of evidence of dissemination in space. We assessed the diagnostic utility of multimodal evoked potentials (EP). In 46% of 85 childhood patients with MS, spatial dissemination was detected by EP before the second clinical attack. EP may constitute an important tool for earlier diagnosis of pediatric MS. [Copyright &y& Elsevier]

In the Division of Pediatric Neurology at the University Medical Center Göttingen we observed that many patients with Bell palsy are overweight or obese. To evaluate whether overweight and obesity are associated with increased risk of Bell palsy in children we conducted this single-centered retrospective study by performing a database search for International Classification of Diseases (ICD)-10 primary and secondary diagnosis of G51.0 (facial nerve palsy) between January 1, 2010, and December 31, 2020. For risk assessment, patients' body mass indices (BMIs) were compared with BMI data of controls from a nationwide child health survey. In total, 202 patients with peripheral facial nerve palsies (pFPs) were included, of which nearly half were classified as Bell palsies; 38% and 24% of the patients with Bell palsy and pFP had a BMI above the 90th percentile, respectively. High BMI was associated with statistically increased odds of Bell palsy in the group of overweight and obese patients (BMI >90th percentile; odds ratio [OR], 2.42; 95% confidence interval [CI], 1.6 to 3.8; P < 0.001) and solely obese patients (BMI >97th percentile; OR, 2.43; 95% CI, 1.4 to 4.3; P = 0.003). We could confirm our observation that overweight and obesity are associated with increased risk of Bell palsy in children. [ABSTRACT FROM AUTHOR]

Background: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease.Methods: We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease.Findings: We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia.Interpretation: Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder.Funding: Eva Luise and Horst Köhler Foundation for Humans with Rare Diseases. [ABSTRACT FROM AUTHOR]

Peroxisomes are no longer regarded as autonomous organelles because evidence for their interplay with other cellular organelles is emerging. Peroxisomes interact with mitochondria in several metabolic pathways, including β-oxidation of fatty acids and the metabolism of reactive oxygen species. Both organelles are in close contact with the endoplasmic reticulum (ER) and share several proteins, including organelle fission factors. Today, the study of peroxisome biogenesis disorders mainly focuses on metabolic defects such as accumulation of very long chain fatty acids or plasmalogen deficiency. In addition to metabolic dysregulation, mitochondria and ER abnormalities have also been observed. Whether these contribute to disease pathology is not yet known, but recent findings suggest that this possibility should be considered. Here, we discuss the potential involvement of organelle interplay in peroxisomal disorders. [Copyright &y& Elsevier]

The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1 , a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent. [ABSTRACT FROM AUTHOR]

Abstract: Here we demonstrate that miRNA regulation in marmoset (Callithrix jacchus) and C57/BL6 mouse EAE lesions largely resembles miRNA regulation in active human MS lesions. Detailed quantitative PCR analyses of the most up- and downregulated miRNAs of active human MS lesions in dissected lesions from marmoset EAE brains and inflamed spinal cords of EAE mice revealed that the conserved and highly regulated miRNAs, miRNA-155, miRNA-142-3p, miRNA-146a, miRNA-146b and miRNA-21, turned out to be similarly upregulated in marmoset and mouse EAE lesions. [Copyright &y& Elsevier]

The neurodegenerative disease X-linked adrenoleukodystrophy (X-ALD) is characterized by the abnormal accumulation of very long chain fatty acids. Mutations in the gene encoding the peroxisomal ATP-binding cassette half-transporter, adrenoleukodystrophy protein (ALDP), are the primary cause of X-ALD. To gain a better understanding of ALDP dysfunction, we searched for interaction partners of ALDP and identified binary interactions to proteins with functions in fatty acid synthesis (ACLY, FASN, and ACC) and activation (FATP4), constituting a thus far unknown fatty acid synthesis-transport machinery at the cytoplasmic side of the peroxisomal membrane. This machinery adds to the knowledge of the complex mechanisms of peroxisomal fatty acid metabolism at a molecular level and elucidates potential epigenetic mechanisms as regulatory processes in the pathogenesis and thus the clinical course of X-ALD. [ABSTRACT FROM AUTHOR]

Abstract: Abnormalities of CNS white matter are frequently detected in patients with neurological disorders when MRI studies are performed. Among the many causes of such abnormalities, a large group of rare genetic diseases poses considerable diagnostic problems. Here we present a compilation of genetic leukoencephalopathies to consider when one is confronted with white matter disease of possibly genetic origin. The table contains essentials such as age at onset of symptoms, clinical and MRI characteristics, basic defect, and useful diagnostic studies. The table serves as a diagnostic check list. [Copyright &y& Elsevier]

Late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood, is caused by mutations in the TPP1 gene that encodes tripeptidyl-peptidase I. We show that purified TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity. We crystallized the fully glycosylated TPP1 precursor under conditions that implied partial autocatalytic cleavage between the prosegment and the catalytic domain. X-ray crystallographic analysis at 2.35 Å resolution reveals a globular structure with a subtilisin-like fold, a Ser475-G1u272-Asp360 catalytic triad, and an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. In contrast to other S53 peptidases, the TPP1 structure revealed steric constraints on the P4 substrate pocket explaining its preferential cleavage of tripeptides from the unsubstituted N terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1. 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. [ABSTRACT FROM AUTHOR]

