3 research outputs found
Polycystic renal disease : an update
La enfermedad renal poliquística (PKD) es una enfermedad genética común que
consiste en la aparición progresiva de lesiones quísticas en los riñones, que remplazan
el parénquima renal, lo que conduce a enfermedad renal crónica terminal. La PKD
tiene dos patrones de herencia: autosómico dominante y autosómico recesivo. La
forma autosómica dominante es más común y menos grave que la autosómica recesiva.
Se conoce que la PKD es causada por mutación en varios loci humanos. La forma
autosómica dominante puede ser causada por mutaciones en dos genes diferentes
(PKD1 y PKD2); en tanto que la forma autosómica recesiva solo tiene un gen causal
(PKHD1). Existen numerosas publicaciones que buscan explicar la fisiopatología de
la enfermedad. Esto refleja un esfuerzo internacional por comprender la naturaleza
de la enfermedad, para desarrollar terapias que eviten la aparición de los quistes o la
progresión de los que ya están instaurados. El objetivo de esta revisión es difundir
el conocimiento que se tiene hasta el momento, acerca de la enfermedad renal
poliquística. Por lo tanto, realizamos un breve recuento de las características clínicas
de la enfermedad y el tratamiento actual disponible.Artículo de revisión53-68Polycystic Kidney Disease (PKD) is a common
genetic condition, which is characterized
by gradual appearance of multiple cysts in the
kidneys; this causes the destruction of renal
parenchyma leading to chronic renal disease.
PKD has two patterns of inheritance: autosomal
dominant and autosomal recessive. The
autosomal dominant form is more common
and less severe than the autosomal recessive. It
is known that PKD is caused by mutation in several
human loci. The autosomal dominant form
can be caused by mutations in 2 different genes
(PKD1 and PKD2). The autosomal recessive
form has only one causal gene (PKHD1). There
are numerous publications worldwide that seek
to explain the pathophysiology of the disease;
this reflects an international effort to understand
the nature of the disease, to develop therapies
to prevent the appearance of cysts or the progression
of those already existent lesions. The objective
of this review is to update the knowledge we
have so far, about polycystic kidney disease therefore
we decided to conduct a brief review of
the clinical features of disease and the treatment
available today
At a glance:the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years
Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients’ clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype–phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0–64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype–phenotype relationships for “frequent” NPC1 variants.</p
An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients
To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients ( n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs