Phelan-McDermid Syndrome (PMS) is a rare neurodevelopmental disorder that presents significant challenges from infancy onward. It is a complex genetic condition affecting multiple body systems, most notably the brain’s development and function. Individuals diagnosed with PMS typically require lifelong support and specialized medical attention due to the condition’s wide-ranging effects.
Genetic Foundations and Core Developmental Symptoms
Phelan-McDermid Syndrome is caused by a deletion on the long arm of chromosome 22 (22q13.3), often called 22q13 deletion syndrome. This genetic change is typically a de novo event, meaning it is a spontaneous alteration in the genetic material and is not inherited from the parents in most cases. The size of the deleted segment can vary significantly between individuals, which contributes to the wide spectrum of symptoms observed.
The loss of genetic material in this region almost always involves the SHANK3 gene, which is considered the major contributor to the neurological features of the syndrome. The SHANK3 protein is a crucial scaffolding component found at the postsynaptic density of excitatory synapses, the junctions where brain cells communicate. When one copy of the SHANK3 gene is missing or non-functional, the resulting haploinsufficiency disrupts the structure and function of these synaptic connections, impairing communication within the brain.
Initial symptoms manifest early in life, often during infancy. One of the most consistent findings is global developmental delay, with children failing to reach milestones like rolling over, sitting, and walking at expected times. Low muscle tone, known as hypotonia, is also a common feature present from birth, which contributes to feeding difficulties and delayed motor skills. Speech and language are typically severely affected, with many individuals experiencing delayed or absent expressive language. Many children with PMS also exhibit characteristics associated with Autism Spectrum Disorder (ASD), such as repetitive behaviors, social communication difficulties, and sensory sensitivities.
The Clinical Trajectory: Is Phelan-McDermid Syndrome Progressive?
The underlying genetic condition is not considered a progressive or neurodegenerative disorder, unlike conditions where the nervous system deteriorates over time. The genetic alteration is present from conception, and the core neurological deficits are stable. This means the established level of intellectual and developmental disability does not typically worsen due to ongoing neurodegeneration.
While the underlying disorder is stable, the clinical presentation and symptoms change and evolve as the individual ages, which can sometimes be misinterpreted as a progressive decline. While intellectual disability and communication impairment remain consistent, new, complex symptoms often emerge during adolescence and adulthood. These changes represent the maturation of the individual within the context of their disability, rather than a deterioration of the neurological structure itself.
One of the most significant changes in the clinical trajectory is the increased likelihood of seizures and neuropsychiatric issues in older individuals. Seizures affect a substantial percentage of people with PMS, and their onset can be highly variable, sometimes occurring later in life. The development of epilepsy can be particularly challenging, as it may lead to a temporary or sustained loss of previously acquired skills, a phenomenon known as regression. Furthermore, adolescence and adulthood bring a risk of severe neuropsychiatric decompensation, including the emergence of symptoms resembling psychosis, bipolar disorder, or catatonia. These behavioral changes and skill loss are linked to the SHANK3 gene’s role in synaptic function and are a feature of the maturing disorder, not a sign of classic neurodegeneration.
Long-Term Support and Medical Management
Management requires a multidisciplinary approach focused on supporting the individual through their lifespan and addressing co-occurring medical issues. Individuals with PMS often face a range of systemic complications that require specialized monitoring and intervention beyond the core developmental challenges.
Seizure disorders, including epilepsy, are a significant concern, often affecting a third or more of individuals with PMS. Types of seizures vary, with atypical absence seizures being frequently reported. Effective management involves tailored antiepileptic drug regimens, which can be complex, as some individuals experience drug-resistant epilepsy.
Gastrointestinal issues are highly common and require ongoing medical surveillance. Chronic constipation, gastroesophageal reflux (GERD), and poor feeding frequently lead to discomfort and nutritional deficiencies. These digestive issues are managed through dietary adjustments, medication, and sometimes specialized feeding plans.
The genitourinary system also requires specialized attention, as some individuals are born with renal abnormalities, such as kidney cysts or vesicoureteral reflux. Regular renal ultrasounds and monitoring are recommended to detect these conditions early and prevent complications that could affect kidney function over time.
For the behavioral and neuropsychiatric challenges, management involves a combination of behavioral therapies, environmental supports, and sometimes psychotropic medications. The emergence of severe anxiety, self-injurious behavior, or catatonia in older individuals necessitates careful psychiatric evaluation and intervention. Given that individuals with PMS often have a high tolerance for pain, caregivers and medical professionals must remain vigilant for subtle cues indicating physical discomfort or underlying medical issues that may be driving behavioral changes.