What is the Urban Wiethe Syndrome? Understanding Urbach-Wiethe Disease

With fewer than 400 cases reported worldwide, Urbach-Wiethe disease (UWD) is an extremely rare genetic condition. Often mistakenly referred to as the Urban Wiethe syndrome, it is an autosomal recessive disorder that affects the skin, mucous membranes, and internal organs due to the deposition of hyaline-like material.

Quick Summary

Urbach-Wiethe disease, a rare genetic disorder and not the Urban Wiethe syndrome, involves the deposition of a hyaline substance in tissues, leading to symptoms like a hoarse voice, skin lesions, and neuropsychiatric problems due to mutations in the $ECM1$ gene.

Key Points

• Misnomer Clarification: The correct medical term is Urbach-Wiethe disease, not Urban Wiethe syndrome, though both refer to the same condition.

• Genetic Origin: It is a rare autosomal recessive disorder caused by a mutation in the $ECM1$ gene, which leads to the deposition of hyaline material.

• Distinctive Symptoms: Cardinal signs include hoarseness from infancy and waxy, beaded papules on the eyelids (moniliform blepharosis).

• Neurological Features: Bilateral calcification of the amygdala is common, potentially leading to impaired fear processing, seizures, and other neuropsychiatric issues.

• Symptomatic Management: While there is no cure, various treatments like laser surgery, medication, and supportive therapies can manage symptoms effectively.

• Generally Favorable Prognosis: The life expectancy for individuals with UWD is typically normal, provided that complications like respiratory issues are addressed.

What is the Urbach-Wiethe Disease?

Urbach-Wiethe disease (UWD), also known as lipoid proteinosis or hyalinosis cutis et mucosae, is a rare genetic disorder first described by Austrian doctors Erich Urbach and Camillo Wiethe in 1929. It is an autosomal recessive condition, meaning an individual must inherit two copies of the mutated gene, one from each parent, to develop the disease. The condition is characterized by the accumulation of a waxy, hyaline-like substance in various parts of the body, particularly the skin, mucous membranes, and internal organs. While the name is commonly misspelled or misspoken as 'Urban Wiethe syndrome', the correct medical name acknowledges its discoverers and points to its key features. Although the disease is found globally, a significant number of reported cases have occurred in South Africa due to a common founder effect from a German ancestor.

The Genetic Cause: $ECM1$ Mutation

Research has identified the root cause of UWD as a mutation in the extracellular matrix protein 1 ($ECM1$) gene, located on chromosome 1q21. The $ECM1$ gene provides instructions for creating a protein that plays a crucial role in cell adhesion, epidermal differentiation, and wound healing. When this gene is mutated and a non-functional or missing ECM1 protein is produced, it leads to the characteristic deposition of hyaline material in various tissues. Over 50 different loss-of-function mutations within the $ECM1$ gene have been identified, all contributing to the same outcome of systemic material accumulation. This progressive buildup disrupts the normal function of affected tissues, leading to the wide range of symptoms seen in patients with UWD.

Clinical Manifestations and Symptoms

The symptoms of Urbach-Wiethe disease can vary greatly among individuals but often involve the skin, mucous membranes, and the central nervous system. The disease typically begins in infancy and progresses slowly over time.

Cutaneous and Oral Symptoms

• Hoarseness: Often the first and most striking symptom, a weak cry or hoarse voice is present from birth or early infancy due to the infiltration and thickening of the vocal cords and larynx.
• Moniliform Blepharosis: A classic sign of the disease is the presence of waxy, beaded papules along the margins of the eyelids.
• Skin Fragility and Scarring: Minor trauma can lead to blisters and poor wound healing, resulting in an abundance of varicelliform (pox-like) scars, especially on the face and limbs.
• Hyperkeratotic Nodules: Thickened, wart-like plaques often develop over friction-prone areas like the elbows and knees.
• Oral Infiltration: Thickening and infiltration can affect the tongue, lips, and frenulum, potentially leading to ankyloglossia (restricted tongue movement) and speech impediments.
• Dental Abnormalities: Hypoplasia or malformation of teeth, particularly lateral incisors and premolars, can occur.

Neurological and Neuropsychiatric Symptoms

• Amygdala Calcification: Symmetrical, bilateral calcification of the amygdala, a brain region involved in fear processing, is a common feature, although not universally present.
• Impaired Fear Response: Due to amygdala damage, patients may exhibit a diminished ability to process fear and recognize fear in others' facial expressions.
• Seizures: Some patients experience seizures, which can sometimes present as anxiety or panic attacks.
• Behavioral Issues: Cognitive and neuropsychiatric issues like memory impairment, anxiety, and rage attacks can occur.

Diagnosing Urbach-Wiethe Disease

Diagnosing UWD involves a combination of clinical observation, imaging, and laboratory tests.

