Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

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Whole sequence of the mitochondrial DNA genome of Kearns Sayre Syndrome patients: identification of deletions and variants Mitochondria both produce the energy of the cell as ATP via respiration and regulate cellular metabolism. Accordingly, any deletion or mutation in the mitochondrial DNA (mtDNA) may result in a disease. One of these diseases is Kearns Sayre syndrome (KSS), described for the first time in 1958, where different large-scale deletions of different sizes and at different positions have been reported in the mitochondrial genome of patients with similar clinical symptoms. In this study, sequences of the mitochondrial genome of three patients with clinic features of KSS were analyzed. Our results revealed the position, heteroplasmy percentage, size of deletions, and their haplogroups. Two patients contained deletions reported previously and one patient showed a new deletion not reported previously. These results display for the first time a systematic analysis of mtDNA variants in the whole mtDNA genome of patients with KSS to help to understand their association with the disease.

Patients with ARCL-IIA harbor mutations in ATP6V0A2 that codes for an organelle proton pump. The ARCL-IIA syndrome characteristically presents a combined glycosylation defect affecting N-linked and O-linked glycosylations, differentiating it from other cutis laxa syndromes and classifying it as a Congenital Disorder of Glycosylation (ATP6V0A2-CDG). We studied two Mexican Mestizo patients with a clinical phenotype corresponding to an ARCL-IIA syndrome. Both patients presented abnormal transferrin (N-linked) glycosylation but Patient 1 had a normal ApoCIII (O-linked) glycosylation profile. Mutational screening of ATP6V0A2 using cDNA and genomic DNA revealed in Patient 1 a previously reported homozygous nonsense mutation c.187C>T (p.R63X) associated with a novel clinical finding of a VSD. In Patient 2 we found a homozygous c.2293C>T (p.Q765X) mutation that had been previously reported but found that it also altered RNA processing generating a novel transcript not previously identified (r.2176_2293del; p.F726Sfs*10). This is the first report to describe Mestizo patients with molecular diagnosis of ARCL-IIA/ATP6V0A2-CDG and to establish that their mutations are the first to be found in patients from different regions of the world and with different genetic backgrounds.

Epidermolytic palmoplantar keratoderma (EPPK), an autosomal-dominant genodermatosis, is the most frequently occurring hereditary palmoplantar keratoderma. EPPK is characterized by hyperkeratosis of the palms and soles. Approximately 90% of patients present with mutations in the KRT9 gene, which encodes for keratin 9. Many of these mutations are located within the highly conserved coil 1A region of the alpha-helical rod domain of keratin 9, an important domain for keratin heterodimerization. The objective was to assess the clinical and molecular characteristics of a Mexican family with EPPK. The clinical characteristics of members of this family were analyzed. The KRT9 gene of affected members was polymerase chain reaction amplified from genomic DNA and sequenced. All affected members of the family had hyperkeratosis of the palms and soles with knuckle pads. The R163W mutation in the KRT9 gene was present in all affected individuals who were tested. Although R163W is the most frequent KRT9 mutation in patients with EPPK, only two families have been reported with knuckle pads associated with this mutation. Our findings indicate that knuckle pads can be associated with EPPK and the R163W mutation in a family with a genetic background different from that described here.

Educational programs are a fundamental part of the global efforts to increase PID diagnosis and care. To be successful, such programs should include public relations, reach for first-contact physicians, and aim to develop an efficient referral network with molecular diagnostic capability. Enhancing medical knowledge on PID is a successful strategy to improve early diagnosis and treatment.

Hawkinsinuria is an autosomal dominant disorder of tyrosine metabolism. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene ( HPD) result in an altered HPD enzyme, causing hawkinsin and tyrosine accumulation. Persistent metabolic acidosis and failure to thrive are common features in patients with hawkinsinuria. We present the first known Latin American patient diagnosed with hawkinsinuria, and the tenth reported patient in the literature. We aim to establish clinical practice guidelines for patients with hawkinsinuria. The patient’s plasma tyrosine level was 21.5 mg/dL, which is several times higher than the reference value. Mutation analysis indicated heterozygosity for V212M and A33T variants in HPD. In the case of altered tyrosine levels found during newborn screening, we propose exclusive breastmilk feeding supplemented with ascorbic acid. Amino acid quantification is useful for monitoring treatment response. If tyrosinemia persists, protein intake must be decreased via a low-tyrosine diet. Molecular studies can be used to confirm a patient’s disease etiology. Further reports are required to elucidate new pathogenic and phenotypic variations to enable the development of an appropriate therapeutic approach.