MEDG550/Student Activities/Urbach-Wiethe Disease

From UBC Wiki

Urbach-Wiethe Disease, is also known as Lipoid Proteinosis of Urbach and Wiethe, Lipoid Proteinosis, or Hyalinosis Cutis et Mucosae. It is a genetic autosomal recessive condition that is caused by gene changes in both copies of an individual’s ECM1 gene[1]. It is typically associated with skin, mouth, and voice problems, but types of problems, when they appear and their severity can widely vary, even within a family[2]. Urbach-Wiethe Disease is very rare, there have been roughly 400 individuals diagnosed with the condition worldwide[3].

Clinical Features

Clinical features of Urbach-Wiethe Disease vary greatly from person to person[4].

Example of skin problems, such as eyelid bumps and hardened skin, of an individual with Urbach-Wiethe Disease

Seen in nearly all individuals

  • Blistering, thickening, scarring or lesions of the skin, particularly in the mouth, face and extremities (eg. elbows and knees)[1]
  • Acne and bumps on the face[1]
    • Often, small bead-like lumps on the eyelids
  • Hoarse voice[5]
    • Is in nearly all people with the condition
    • Typically is seen at birth or as a newborn (eg. weak crying)
    • Is usually lifelong
    • This may progress into more severe voice problems or total loss of voice

Seen Commonly

  • Poor dental and gum health[6]
  • Breathing difficulties or frequent respiratory infections[5]
  • Neuropsychiatric disorders[7]
    • Issues with day-to-day memory
    • Aggression, rage and paranoia
    • Hallucination
    • Absence of fear
    • Can appear in childhood and progress through lifetime
    • May occur due to calcium build up in regions of the amygdalaein the brain

Seen infrequently

  • Epilepsy/seizures[8]
  • Frequent swelling of parotid glands[9]
  • Hair loss (patches or thinning)[1]
  • Spontaneous nervous system hemorrhaging[10]

Diagnosis

Urbach-Wiethe Disease can be diagnosed by molecular genetic testing or by skin biopsy.

Molecular Genetic Testing

Single-gene (ECM1), multi-gene (ECM1 and other genes), exome sequencing, genome sequencing are all forms of molecular genetic testing that can identify the genetic changes that causes Urbach-Wiethe Disease using a DNA sample[11]. Depending on which clinical characteristics are present, and if Urbach-Wiethe is suspected, different molecular genetic tests may be considered. Genetic testing can describe the type of gene change, which may be helpful to specialists who are helping manage the condition.

Skin Biopsy

There are 3 approaches to using a skin biopsy to diagnose Urbach-Wiethe Disease[11]. Hematoxylin and eosin, and periodic acid-Schiff-diastase are used to stain the skin tissue sample to find abnormalities that are seen with Urbach-Wiethe Disease[12]. Immunolabeling using antibodies on the skin biopsy can detect low levels of ECM1 proteins, which is also seen in Urbach-Wiethe Disease[9].

Treatment, Management, and Surveillance

Treatment

There is no cure for Urbach-Wiethe Disease[11]. The common health problems are treated individually by appropriate specialists to manage the disease.

Management

  • Breathing problems and airway blockage: throat surgery to reduce severity as required/possible[11]
  • Skin problems: medications for skin softening, acne, lesions, etc.[11]
  • Voice hoarseness: oral medication to improve voice[11]
  • Seizures: anti-seizure medication as determined by a specialist[13]

Surveillance

  • Ear, nose, and throat doctor (otolaryngologist) – every 6 months for airway and voice assessment[11]
  • Skin, hair, and nails doctor (dermatologist) – every 6 months for skin and hair problems[11]
  • Brain and nervous system doctor (neurologist) – every year to assess emotional and cognitive development, and monitor for epilepsy/seizures[11]

Genetics

ECM1 Gene

ECM1 is a gene that tells the body to make a protein that helps in making bone and blood vessels. The protein from ECM1 works with other proteins in the body to also maintain the skin and homeostasis[1].

Type of Gene Change

Urbach-Wiethe Disease is an autosomal recessive condition, meaning that in order for an individual to develop the disease, they need to have a gene change on both copies of the ECM1 gene[14]. The gene changes causing Urbach-Wiethe Disease leads to the protein ECM1 makes either not working properly, or not being made at all[9]. This is called a loss-of-function gene change.

Genetic Counselling

Mode of Inheritance

Autosomal Recessive Inheritance Pattern of Urbach-Wiethe Disease

In our body we have trillions of cells. These cells contain chromosomes, which is the way that our genetic information, or DNA is packaged. Humans have 23 pairs of chromosomes, they get one copy of each chromosome from their mother, and the other from their father. Within these chromosomes are genes. Genes are like the instruction manual for our bodies to build important proteins that make sure our bodies work the way they should. If there are gene changes, or mutations, then different health conditions may appear, depending on what protein the gene is supposed to make, and how this protein is affected. Urbach-Wiethe Disease is inherited in an autosomal recessive way, meaning that an individual needs to have 2 gene changes, one in each ECM1 gene to have the condition[14].

Risk

Risk to Parents of someone with Urbach-Wiethe Disease

  • Parents are assumed to have one gene change each, which they by chance passed to their child with the condition[11]. People who have one copy of the gene change in ECM1 are called carriers, and they usually do not have any of the associated health problems[4], however, some carriers may experience some voice hoarseness in colder seasons, and have a firmer tongue[4].
  • Genetic testing may be considered for parents of someone with Urbach-Wiethe Disease for the intent of assessing risk for family[11].
  • If an ECM1 genetic change is found in only one parent, then one of the genetic changes in the affected individual is de novo[11]. This mean that this gene change is not inherited, it is appearing by chance in this person for the first time.

Risk to Siblings of someone with Urbach-Wiethe Disease

  • If the parents are both carriers, then there is:
    • A 25% chance that a gene change will be inherited from the mother and the father and that child will have Urbach-Wiethe Disease
    • A 50% chance that only one gene change will be inherited (either from the mother or the father) and that child will be a carrier as well
    • A 25% chance that no gene changes will be inherited and the child does not have the disease and they are not a carrier
  • If only one parent is identified to be a carrier then there is:
    • A 25% chance that the one gene change will be inherited and that child will be a carrier as well
    • A 75% that no gene changes will be inherited and the child does not have the disease and they are not a carrier

Risks to Children of someone with Urbach-Wiethe Disease

Since Urbach-Wiethe is very rare[3], it is highly unlikely that the partner of someone with Urbach-Wiethe Disease would also carry any ECM1 gene changes. Assuming this, their children will all be carriers, as they will inherit only one gene change in ECM1.

Genetic Counselling Considerations

Genetic counselling should be considered for any individuals with suspected or diagnosed Urbach-Wiethe Disease, or individuals who are carriers, or potential carriers[11]. This can provide important information for family planning and assessing risk for children. Genetic counselling may be a valuable way for individuals to have a better understanding of the disease, the cause of the disease, and who may be at risk. Genetic counselling may also help individuals with Urbach-Wiethe Sydnrome cope with the emotional burden associated with a diagnosis of a rare condition, provide emotional support and connect them with valuable resources.

Resources

Because Urbach-Wiethe is a rare condition, there are limited patient-oriented resources, or patient support groups.

Genetic and Rare Disease (GARD): https://rarediseases.info.nih.gov/diseases/3268/lipoid-proteinosis-of-urbach-and-wiethe

  • This website provides an overview of Urbach-Wiethe Disease and resources for finding specialists, such as a medical geneticist or a genetic counsellor.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Hamada, T (March 2003). "Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation". J Invest Dermatol.
  2. ↑ Urbach, E (1929). "Lipoidosis cutis et mucosae". Virchows Arch. Path. Anat.
  3. ↑ 3.0 3.1 LeWitt, TM (Nov 2021). "Lipoid Proteinosis". StatPearls [Internet].
  4. ↑ 4.0 4.1 4.2 Youssefian, L (Mar 2015). "Lipoid proteinosis: phenotypic heterogeneity in Iranian families with c.507delT mutation in ECM1". Exp Dermatol.
  5. ↑ 5.0 5.1 Savage, MM (1988). "Lipoid proteinosis of the larynx: a cause of voice change in the infant and young child". Int J Pediatr Otorhinolaryngol.
  6. ↑ Ravi Prakash, S (2013). "Oral manifestations of lipoid proteinosis: a case report and literature review". Saudi Dent J.
  7. ↑ Thornton, HB (2008). "The neuropsychiatry and neuropsychology of lipoid proteinosis". J Neuropsychiatry Clin Neurosci.
  8. ↑ Claeys, KG (2007). "Epilepsy and migraine in a patient with Urbach-Wiethe disease". Seizure.
  9. ↑ 9.0 9.1 9.2 Chan, I (2007). "The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1". Exp Dermatol.
  10. ↑ Siebert, M (2003). "Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease". Brain.
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 Vahidnezhad, H (2021). "Lipoid Proteinosis". GeneReviews [Internet].
  12. ↑ An, I (2019). "Histopathological findings in patients with lipoid proteinosis". Turk J Dermatol.
  13. ↑ Omrani, HG (2012). "Should we think of Urbach–Wiethe disease in refractory epilepsy? Case report and review of the literature". J Neurol Sci.
  14. ↑ 14.0 14.1 Gordon, H (1969). "Lipoid proteinosis in an inbred Namaqualand community". Lancet.
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