Pretzel syndrome

Overview

Pretzel syndrome is a rare genetic disorder formally known as polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE). It is an autosomal recessive condition that was initially identified in a small Old Order Amish community in the United States. The syndrome is colloquially referred to as "Pretzel syndrome" due to the affected infants’ characteristically hyperflexible and twisted limb postures, resembling a pretzel. This condition is associated with a variety of neurological and developmental abnormalities, including seizures, intellectual disability, and brain overgrowth (megalencephaly).

Causes

Pretzel syndrome is caused by mutations in the STRADA gene (also known as LYK5), located on chromosome 17. This gene plays a role in regulating the mTOR (mechanistic target of rapamycin) pathway, which is essential for cell growth and brain development. In individuals with Pretzel syndrome, loss of STRADA function leads to hyperactivation of the mTOR pathway, resulting in abnormal brain growth and neurological dysfunction.

The condition follows an autosomal recessive inheritance pattern, meaning both copies of the gene must carry a mutation for the disorder to manifest. It is most commonly observed in consanguineous populations or isolated communities, such as the Old Order Amish, where the gene mutation has been passed down through generations.

Symptoms

The symptoms of Pretzel syndrome are typically evident in early infancy or at birth. The condition affects multiple systems, primarily the brain and musculoskeletal system. Common signs and symptoms include:

• Hyperflexibility of joints: Unusual postures due to increased joint laxity; limbs may appear twisted or contorted

• Severe epilepsy: Recurrent, treatment-resistant seizures often beginning in infancy

• Polyhydramnios: Excess amniotic fluid during pregnancy, often detected prenatally

• Megalencephaly: Enlarged brain size leading to macrocephaly (large head)

• Developmental delays: Including delays in motor skills, speech, and cognitive functions

• Intellectual disability: Typically moderate to severe

• Hypotonia: Reduced muscle tone, contributing to delayed motor development

• Distinctive facial features: Some children may present with coarse facial features or mild dysmorphisms

The severity of symptoms can vary among affected individuals, though most cases involve significant neurological impairment.

Diagnosis

Diagnosis of Pretzel syndrome involves a combination of clinical evaluation, imaging studies, and genetic testing. Key diagnostic steps include:

• Clinical assessment: Identification of hallmark features such as epilepsy, joint hyperflexibility, and developmental delay

• Prenatal ultrasound: May reveal polyhydramnios or macrocephaly before birth

• Neuroimaging (MRI or CT): Shows megalencephaly and may reveal abnormal cortical development or other structural brain abnormalities

• EEG (electroencephalogram): Assesses seizure activity and patterns

• Genetic testing: Confirms mutation in the STRADA gene and may be recommended for at-risk families

In communities where the syndrome is more prevalent, carrier screening and prenatal genetic testing may be available to help identify affected pregnancies early.

Treatment

There is currently no cure for Pretzel syndrome, and treatment focuses on managing symptoms and improving quality of life. A multidisciplinary approach is essential, involving neurologists, geneticists, developmental specialists, and therapists. Treatment strategies include:

Seizure Management

• Antiepileptic medications: Often required to control seizures, though many cases are refractory and difficult to manage

• Ketogenic diet: A high-fat, low-carbohydrate diet may help in seizure control for some individuals

• Vagus nerve stimulation (VNS): May be considered in drug-resistant cases

Developmental and Supportive Therapies

• Physical therapy: Aims to improve motor function and reduce joint laxity

• Occupational therapy: Supports daily living skills and independence

• Speech and language therapy: Assists with communication difficulties

• Special education programs: Tailored to meet cognitive and behavioral needs

Family and Genetic Support

• Genetic counseling for family members and future reproductive planning

• Support groups and resources for caregivers managing chronic care needs

Prognosis

The prognosis for individuals with Pretzel syndrome is guarded, largely due to the severity of neurological complications such as intractable epilepsy and intellectual disability. Life expectancy may be reduced in some cases, especially when seizures are poorly controlled or if respiratory complications develop. However, with appropriate medical care, supportive therapies, and a structured care environment, some children can achieve improved function and quality of life.

Ongoing research into mTOR inhibitors and targeted therapies may offer future treatment options that address the underlying genetic defect and improve outcomes for affected individuals.