Mitochondrial Dysfunction in Phelan-McDermid Syndrome: Explaining Clinical Variation and Providing a Path Towards Treatment
| Status: | Completed |
|---|---|
| Conditions: | Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 1 - 21 |
| Updated: | 2/7/2015 |
| Start Date: | May 2012 |
| End Date: | May 2015 |
| Contact: | John C Slattery, BA/CCRP |
| Email: | jslattery@uams.edu |
| Phone: | 501-364-3556 |
The purpose of this study is to determine whether a relationship exists between gene
deletion(s) specific to the mitochondrial electron transport chain and presentation of
clinical characteristics in patients with Phelan-McDermid Syndrome (PMS).
deletion(s) specific to the mitochondrial electron transport chain and presentation of
clinical characteristics in patients with Phelan-McDermid Syndrome (PMS).
Phelan-McDermid Syndrome (PMS) results from a deletion within the 22q13 chromosome region.
Most children have specific physical morphology and developmental delays with many
displaying characteristics of autism spectrum disorder (ASD) including abnormalities in
social development. The behavioral aspect of PMS that parallels ASD has raised particular
interest as the SHANK3 gene, which lies in the 22q13 region, is important for synaptic
development, and animal SHANK3 knockout models demonstrate ASD characteristics thereby
confirming the importance of this gene in PMS. However, despite the importance of the SHANK3
gene, individuals with PMS have variations in their development, behavior and medical
characteristics that cannot be fully explained by the SHANK3 deletion.
Recently, Frye (2012) has noted the existence of 6 mitochondrial genes that lie slightly
proximal to the SHANK3 gene within the 22q13 region. These include genes important electron
transport change function (SCO2, NDUFA6), mitochondrial DNA (TYMP) and RNA (TRMU)
metabolism, fatty acid metabolism (CPT1B) and tricarboxylic acid cycle function (ACO2).
Since most Individuals with PMS have deletions that include chromosomal deletion outside of
the SHANK3 region, it is very likely that many, if not most, of children with PMS may have
deletions in these mitochondrial genes. Many of these genes have been linked to
mitochondrial disease, even in the heterozygous state. Even if recognized, mitochondrial
disease is only linked to a homozygous abnormal state (autosomal recessive), the loss of one
gene (heterozygous state) could result in symptomatology when associated with deletions in
other mitochondrial or non-mitochondrial genes. Abnormalities in mitochondrial pathways can
result in neurologic and non-neurologic symptoms including those sometimes seen in children
with PMS. Added with the SHANK3 deletion, abnormalities in these mitochondrial genes could
explain variations in patterns of development and the eventual cognitive potential.
References: Frye RE. Mitochondrial disease in 22q13 duplication syndrome. J Child Neurol.
2012; 27(7):942-9.
Most children have specific physical morphology and developmental delays with many
displaying characteristics of autism spectrum disorder (ASD) including abnormalities in
social development. The behavioral aspect of PMS that parallels ASD has raised particular
interest as the SHANK3 gene, which lies in the 22q13 region, is important for synaptic
development, and animal SHANK3 knockout models demonstrate ASD characteristics thereby
confirming the importance of this gene in PMS. However, despite the importance of the SHANK3
gene, individuals with PMS have variations in their development, behavior and medical
characteristics that cannot be fully explained by the SHANK3 deletion.
Recently, Frye (2012) has noted the existence of 6 mitochondrial genes that lie slightly
proximal to the SHANK3 gene within the 22q13 region. These include genes important electron
transport change function (SCO2, NDUFA6), mitochondrial DNA (TYMP) and RNA (TRMU)
metabolism, fatty acid metabolism (CPT1B) and tricarboxylic acid cycle function (ACO2).
Since most Individuals with PMS have deletions that include chromosomal deletion outside of
the SHANK3 region, it is very likely that many, if not most, of children with PMS may have
deletions in these mitochondrial genes. Many of these genes have been linked to
mitochondrial disease, even in the heterozygous state. Even if recognized, mitochondrial
disease is only linked to a homozygous abnormal state (autosomal recessive), the loss of one
gene (heterozygous state) could result in symptomatology when associated with deletions in
other mitochondrial or non-mitochondrial genes. Abnormalities in mitochondrial pathways can
result in neurologic and non-neurologic symptoms including those sometimes seen in children
with PMS. Added with the SHANK3 deletion, abnormalities in these mitochondrial genes could
explain variations in patterns of development and the eventual cognitive potential.
References: Frye RE. Mitochondrial disease in 22q13 duplication syndrome. J Child Neurol.
2012; 27(7):942-9.
Inclusion Criteria:
- 1-21 years of age
- Diagnosed with Phelan-McDermid Syndrome AND diagnosed with Mitochondrial Disorder
- Diagnosed with Phelan-McDermid Syndrome
Exclusion Criteria:
- none
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