Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

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 have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

Expanding the phenotypic spectrum of ALDH18A1-related autosomal recessive cutis laxa with a description of novel neuroradiological findings

“…However, wrinkled skin was not an early and persistent feature, although this could be related to the ethnicity of the patient. Previous literature has reported cases from prenatal to adult onset (Baumgartner et al , 2000; Bicknell et al , 2008) but has highlighted a need for further description and recognition of the wide clinical spectrum of this disorder (Lefebvre et al , 2018; Angelini et al , 2020).…”

“…To date, 20 patients have been described with ALDH18A1 -related ARCL and 12 different ALDH18A1 variants have been reported (Baumgartner et al , 2000; Bicknell et al , 2008; Zampatti et al , 2012; Skidmore et al , 2011; Martinelli et al , 2012; Gardeitchik et al ., 2014; Wolthuis et al ., 2014; Fischer et al , 2014; Nozaki et al , 2016; Alazami et al , 2016; Lefebvre et al , 2018; Angelini et al , 2020). Patients with ALDH18A1 -related ARCL usually have biallelic variants that are found in the same domains [glutamate-5-kinase (G5K) or glutamyl-5-phosphate reductase (G5PR)] although one severe case is reported with variants affecting both domains (Lefebvre et al , 2018).…”

Análisis de la mutación c.187 C>T en el gen ATP6V0A2 mediante PCR-ARMS

“…La prevalencia de nacimiento de esta EPOF es de 1 en 1,000,000 (Orphanet, 2019) y se han descrito dos tipos: la enfermedad adquirida y la heredada. El tipo heredado o congénito puede ser desarrollado de forma autosómica dominante (ADCL), ligada al cromosoma X (XRCL) o autosómica recesiva (ARCL tipo IA, IB, IIA, IIB, III) (Morales et al, 2011;Angelini et al, 2020).…”

“…El ATP6V0A2 (ATP6V0A2-CDG) codifica para la subunidad a2 del dominio v0 de la ATPasa de tipo vacuolar (V-ATPasa) que consta de 20 exones y 856 aa. La V-ATPasa es una bomba encargada de mantener el gradiente de concentración de H + que permite la homeostasis del pH en diferentes compartimentos celulares, endosomas tempranos, endosomas de reciclaje, endosomas de clasificación, vesículas secretoras y en la red trans-Golgi (TGN) donde ocurre la parte final de la biosíntesis de los glicoconjugados (Angelini et al, 2020;Casey, Grinstein & Orlowski, 2010;Figura 1).…”

“…En los pacientes con ATP6V0A2-CDG la secreción de proteínas a la matriz extracelular se altera, particularmente la tropoelastina que es precursora de la elastina, proteína responsable de la rigidez y características elásticas de la piel. Los pacientes con ATP6V0A2-CDG presentan fontanelas grandes y con retraso en el cierre, fisuras palpebrales oblicuas descendentes, puente nasal prominente, mejillas caídas, surcos nasolabiales prominentes, voz profunda y resonante debido a la laxitud de las cuerdas vocales, divertículos, hernias, alta miopía, malformaciones corticales y cerebelares que ocasionan microcefalia, retraso en el neurodesarrollo, discapacidad intelectual y retraso del desarrollo (Morales et al, 2011;Angelini et al, 2020;Casey et al, 2010;Jefferies et al, 2008;Guillard et al, 2009;Rosnoblet & Peanne, 2013).…”