Jordan's Syndrome (JS) or ''PPP2R5D''-related intellectual disability is a rare
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
neurodevelopmental disorder
Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
caused by ''de novo''
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in the ''
PPP2R5D
Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform is an enzyme that in humans is encoded by the ''PPP2R5D'' gene. Mutations in ''PPP2R5D'' cause Jordan's Syndrome.
Function
The product of this gene belongs to the p ...
'' gene.
It is characterized by
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...
,
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...
, and
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...
.
Children with JS may also have
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
or meet criteria for diagnosis with
autism spectrum disorder
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
.
Signs and symptoms
Symptoms of Jordan's Syndrome (JS) are not formally defined but typically appear in early childhood and can range from mild to severe
global developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, c ...
and
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...
, usually including
speech delay
Speech delay, also known as alalia, refers to a delay in the development or use of the mechanisms that produce speech. Speech – as distinct from language – is the actual process of making sounds, using such organs and structures as the lungs ...
and impairment.
Patients with JS may meet some or all criteria for diagnosis with
autism spectrum disorder
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
due to many shared developmental symptoms.
Initial clinical findings may include
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...
,
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...
,
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
, ophthalmologic abnormalities, and dysmorphic facial features.
Magnetic resonance imaging may further reveal
megalencephaly
Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general populat ...
or defects of the
ventricles or
white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
. Individuals with JS may also have skeletal, cardiac, endocrine, or genital abnormalities.
Certain JS mutations can also cause early-onset
parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy b ...
between ages 20-40.
Genetics
All cases of JS are caused by ''de novo''
missense
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense ...
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
s in ''
PPP2R5D
Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform is an enzyme that in humans is encoded by the ''PPP2R5D'' gene. Mutations in ''PPP2R5D'' cause Jordan's Syndrome.
Function
The product of this gene belongs to the p ...
'', which encodes a subunit of the enzyme
PP2A
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in ...
. At least 8 different pathogenic mutations have been identified: E197K, E198K, E200K, E420K, P201R, W207R, Q211P, and P53S.
Patients are exclusively diagnosed with JS upon discovery of a pathogenic variant of ''PPP2R5D'' via
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
.
As of 2019, at least 23 individuals with JS have been reported.
Mechanisms
The molecular mechanisms underlying JS are unknown. Broadly, PP2A dysfunction is known to be associated with other pathologies such as
Alzheimer's disease,
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
.
Studies of specific JS-causing variants such as E420K have implicated
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...
dysregulation in JS pathogenesis.
Diagnosis
Jordan's Syndrome is diagnosed through molecular genetic testing, most commonly exome sequencing.
Research
''PPP2R5D''-related intellectual disability was named "Jordan's Syndrome" after Jordan Lang, who was diagnosed by
whole exome sequencing
Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subset ...
in 2014.
Lang's parents founded the charitable organization Jordan's Guardian Angels to connect families of individuals with JS. The foundation also funds PPP2R5D research, spanning diverse model systems from
alpaca
The alpaca (''Lama pacos'') is a species of South American camelid mammal. It is similar to, and often confused with, the llama. However, alpacas are often noticeably smaller than llamas. The two animals are closely related and can success ...
s and
fruit flies
Fruit fly may refer to:
Organisms
* Drosophilidae, a family of small flies, including:
** ''Drosophila'', the genus of small fruit flies and vinegar flies
** ''Drosophila melanogaster'' or common fruit fly
** '' Drosophila suzukii'' or Asian fruit ...
to patient-derived
induced pluripotent stem cell
Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed ...
s.
Ten primary investigators are affiliated with the foundation:
*
Wendy Chung
Wendy K. Chung is an American clinical and molecular geneticist and physician. She currently directs the clinical genetics program at NewYork–Presbyterian Hospital / Columbia University Medical Center in New York City and serves as the Kenne ...
(
Columbia University
Columbia University (also known as Columbia, and officially as Columbia University in the City of New York) is a private research university in New York City. Established in 1754 as King's College on the grounds of Trinity Church in Manha ...
)
* Kyle Fink (
University of California, Davis
The University of California, Davis (UC Davis, UCD, or Davis) is a public land-grant research university near Davis, California. Named a Public Ivy, it is the northernmost of the ten campuses of the University of California system. The inst ...
)
* Richard Honkanen (
University of South Alabama
The University of South Alabama (USA) is a public research university in Mobile, Alabama. It was created by the Alabama Legislature in May, 1963, and replaced existing extension programs operated in Mobile by the University of Alabama. The first ...
)
* Veerle Janssens (
Katholieke Universiteit Leuven)
* Ghayda Mirzaa (
Seattle Children's Hospital
Seattle Children's, formerly Children's Hospital and Regional Medical Center, formerly Children's Orthopedic Hospital, is a children's hospital in the Laurelhurst neighborhood of Seattle, Washington. The hospital specializes in the care of infa ...
)
*
Jan Nolta
Jan A. Nolta is an American scientist and the director of the stem cell program at the UC Davis School of Medicine and Institute for Regenerative Cures. She is Scientific Director for the UC Davis Good Manufacturing Practice and editor of the ...
(University of California, Davis)
* Stefan Strack (
University of Iowa
The University of Iowa (UI, U of I, UIowa, or simply Iowa) is a public research university in Iowa City, Iowa, United States. Founded in 1847, it is the oldest and largest university in the state. The University of Iowa is organized into 12 coll ...
)
* Brian Wadzinski (
Vanderbilt University
Vanderbilt University (informally Vandy or VU) is a private research university in Nashville, Tennessee. Founded in 1873, it was named in honor of shipping and rail magnate Cornelius Vanderbilt, who provided the school its initial $1-million ...
)
* Houhui Xia (
University of Rochester
The University of Rochester (U of R, UR, or U of Rochester) is a private university, private research university in Rochester, New York. The university grants Undergraduate education, undergraduate and graduate degrees, including Doctorate, do ...
)
* Yongna Xing (
McArdle Laboratory
The McArdle Laboratory for Cancer Research is a basic cancer research facility located on the University of Wisconsin–Madison campus in Madison, Wisconsin. It houses the university's Department of Oncology . The staff of the McArdle Laboratory ...
)
References
{{reflist
Mental disorders diagnosed in childhood
Neurological disorders in children
Rare genetic syndromes
Autosomal dominant disorders