Publications by authors named "Patroula Smpokou"

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial.

View Article and Find Full Text PDF

The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies.

View Article and Find Full Text PDF

In vitro cell-based data can be used to support the extension of pharmaceutical approval to patient subsets with unique genetic variants. A set of conditions should be satisfied to support the extension of approval. The disease mechanism should be well described, and the impact of variants on protein function should be reasonably understood.

View Article and Find Full Text PDF

Iron-sulfur (Fe-S) clusters are essential cofactors for proteins that participate in fundamental cellular processes including metabolism, DNA replication and repair, transcriptional regulation, and the mitochondrial electron transport chain (ETC). ISCA2 plays a role in the biogenesis of Fe-S clusters and a recent report described subjects displaying infantile-onset leukodystrophy due to bi-allelic mutation of ISCA2. We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA deficiency.

View Article and Find Full Text PDF

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology.

View Article and Find Full Text PDF

Childhood rhabdomyosarcoma (RMS) accounts for approximately 3.5% of cancer cases among children 0 to 14 years of age. Genetic conditions associated with high risk of childhood RMS include Li-Fraumeni syndrome, pleuropulmonary blastoma, Beckwith-Wiedemann syndrome, and some RASopathies, such as neurofibromatosis type 1, Costello syndrome (CS), and Noonan syndrome (NS).

View Article and Find Full Text PDF

Background: The approach to clinical evaluation of the dysmorphic neonate can be challenging and multifaceted. It requires specialized knowledge of rare diagnoses and awareness of immediate versus long-term needs for the newborn and the family.

Purpose: This review summarizes important considerations in the initial evaluation of genetic syndromes, which can present in the neonatal period with variable aspects of dysmorphism.

View Article and Find Full Text PDF

Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.

View Article and Find Full Text PDF

Menkes disease (MD; OMIM 309400) is an X-linked, neurodegenerative disorder resulting from deficient activity of copper-dependent enzymes and caused by alterations in the APT7A gene. In its classic form, it manifests in boys with hypotonia, seizures, skin and joint laxity, hair twisting (pili torti), cerebrovascular tortuosity, and bladder diverticulae. Menkes disease phenotypes have been reported in females with X; autosome translocations-disrupting ATP7A gene function- or ATP7A gene alterations.

View Article and Find Full Text PDF

Objective: The aim of this study was to report the earliest age of diagnosis of common clinical findings in children with PTEN hamartoma tumour syndrome (PHTS).

Design: Medical records of children with PHTS were reviewed; data included growth measurements, presence or absence of specific clinical manifestations and tumours, and documented ages of diagnosis.

Setting: Children with PHTS evaluated at Boston Children's Hospital from 1996 to 2011.

View Article and Find Full Text PDF

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones.

View Article and Find Full Text PDF

Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings.

View Article and Find Full Text PDF