Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA Chloé Angelini, Marie Thibaud, Nathalie Aladjidi, Pierre Bessou, Sébastien Cabasson, Cindy Colson, Caroline Espil-Taris, Cyril Goizet, Marie Husson, Fanny Morice-Picard, et al. To cite this version: Chloé Angelini, Marie Thibaud, Nathalie Aladjidi, Pierre Bessou, Sébastien Cabasson, et al.. Expand- ing the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA. Neu- ropediatrics, Thieme Publishing, 2020, 51 (4), pp.245-250. 10.1055/s-0040-1701671. hal-02875148 HAL Id: hal-02875148 https://hal-normandie-univ.archives-ouvertes.fr/hal-02875148 Submitted on 10 Mar 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Published online: 2020-03-06 Original Article 245 Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA Chloé Angelini1,2 Marie Thibaud3 Nathalie Aladjidi4,5 Pierre Bessou6 Sébastien Cabasson3 Cindy Colson7 Caroline Espil-Taris3 Cyril Goizet1,2 Marie Husson3 Fanny Morice-Picard8 Annachiara De Sandre-Giovannoli9,10 Jean-Michel Pédespan3 1 Service de Génétique Médicale, CHU de Bordeaux and Laboratoire Address for correspondence Chloé Angelini, MD, Service de MRGM, INSERM U1211, University of Bordeaux, Bordeaux, France Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, 2 CentredeRéférenceNeurogénétique,ServicedeGénétique INSERM U1211, University of Bordeaux, Bordeaux, France Médicale, CHU de Bordeaux, Bordeaux, France (e-mail: [email protected]). 3 Service de Neurologie Pédiatrique, CHU de Bordeaux, Bordeaux, France 7 Normandie Univ, UNICAEN, CHU de Caen Normandie, Department 4 Pediatric Hematology Unit, CIC1401, INSERM CICP, University of Genetics, EA7450 BioTARGen, Caen, France. Hospital of Bordeaux, Bordeaux, France 8 Centre de Référence des Maladies Rares de la Peau, Service de 5 Centre de référence national des cytopénies auto-immunes de Dermatologie Pédiatrique, CHU de Bordeaux, Bordeaux, France l’enfant (CEREVANCE), University Hospital of Bordeaux, Bordeaux, 9 Service de Génétique Médicale, Hôpital La Timone Enfants, AP-HM, France Marseille, France 6 Service de Radiologie Pédiatrique, CHU de Bordeaux, 10CRB-TAC, Centre de ressources biologiques de l’AP-HM, Hôpital La Bordeaux, France Timone Enfants, AP-HM, Marseille, France Neuropediatrics 2020;51:245–250. Abstract Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients Keywords have been described. ► cutis laxa We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with ► ALDH18A1 an extremely severe phenotype, including novel neurological findings. This description ► neurological findings enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type ► vascular tortuosity IIIA, and provides an additional description of this syndrome. Introduction different forms of inherited cutis laxa syndromes have been described.2 Cutis laxa represents a spectrum of clinical entities, includ- Cutis laxa type IIB (OMIM#612940), type IIIA This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ing lax and hyperelastic skin with visible veins. It is caused (OMIM#219150), and type IIIB (OMIM#614438), are known by defective elastin synthesis, structural abnormalities of as De Barsy syndrome, and are associated with pathogenic the extracellular matrix, and also defects in metabolic variants in PYCR1 and ALDH18A1, two genes playing an pathways. These diseases may be acquired or inherited. important role in proline metabolism.3 Inherited cutis laxa are very rare diseases and show differ- PYCR1 encodes for pyrroline-5-carboxylate reductase, an ent inheritance patterns (autosomal dominant, autosomal enzyme involved in the last steps of proline synthesis from recessive, and X-linked recessive inheritance).1 To date, 13 glutamate.4 PYCR1 pathogenic variants can lead to cutis laxa, received © 2020 Georg Thieme Verlag KG DOI https://doi.org/ July 11, 2019 Stuttgart · New York 10.1055/s-0040-1701671. accepted after revision ISSN 0174-304X. December 28, 2019 published online March 6, 2020 246 Expanding the Spectrum of Neurological Manifestations in Cutis Laxa Angelini et al. autosomal recessive, type IIB and type IIIB, with a phenotypic During pregnancy appeared severe intrauterine growth overlap, and are characterized by a cutis laxa of variable retardation (IUGR), associated to