Luc Régal

Bio: Luc Régal is an academic researcher from Katholieke Universiteit Leuven. The author has contributed to research in topics: Newborn screening & Glycosylation. The author has an hindex of 17, co-authored 36 publications receiving 1255 citations.

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Abstract: Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency.

Abstract: OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency. METHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. RESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). CONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy

Abstract: Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm5U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.

The G93C Mutation in Superoxide Dismutase 1: Clinicopathologic Phenotype and Prognosis

Abstract: Background: Twenty percent of familial amyotrophic lateral sclerosis (ALS) is caused by mutations in the superoxidedismutase1gene(SOD1).Fewdataexistontheir clinicopathologic phenotypes. Objectives: To determine the clinical and pathologic phenotype associated with the G93C mutation in SOD1 and to compare survival in familial ALS related to this mutation with survival in other ALS subgroups. Design: Retrospective study. Setting:Tertiary referral center for neuromuscular disorders.

Mutations in PEX10 are a cause of autosomal recessive ataxia.

Abstract: Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia.

The changing scene of amyotrophic lateral sclerosis

Abstract: Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

New insights into the immunopathogenesis of systemic lupus erythematosus

Abstract: In this Review, Tsokos et al. describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE.

Aicardi–Goutières syndrome and the type I interferonopathies

Abstract: This Review describes the type I interferonopathies — a set of Mendelian disorders associated with the upregulation of type I interferon activity. The authors explain how defects in key components of innate immune signalling pathways can lead to these diseases and discuss the immunological insights that have resulted from their study.

The phenotypic variability of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a genotypically and phenotypically heterogeneous disease, as reflected in the variability in age and site of onset, extent of extramotor involvement, and survival. Cognitive involvement is also common, and corroborates the connection between ALS and frontotemporal lobar degeneration. In this article, Robberecht and Swinnen review phenotypic heterogeneity in ALS and discuss some of its implications for understanding ALS pathogenesis and development of therapeutic interventions. Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3–5 years after onset—a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

Abstract: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.