Key diagnostic criteria often include:

• The combination of persistent hoarseness from infancy and specific skin lesions.
• Confirmation via skin biopsy, which reveals the characteristic periodic acid-Schiff (PAS)-positive, hyaline material in the dermis and around blood vessels.
• Computed tomography (CT) scans or magnetic resonance imaging (MRI) of the brain can detect the typical bilateral amygdala calcifications.
• Genetic testing to identify specific mutations in the $ECM1$ gene provides a definitive diagnosis.

Management and Prognosis

There is currently no cure for Urbach-Wiethe disease, so treatment focuses on managing the symptoms and improving the patient's quality of life. The prognosis for UWD is generally good in terms of lifespan, provided that potential complications, such as respiratory obstruction, are managed effectively.

Symptom Management Strategies:

• For Vocal Cords and Eyelid Papules: Laser surgery, such as CO2 laser therapy, can be used to reduce the thickness of the vocal cords and remove papules, improving voice quality and appearance.
• For Respiratory Issues: In severe cases of laryngeal infiltration, a tracheostomy may be required to secure the airway.
• For Skin Lesions: Medications like oral retinoids (e.g., acitretin) and other therapies have been used with varying success to improve skin features.
• For Neurological Symptoms: Anti-seizure medications can control seizures, while cognitive behavioral therapy (CBT) and other forms of psychological support can help manage psychiatric symptoms.

Comparison Table: Urbach-Wiethe vs. Related Conditions

To highlight the unique characteristics of UWD, here is a comparison with other conditions sometimes considered in the differential diagnosis.

Feature	Urbach-Wiethe Disease (UWD)	Amyloidosis	Mucopolysaccharidosis (e.g., MPS III)
Genetic Basis	Autosomal recessive; mutation in $ECM1$ gene.	Variable; can be inherited or acquired.	Autosomal recessive or X-linked; defect in lysosomal enzymes.
Deposited Material	Hyaline-like, PAS-positive material.	Amyloid protein fibrils.	Glycosaminoglycans (GAGs).
Prominent Symptoms	Infant hoarseness, waxy eyelid papules, skin fragility.	Varies, but often includes fatigue, weight loss, organ enlargement.	Intellectual disability, coarse facial features, organ damage.
Neurological Impact	Bilateral amygdala calcification, altered fear response.	Peripheral neuropathy, cognitive issues.	Neurodegeneration, cognitive impairment.
Diagnostic Method	Skin biopsy, genetic testing, CT scan.	Biopsy, staining (Congo red), organ function tests.	Enzyme assays, genetic testing.

Conclusion

What is the Urban Wiethe syndrome? It is a misnomer for Urbach-Wiethe disease (UWD), a validated and studied genetic condition caused by mutations in the $ECM1$ gene. This rare disease leads to a range of progressive symptoms affecting the skin, mucous membranes, and central nervous system due to the accumulation of hyaline material. While there is no cure, a combination of laser surgery, medication, and psychological support helps manage symptoms and maintain a relatively normal lifespan for those affected. Accurate diagnosis, often initiated by recognizing the early onset of hoarseness and characteristic skin lesions, is crucial for timely management and improved quality of life. The ongoing study of UWD and the $ECM1$ gene continues to provide valuable insights into its underlying mechanisms and potential future therapies.

For more information, visit the Wikipedia page for a detailed overview: Urbach–Wiethe disease.

Frequently Asked Questions

What is the primary cause of Urbach-Wiethe disease?

Urbach-Wiethe disease is caused by a loss-of-function mutation in the $ECM1$ (extracellular matrix protein 1) gene. This genetic mutation leads to the progressive accumulation of a hyaline-like material in the skin, mucous membranes, and other organs.

Are 'Urban Wiethe syndrome' and 'Urbach-Wiethe disease' the same thing?

No, 'Urban Wiethe syndrome' is a common misspelling. The correct medical term is Urbach-Wiethe disease, named after the doctors Erich Urbach and Camillo Wiethe who first described it.

What are the first signs of Urbach-Wiethe disease?

The first sign is often a weak cry or hoarse voice in infancy due to the infiltration and thickening of the vocal cords. Skin lesions and beaded papules on the eyelids develop in early childhood.

How is Urbach-Wiethe disease diagnosed?

Diagnosis is based on a clinical examination (looking for hoarseness and specific skin lesions), a skin biopsy revealing hyaline material, genetic testing for the $ECM1$ mutation, and imaging like a CT scan to check for amygdala calcifications.

Is there a cure for Urbach-Wiethe disease?

No, there is currently no cure for Urbach-Wiethe disease. Treatment focuses on managing the individual symptoms through methods such as laser surgery, medication, and psychological support.

What is the life expectancy for someone with Urbach-Wiethe disease?

Patients with Urbach-Wiethe disease typically have a normal life expectancy. The condition is generally not life-threatening, provided that complications like respiratory obstruction are addressed properly.

How does Urbach-Wiethe disease affect emotions?

Due to calcification in the amygdala, a part of the brain involved in emotional processing, some individuals with UWD may experience a diminished ability to process or recognize fear. This can impact social interactions and emotional responses.