oligoamnios. Amniocente- severity, abnormal growth, developmental delay, and asso- sis was done to perform a genetic work up, including an ciated skeletal abnormalities. array-comparative genomic hybridization and a karyotype, ALDH18A1 encodes for delta-1-pyrroline-5-carboxylate both were normal. synthase (P5CS), an enzyme that catalyzes the reduction of He was born at 34 gestational weeks by a cesarean section, glutamate to delta1-pyrroline-5-carboxylate, and plays a key planned because of IUGR. He needed breathing assistance role in the de novo biosynthesis of proline, ornithine, and immediately after birth, with noninvasive ventilation, during arginine.5 ALDH18A1 pathogenic variants are responsible for 3 hours. He weighed 1.66 kg (–3.9 standard deviation [SD]), cutis laxa, autosomal recessive, type IIIA, cutis laxa autoso- measured 40 cm (–5SD), and his head circumference was mal dominant 3 (OMIM#616603), and also spastic paraple- 31 cm (–3.8 SD). gia 9A, autosomal dominant (OMIM#601162), and 9B, Examination at birth revealed a large fontanel, adductus autosomal recessive (OMIM#616586). There is a phenotypic thumbs, global hypotonia, and a major systolic cardiac overlap between these four syndromes, with variable neuro- murmur. Transfontanellar ultrasound was normal, as well logic symptoms. as an electroencephalogram, an abdominal ultrasound, and Cutis laxa, autosomal recessive, type IIIA, is a rare genetic skeletal X-rays. Cardiac ultrasound found a large ventricular condition.6,7 Only about 20 patients have been described in the septal defect and a large atrial septal defect. Ophthalmologi- literature.8 Its clinical spectrum includes abundant and wrin- cal examination with eye fundoscopy revealed bilateral kled skin, skeletal anomalies, neurodevelopmental disorders, corneal clouding. cataract and corneal clouding, and, in some cases, severe Neurological examination worsened with months and he neurological symptoms such as major developmental delay, presented with four limbs spasticity, permanent tremor, and hypotonia in infancy, hyperreflexia, athetoid movements, and eye twitching. He had also severe dystonia and four limbs seizures.9,10 The cellular phenotype is characterized by dimin- contractures that led to hip and shoulder dislocations ished production of collagen types I and III, altered elastin (►Fig. 1). Adductus thumbs as well as calcaneus valgus ultrastructure, and diminished cell proliferation.11 feet were persistent. Cutis laxa, autosomal dominant 3, is characterized by He presented at age 5 months partial seizures with focal excessive skin with visible veins, cataract or corneal clouding, onset and motor manifestations (focal myoclonia), recorded clenched fingers, pre- and postnatal growth retardation, and on electroencephalogram with multifocal spikes, and slow moderate intellectual disability. Some patients may also waves with very slow background activity and absence of present muscular hypotonia with brisk muscle reflexes and sleep spindles (►Fig. 2). He was from then effectively treated cranial vessel tortuosity with foramen magnum stenosis. The with oxcarbazepine. phenotype seems to be less severe than cutis laxa, autosomal A brain MRI was performed at age 8 months (►Fig. 3). recessive, type IIIA, but with a greater neurological involve- Diffuse supra- and infratentorial cortical atrophy was ment, with hypertonia, spasticity, and brain magnetic reso- found, with brain stem contours distortions, associated to nance imaging (MRI) abnormalities, such as tortuous a thin corpus callosum and large ventricles due to gray intracranial vessels, widened perivascular spaces, and white matter paucity. A severe dysmyelination was observed with matter signal anomalies on T2 and fluid-attenuated inver- abnormal spectroscopy (lactate increased and N-acetyl sion recovery (FLAIR) sequences.12 aspartate decreased). Basal ganglia were hardly identified. Spastic paraplegia 9A is a neurologic disorder with pro- Willis polygon vessels were abnormal, and described as gressive spasticity appearing from adolescence to adulthood. megadolichovessels. Patients present with lower limbs spasticity, and may have He exhibited a severe failure to thrive during follow-up. additional features, such as cataract,