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Introduction: Pompe Disease (PD) is a lysosomal disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), primarily manifesting as a progressive myopathy with early respiratory involvement. Enzyme replacement therapy (ERT) is available since 2006., Materials and Methods: We describe 13 patients with partial GAA deficiency, followed at Hospital 12 de Octubre, 8 of whom were receiving treatment., Results: 8 patients exhibit symptoms, all with late onset. They display axial and proximal weakness predominantly in the lower limbs but maintain autonomous gait. Five patients require non-invasive mechanical ventilation due to respiratory insufficiency. All symptomatic patients receive ERT, and in 7/8 (87.5%), there is a decline in motor and pulmonary function after an average of 8.25 years of treatment (baseline and post-treatment FVC and 6MWT mean 86.6% vs 70.8% and 498 vs 430 meters, respectively)., Conclusion: Not all patients with partial GAA deficiency experience symptoms of PD, and symptomatic patients, despite ERT with recombinant alpha-glucosidase, mostly experience a gradual decline in motor and respiratory function., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3' of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent. Recently, a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants. We describe two unrelated Spanish patients presenting with slowly progressive gait disturbance, distal-predominant weakness, and mildly elevated creatine kinase (CK) levels since their 6th decade. Electromyography revealed abnormal spontaneous activity and a myopathic pattern. Muscle magnetic resonance imaging (MRI) showed marked fatty replacement in distal leg muscles. A muscle biopsy, performed on one patient, revealed myopathic changes with rimmed vacuoles. Both patients carried the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variants. Digenic inheritance is supported by evidence from unrelated pedigrees and a plausible biological interaction between both proteins in protein quality control processes. Recent functional studies and additional case descriptions further support this. Clinical suspicion is necessary to seek both variants., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & Aims: Transcription co-activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis., Methods: Tcf20 knock-out (Tcf20 -/- ) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass-spectrometry., Results: Characterization of Tcf20 -/- newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl 4 -induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild-type mice, along with abnormal behavioural patterns compatible with autism-like phenotypes. Tcf20 -/- embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma., Conclusions: We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including PERP , a gene encoding a crucial component of desmosomes that has been associated with dominant and recessive keratoderma. We report a patient with recessive erythrokeratoderma (EK) in which whole exome sequencing (WES) prioritized by human phenotype ontology (HPO) terms revealed the presence of the novel variant c.153C > A in the N-terminal region the PERP gene. This variant is predicted to have a nonsense effect, p.(Cys51Ter), resulting in a premature stop codon. We demonstrated a marked reduction in gene expression in cultured skin fibroblasts obtained from the patient. Despite the PERP gene is expressed at low levels in fibroblasts, our finding supports a loss-of-function (LoF) mechanism for the identified variant, as previously suggested in recessive EK. Our study underscores the importance of integrating HPO analysis when using WES for molecular genetic diagnosis in a clinical setting, as it facilitates continuous updates regarding gene-clinical feature associations.

Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness., Methods: Our method involved the description of three cases of CMS that were initially characterized as probable PMM., Results: All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK , DOK7 , and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases., Conclusions: Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy.

Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome., Competing Interests: None declared., (Thieme. All rights reserved.)

The biallelic pathogenic repeat (AAGGG) 400-2000 intronic expansion in the RFC1 gene has been recently described as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and as a major cause of late-onset ataxia. Since then, many heterozygous carriers have been identified, with an estimated allele frequency of 0.7% to 4% in the healthy population. Here, we describe in two affected CANVAS sisters the presence of the nonsense c.724C > T p.(Arg242*) variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene. Further RNA analysis demonstrated a reduced expression of the p.Arg242* allele in patients confirming an efficient nonsense-mediated mRNA decay. We also highlight the importance of considering the sequencing of the RFC1 gene for the diagnosis, especially in patients with CANVAS diagnosis carriers of the AAGGG repeat expansion., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an autosomal recessive vascular disorder caused by biallellic variants in HTRA1. Recently, it has been reported that several heterozygous mutations in HTRA1 are responsible for a milder late-onset cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. The majority of them are missense that affects the Htr1A protease activity due to a dominant-negative effect caused by defective trimerization or monomer activation. The molecular mechanism related to the structural destabilization of the protein supports the practical utility of integrating computational stability predictors to prioritize candidate variants in this gene. In this work, we report a family with several members diagnosed with subcortical ischemic events and progressive cognitive impairment caused by the novel c.820C > G, p.(Arg274Gly) heterozygous variant in HTRA1 segregating in an autosomal dominant manner and propose its molecular mechanism by a three-dimensional model of the protein's structure., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: SQSTM1 -variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p. (Pro146_Cys154dup) in the SQSTM1 gene in a family with a new phenotype characterized by a personality disorder and behavioral variant frontotemporal dementia (bvFTD). We review the literature on frontotemporal dementia (FTD) associated with SQSTM1 . Methods: The index case and relatives were described, and a genetic study through Whole Exome Sequencing was performed. The literature was reviewed using Medline and Web of Science. Case reports, case series, and cohort studies were included if they provided information on SQSTM1 mutations associated with FTD. Results : Our patient is a 70-year-old man with a personality disorder since youth, familial history of dementia, and personality disorders with a 10-year history of cognitive decline and behavioral disturbances. A diagnosis of probable bvFTD was established, and the in-frame duplication c.436_462dup in the SQSTM1 gene was identified. Segregation analysis in the family confirmed that both affected sons with personality disorder were heterozygous carriers, but not his healthy 65-year-old brother. A total of 14 publications about 57 patients with SQSTM1 -related FTD were reviewed, in which the bvFTD subtype was the main phenotype described (66.6%), with a predominance in men (63%) and positive family history in 61.4% of the cases. Conclusions: We describe a heterozygous in-frame duplication c.436_462dup p.(Pro146_Cys154dup) in the SQSTM1 gene, which affects the zinc-finger domain of p62, in a family with a personality disorder and bvFTD, expanding the genetics and clinical phenotype related to SQSTM1 .

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Meningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello-Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87)., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.