Abstract: Despite the clinical significance of central apneas in a wide range of disorders little is known about their pathogenesis. Research in this field has been hindered by the lack of appropriate animal models. Our goal was to determine whether the C57BL/6J mouse strain, which has an inherited predisposition for dysrhythmic breathing, exhibits spontaneous apneas. In vivo plethysmography of unanesthetized, unrestrained adult C57BL/6J mice revealed a regular occurrence of spontaneous apneas. In situ recordings from respiratory outputs (phrenic, vagal, hypoglossal nerves) in the working heart–brainstem preparation (WHBP) also showed spontaneous central apneas accompanied by laryngeal closure as indicated by tonic vagal postinspiratory activity and increase in subglottal pressure. The apneas were further characterized by a hypoglossal discharge with delayed onset compared to the tonic vagal postinspiratory activity. We conclude that spontaneous central apneas with active laryngeal closure occur in C57BL/6J mice. This mouse strain is a useful animal model to study neuronal mechanisms that underlie the generation of spontaneous central apneas. [Copyright &y& Elsevier]

The adrenoleukodystrophy protein (ALDP) and the 70-kDa peroxisomal membrane protein (PMP70) are half-ATP-binding cassette (ABC) transporters in the mammalian peroxisome membrane. Mutations in the gene encoding ALDP result in a devastating neurodegenerative disorder, X-linked adrenoleukodystrophy (X-ALD) that is associated with elevated levels of very long chain fatty acids because of impaired peroxisomal β-oxidation. The interactions of peroxisomal ABC transporters, their role in the peroxisomal membrane, and their functions in disease pathogenesis are poorly understood. Studies on ABC transporters revealed that half-transporters have to dimerize to gain functionality. So far, conflicting observations are described for ALDP. By the use of in vitro methods (yeast two-hybrid and immunoprecipitation assays) on the one hand, it was shown that ALDP can form homodimers as well as heterodimers with PMP70 and ALDR, while on the other hand, it was demonstrated that ALDP and PMP70 exclusively homodimerize. To circumvent the problems of artificial interactions due to biochemical sample preparation in vitro, we investigated protein-protein interaction of ALDP in its physiological environment by FRET microscopy in intact living cells. The statistical relevance of FRET data was determined in two different ways using probability distribution shift analysis and Kolmogorov-Smirnov statistics. We demonstrate in vivo that ALDP and PMP70 form homodimers as well as ALDP/PMP70 heterodimers where ALDP homodimers predominate. Using C-terminal deletion constructs of ALDP, we demonstrate that the last 87 C-terminal amino acids harbor the most important protein domain mediating these interactions, and that the N-terminal transmembrane region of ALDP has an additional stabilization effect on ALDP homodimers. Loss of ALDP homo- or heterodimerization is highly relevant for understanding the disease mechanisms of X-ALD. [ABSTRACT FROM AUTHOR]

Abstract: Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions. [Copyright &y& Elsevier]

Abstract: Mutations in the ATP1A3 gene are associated with rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) as well as RDP/AHC intermediate presentations. Phenotypic diversity is being recognized. In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP. A novel heterozygous ATP1A3 missense mutation c.2600G>A (p.Gly867Asp, G867D) was detected in a 15-year-old girl. Her clinical phenotype is partially consistent with an intermediate presentation between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism and comprises additional yet unreported features. With onset at 4½years of age recurrent paroxysmal flaccid hemiplegia alternating in laterality was triggered by watching television or playing computer games. Occlusion of both eyes reliably stopped the plegic attacks with the patient remaining awake. Our observation further widens the phenotypic spectrum associated with ATP1A3 mutations. [Copyright &y& Elsevier]

Idiopathic hypothalamic dysfunction is a rare disorder presenting at age 3-7 years. Severe hypothalamic and brainstem dysfunction leads to death in 25% of patients. The disease is presumed to be autoimmune, or in some cases paraneoplastic. No successful treatment has been reported. Patient V. developed hyperphagia, hypersomnia, and extreme aggression at age 7 years, accompanied by episodes of hyperthermia, hypothermia, sinus bradycardia, hypernatremia, hyponatremia, persistent hyperprolactinemia, hypothyroidism, and growth-hormone deficiency. At age 9 years, a diagnosis of idiopathic hypothalamic dysfunction was rendered, and immunoglobulin therapy was commenced. Nine courses of immunoglobulins, at a dose of 2 g/kg every 4 weeks, were administered. Reproducible improvements in behavior and no further episodes of hyponatremia or hypernatremia and sinus bradycardia were evident. The endocrinologic abnormalities and poor thermoregulation remained. Administration of immunoglobulins during late stages of idiopathic hypothalamic dysfunction led to improvement in some but not all signs. Assuming an autoimmune basis for this disorder, treatment during early stages of disease should be more effective. To facilitate such early treatment, increased awareness of this disorder is necessary, to allow for early diagnosis. [Copyright &y& Elsevier]