Great clinical variability of Nance Horan syndrome due to deleterious NHS mutations in two unrelated Spanish families.

Background: Nance-Horan syndrome (NHS) is an X-linked rare congenital disorder caused by mutations in the NHS gene. Clinical manifestations include congenital cataracts, facial and dental dysmorphism and, in some cases, intellectual disability. The aim of the present work was to identify the genetic cause of this disease in two unrelated Spanish NHS families and to determine the relative involvement of this gene in the pathogenesis.Materials and methods: Four members of a two-generation family, three males and one female (Family 1), and seven members of a three-generation family, two males and five females (Family 2) were recruited and their index cases were screened for mutations in the NHS gene and 26 genes related with ocular congenital anomalies by NGS (Next Generation Sequencing).Results: Two pathogenic variants were found in the NHS gene: a nonsense mutation (p.Arg373X) and a frameshift mutation (p.His669ProfsX5). These mutations were found in the two unrelated NHS families with different clinical manifestations.Conclusions: In the present study, we identified two truncation mutations (one of them novel) in the NHS gene, associated with NHS. Given the wide clinical variability of this syndrome, NHS may be difficult to detect in individuals with subtle clinical manifestations or when congenital cataracts are the primary clinical manifestation which makes us suspect that it can be underdiagnosed. Combination of genetic studies and clinical examinations are essential for the clinical diagnosis optimization.

Letter to the Editor: In the last CTO issue members of SEHOP SEAP and SEFH headed by Pilar Garrido

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Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.

BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.

[Advances in the molecular genetics of the hereditary neuropathies]. / Avances en la genética molecular de las neuropatías hereditarias.

OBJECTIVE: We reviewed current knowledge of the molecular and genetic bases of hereditary peripheral neuropathies, with special emphasis on the senso motor neuropathies and their different clinical phenotypes. DEVELOPMENT: The peripheral neuropathies show great clinical variability and genetic heterogeneity. To date 12 genes and over 20 genetic loci have been described in relation to Charcot Marie Tooth disease and related neuropathies. The commonest form is the type 1A Charcot Marie Tooth disease (CMT1A) caused by tandem duplication of a monomer of 1.5 megabases (Mb) on chromosome 17q11.2. The CMT 1A duplication is found in 70% of the patients with CMT 1. The deletion of 1.5 Mb is the most prevalent mutation (85%) in hereditary neuropathy with susceptibility to paralysis due to pressure. This monomer includes the PMP22 gene which is affected by a genetic dose effect. The different proteins encoded by the genes described are well expressed in the Schwann cell and in the nerve axon. They have different functions. There are the structural proteins of myelin, transcription factors, cytoskeleton components, molecular motors of the microtubules, proteins involved in growth and cellular differentiation or with presumed enzyme activity. CONCLUSIONS: Diagnosis of molecular pathology is important for genetic counselling. The development of new treatment for hereditary neuropathies is based on the generation of animal models for the different genes and on understanding the role of the proteins involved in axon Schwann cell interaction.

Avances en la genética molecular de las neuropatías hereditarias / Advances in the molecular genetics of the hereditary neuropathies

Objetivo. Se muestra una revisión del estado actual de los conocimientos sobre las bases genéticas y moleculares de las neuropatías periféricas hereditarias, haciendo especial hincapié en las neuropatías sensitivomotoras y sus distintos fenotipos clínicos. Desarrollo. Las neuropatías periféricas exhiben una gran variabilidad clínica y heterogeneidad genética. Hasta el momento se han descrito 12 genes y más de 20 loci génicos asociados a la enfermedad de Charcot-MarieTooth y neuropatías relacionadas. La forma más frecuente es la enfermedad de Charcot-Marie-Tooth tipo 1A (CMT1A), causada por la duplicación en tándem de un monómero de 1,5 megabases (Mb) en el cromosoma 17q11.2. La duplicación CMT1A se encuentra en el 70 por ciento de los enfermos de CMT1. La deleción de 1,5 Mb es la mutación más prevalente (85 por ciento) en la neuropatía hereditaria con susceptibilidad a la parálisis por presión. Este monómero incluye el gen PMP22 , que se ve afectado por un efecto de dosis génica. Las diferentes proteínas codificadas por los genes descritos se expresan en la célula de Schwann o en el axón neuronal, y tienen distintas funciones; hay proteínas estructurales de mielina, factores de transcripción, componentes del citoesqueleto, motores moleculares de los microtúbulos, y proteínas involucradas en el crecimiento y diferenciación celular, o con supuesta actividad enzimática. Conclusiones. La determinación de la patología molecular es importante para el consejo genético. El desarrollo de nuevas terapias para el tratamiento de las neuropatías hereditarias se fundamenta en la generación de modelos animales para los diferentes genes y en el conocimiento del papel de las proteínas en la interacción axón-célula de Schwann (AU)