The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the ...diagnostic role of α‐galactosidase A activity (α‐Gal A), levels of lyso‐Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α‐Gal A activity in suspected FD patients in DBS was made followed by lyso‐Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α‐Gal A was more sensitive than lyso‐Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.
Measurement of α‐Galactosidase A enzymatic activity in 2381 suspected Fabry disease patients in dried blood spot (DBS) let us an accuracy screening to proceed to the final diagnosis in the same initial sample. Proposed diagnostic algorithm for screening where it is not possible to sequence all women. Enzyme activity cut‐off points for men and women from the ROC study. Thirteen different genetic variants in the GLA gene were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA) and another one reconsidered as pathogenic when previous publication consider it like uncertain significance (c.239G > A).
Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), ...including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment.
An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period).
The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of −60% (6.6) at week 4 (first post-baseline assessment) and −61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean standard deviation at baseline, −2.630 1.17, n = 8; at week 48, −2.045 0.27, n = 7) and growth velocity (mean SD Z-score at baseline, −2.59 1.49, n = 4; at week 48, −0.39 2.10, n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects.
In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age.
Trial registration: NCT02418455.
The proximal 19p13.3 microdeletion/microduplication (prox19p13.3del/dup) syndrome is a recently described disorder with common clinical features including developmental delay, intellectual ...disability, speech delay, facial dysmorphic features with ear defects, anomalies of the hands and feet, umbilical hernia and hypotonia. While deletions are associated with macrocephaly, patients with duplications have microcephaly. The smallest region of overlap in multiple patients (113.5 kb) included three genes and one pseudogene, with a suggested major role of PIAS4 in determination of the phenotype and head size in these patients. Here, we refine the prox19p13.3del/dup with four additional patients: two with microdeletions, one with microduplication and one family with single‐nucleotide nonsense variant in PIAS4. The patient with the PIAS4 loss of function variant displayed a phenotype quite similar to deletion patients ‐including the macrocephaly and many other core features of the syndrome. Patient's SNV was inherited from her mother who is similarly affected. Thus, our data indicate that PIAS4 is a major contributor to the proximal 19p13.3del/dup syndrome phenotype. In summary, we report the first patient with a pathogenic variant in PIAS4‐ and three additional rearrangements at the proximal 19p13.3 locus. These observations add further evidence about the molecular basis of this microdeletion/microduplication syndrome.
Clinical and genetic management of patients with rare syndromes is often a difficult, confusing, and slow task.
Male child patient with a multisystemic disease showing congenital heart defects, ...facial dysmorphism, skeletal malformations, and eye anomalies.
The patient remained clinically undiagnosed until the genetic results were conclusive and allowed to associate its clinical features with the germline ABL1 mutations-associated syndrome.
We performed whole-exome sequencing to uncover the underlying genetic defect in this patient. Subsequently, family segregation of identified mutations was performed by Sanger sequencing in all available family members.
The only detected variant compatible with the disease was a novel heterozygous nonframeshift de novo deletion in ABL1 (c.434_436del; p.Ser145del). The affected residue lays in a functional domain of the protein, it is highly conserved among distinct species, and its loss is predicted as pathogenic by in silico studies.
Our results reinforce the involvement of ABL1 in clinically undiagnosed cases with developmental defects and expand the clinical and genetic spectrum of the recently reported ABL1-associated syndrome. In this sense, we described the third germline ABL1 causative mutation and linked, for the first time, ocular anterior chamber anomalies to this pathology. Thus, we suggest that this disorder may be more heterogeneous than is currently believed and may be overlapping with other multisystemic diseases, hence genetic and clinical reassessment of this type of cases should be considered to ensure proper diagnosis.
Mucopolysaccharidosis type VII (Sly syndrome) is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme beta-glucuronidase. Precise data regarding its ...epidemiology are scarce, but birth prevalence is estimated to vary from 0.02 to 0.24 per 100,000 live births. The clinical course and disease progression are widely heterogeneous, but most patients have been reported to show signs such as skeletal deformities or cognitive delay. Additionally, detection criteria are not standardized, resulting in delayed diagnosis and treatment. We present a cohort of 9 patients with mucopolysaccharidosis VII diagnosed in the Iberian Peninsula, either in Spain or Portugal. The diagnostic approach, genetic studies, clinical features, evolution and treatment interventions were reviewed. We found that skeletal deformities, hip dysplasia, hydrops fetalis, hepatosplenomegaly, hernias, coarse features, respiratory issues, and cognitive and growth delay were the most common features identified in the cohort. In general, patients with early diagnostic confirmation who received the appropriate treatment in a timely manner presented a more favorable clinical evolution. This case series report helps to improve understanding of this ultra-rare disease and allows to establish criteria for clinical suspicion or diagnosis, recommendations, and future directions for better management of patients with Sly syndrome.
Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid alpha-glucosidase gene (GAA) that produces defects in the lysosomal acid ...alpha-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype-phenotype correlation. A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7-64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them alpha-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.
Several studies show great heterogeneity in the type of genetic test requested and in the clinicopathological characteristics of patients with ASD. The following study aims, firstly, to explore the ...factors that might influence professionals' decisions about the appropriateness of requesting genetic testing for their patients with ASD and, secondly, to determine the prevalence of genetic alterations in a representative sample of children with a diagnosis of ASD. Methods: We studied the clinical factors associated with the request for genetic testing in a sample of 440 children with ASD and the clinical factors of present genetic alterations. Even though the main guidelines recommend genetic testing all children with an ASD diagnosis, only 56% of children with an ASD diagnosis were genetically tested. The prevalence of genetic alterations was 17.5%. These alterations were more often associated with intellectual disability and dysmorphic features. There are no objective data to explicitly justify the request for genetic testing, nor are there objective data to justify requesting one genetic study versus multiple studies. Remarkably, only 28% of males were genetically tested with the recommended tests (fragile X and CMA). Children with dysmorphic features and organic comorbidities were more likely to be genetic tested than those without. Previous diagnosis of ASD (family history of ASD) and attendance at specialist services were also associated with Genetically tested Autism Spectrum Disorder GTASD. Our findings emphasize the importance of establishing algorithms to facilitate targeted genetic consultation for individuals with ASD who are likely to benefit, considering clinical phenotypes, efficiency, ethics, and benefits.
Rare diseases are heterogeneous life-threatening or seriously debilitating conditions that affect < 1 in 2000 individuals, and most have a genetic component. The diagnostic process is usually based ...on classic clinical practices, such as physical examination, personal and family history (inheritance pattern), laboratory tests and image studies, but diagnosis can be delayed several years after the initiation of symptoms. The advances in molecular genetics that have taken place in recent years have led to an important shift in medical practice and in its approach to the diagnosis and treatment of many rare diseases. The objective of this review is to promote a better understanding of the mechanisms underlying genetic diseases in humans and the tools available for their diagnosis. A practical example of X-linked hypophosphataemic rickets is described.
Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa ...administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.
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