Luigi Boccuto, MD

Active Research Projects

Metabolic profiling of Autism Spectrum Disorder (ASD)

This area of interest includes several projects that are focused on characterizing the metabolic profile of cells obtained from individuals with autism spectrum disorder (ASD). Different cell types (lymphoblasts, fibroblasts, iPSCs) have been tested utilizing the Biolog Phenotype Mammalian Microarray (PM-M) technology. The platform includes 8 plates (PM-M1 to M8) plus the custom tryptophan plate, realized by Biolog in collaboration with GGC in consideration of preliminary data highlighting the abnormal utilization of the amino acid tryptophan in ASD cells (Boccuto et al., Mol Aut 2013).

The main studies characterizing this area of interest are:

  • Development of a classifier algorithm utilizing cellular metabolic profiles to distinguish individuals with ASD from patients with other neurodevelopmental disorders and typically developing controls
  • Investigation of metabolic abnormalities in targeted pathways in cells from patients with ASD
  • Endophenotyping of clinically selected subgroups of patients with ASD (collaboration with STALICLA)
  • In vitro assessment of beneficial effects of potential therapeutic compounds on ASD cell lines
  • Development of a quick and reliable blood-based diagnostic test for ASD (collaboration with CIRCA Bioscience in the STTR grant)
  • Functional investigation of the effects of disruption of epigenetic regulation and mitochondrial metabolism in ASD cells (multicenter collaboration in the EPSCoR/IDeA grant)
  • Metabolic profiling of syndromic forms of ASD (i.e., Fragile X syndrome).


Genotype-phenotype correlation of Phelan-McDermid syndrome (PMS)

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by global developmental delay, neonatal hypotonia, seizures, sleep disturbances, ASD or autistic traits, and minor dysmorphic traits. This condition is usually caused by chromosomal rearrangements affecting the 22q13 region or loss-of-function variants of the SHANK3 gene. However, PMS has been associated with both genotypic and phenotypic variability.

GGC has been historically involved in the research of PMS since the first description of the condition by Drs. Katy Phelan and Curtis Rogers in the 1990s and a large cohort of PMS patients has been collected through the years in collaborations with the PMS Foundation. The PMS Program has been created at GGC and is lead by Dr. Rogers on the clinical side and by Dr. Boccuto on the research one to further investigate the genotype-phenotype correlation underlying the significant variability described in patients affected with this condition. The main study in the PMS Program is “Characterization of the relationship between genotype and neurobehavioral phenotype in individuals with Phelan-McDermid syndrome (IRB Pro00057738)”. The study is composed by three parts:

  1. Clinical evaluation via phone questionnaires focused on three main features of PMS
       a. Behavioral issues, particularly autistic traits
       b. Seizures
       c. Sleep disturbances

  2. Sequence screening of candidate genes in the 22q13 region (“second hit” model) in order to identify modifying variants affecting the severity of the clinical presentation in PMS patients

  3. Metabolic profiling of lymphoblastoid cell lines from PMS patients and correlation with neurobehavioral and genetic features.

Side projects are also currently ongoing:

  • Metabolic profiles of cells from PMS patients that have been submitted to whole exome sequencing (WES)
  • TAD analysis of the genes mapping in the 22q13 region and correlation with the PMS signs and symptoms
  • Identification of candidate 22q13 genes and functional characterization of their contribution to the PMS phenotype (ALG12, PNPLA3).

Functional characterization of conditions with segmental overgrowth

Mosaic gain-of-function variants in genes of the PI3K-AKT pathway have been associated with several conditions characterized by segmental overgrowth. A genetic screening of the PI3K-AKT genes has been conducted on samples from patients with segmental overgrowth collected at GGC and in other national and international centers.

The activating effect of gene variants on the PI3K-AKT pathway has been assessed by AKT phosphorylation after starvation, that confirmed the constitutive activation of the AKT protein leading to excessive cell growth and proliferation. Further studies have been performed to characterize the effect of gain-of-function mutations in different PI3K-AKT genes: AKT phosphorylation after stimulation and energy production in response to the exposure to growth factors activating the PI3K-AKT pathway, assessed by utilizing the Biolog Phenotype Microarray PM-M7. These functional assays showed different profiles according to the gene affected by the variant (i.e. PIK3CA vs. AKT1).

A series of compounds with potential therapeutic effects have been tested on the PM-M7 array in order to assess the capacity to rescue normal metabolic responses to growth factors.

These studies can provide functional characterization of different gain-of-function variants of the PI3K-AKT genes, select molecular-metabolic profiles even in the absence of a detected mosaic mutation, and identify effective drugs for the treatment of conditions with segmental overgrowth.

Other minor projects are based on the metabolic characterization of cell lines from individuals with other neurodevelopmental disorders, mostly XLID.

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Meet the Shorter Boys

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