Urbach-Wiethe or Lipoid proteinosis, is a rare hereditary disorder transmitted by an autosomal recessive gene located on chromosome 1q21 encoding extracellular protein one (ECM1).The cumulative total of 250 – 300 cases have been reported in literature since it was officially reported in 1929.

1. Fear Processing Defect
in patients of Urbach-
Wiethe disease
Presentedby: Shalimar Shadeed.
Supervisor: Prof. Adnan Al-Qurashi.

2. What is Urbach-Wiethe / Lipoid Proteniosis?
Urbach-Wiethe or Lipoid proteinosis, also known as
Hyalinosis cutis et mucosae Disease, is a rare hereditary
disorder transmitted by an autosomal recessive gene located on
chromosome 1q21 encoding extracellular protein one (ECM1)
The cumulative total of 250 – 300 cases since it was officially
reported in 1929.
The disorder is a systemic illness characterized with
dermatological and neuropsychological implications.
Dermatological complications are due to disturbance in the
metabolism of lipids and proteins involving the skin and mucous
membranes.

3. ECM1 function and pathogenic mutations
contribution to UWD.
The extracellular matrix protein 1 (ECM1) is a secreted glycoprotein, which
plays an important role in the structural and functional biology of the skin where
it has an important role in the extracellular matrix formation, cell adhesion, cell
signaling, and regulation of tissue differentiation and/or maturation.
The ECM1 protein importance comes from its physiological and biological role
in epidermal differentiation, where it binds dermal collagens and proteoglycans.
The pathophysiology of Urbach- wiethe disease has been shown to result
from loss of function mutations in the ECM1 gene located on chromosome
1q21, which results due to 41 different pathogenic mutations, mostly nonsense,
missense or splice site mutations with the majority occurring in exon 6 or 7
of the 10-exons in ECM1 gene.

4. Figure 1:
Segment of the long arm of
Chromosome 1, where the ECM1
mutation occurs at 1q21.

5. This disease is characterized by
dermatological problems
generalized by thickening of the
skin and mucosal infiltration with
scarring of the skin.
Histologically these patients show
vascular anomalies that represent
severe functional defects, caused
by an excessive deposition of
hyaline-like (glassy) material which
presumably lead to the
disruption/reduplication of the
basement membrane and the
underlying dermal blood vessels
• Pathophysiology of the disease
figure 2:Hyaline infiltration
Figure 3:scaring of the skin.

6. Clinical manifestations
The most classic symptoms are hoarseness of speech, often from birth or infancy, and
skin lesions.
Beading of the papules around the eyelids is a very common symptom and is often
used as part of a diagnosis of the disease
There is considerable clinical variability among lipoid proteinosis subjects and lesions
may increase in severity and extent with age.
Bilateral, circumscribed, and symmetrical calcification in the medial temporal regions is
observed in 50 -70% of patients and are associated with neuropsychiatric sequelae
including epilepsy and psychotic symptoms.
These calcifications often affect the amygdala which is made up of two tiny almond
shaped lobes near the brainstem, it is involved in processing biological relevant stimuli
and in emotional long term memory.

7. • Figure4: The lid margins show typical beading ,
and lashes are present, being even
hypertrophic on the upper lids.

8. Figure 5: beaded arrangement of small pearly
nodules and papules of the right eyelid.
Beading of the papules around the eyelids is a
very common symptom and is often used as
part of a diagnosis of the disease

9. UWD & Fear Processing defect.
Lesions of the amygdala occurring with this degenerative condition, is associated with
calcium deposition in the amygdala.
If the lesion occurs early in life, patients with bilateral amygdala damage fail to learn the
cues that normal subjects use to discern fear in facial expressions and to discriminate
fine differences in other facial expressions.
Thus Urbach-Wiethe disease disrupts the unconscious processing of cues to fear in
both real faces and imagined faces drawn from memory.
There is no information about ECM1 expression in human brain outside of blood
vessels, and the relevance to brain is less obvious. ECM1 interacts with other proteins
making up the extracellular matrix often regulating bioactivity of the binding partner
including matrix metalloproteinase which has an important role in temporal lobe synaptic
physiology .

10. Continue…
The brain pathophysiology of ECM1 mutations has hypothesized to result from
defect in cerebrovascular basement membrane that cause fibrinoid changes and
calcifications of vessel walls.
Lipoid proteinosis has been associated with difficulty in coping with emotionally
loaded memory and impaired executive control over social behavior.
There has, however, been significant variability in neuropsychiatric and
neuropsychological findings across studies.
In some studies there has been no evidence of psychiatric symptomatology and
Siebert et al., did not find that lipoid proteinosis necessarily impaired the recognition
of basic emotions such as fear and anger.
Urbach-wiethe has been associated with both intact intelligence and mental
retardation.

11. Materials and methods:
Volunteers:
Two female monozygotic twins (36-year-old) suffering from lipoid proteinosis of
Urbach-Wiethe disease and 15 age- and education-matched healthy female control
subjects on a behavioral facial emotion recognition task.
Molecular Genetics:
the underlying mutation in the twins was determined, by whole-genomic DNA was
extraction from 10 ml aliquots of EDTA-anti coagulated venous blood using a
salting-out method. A set of 7 primer pairs was used to amplify 7 polymerase chain
reaction (PCR) fragments covering the 10 exons of the ECM1 gene from the
twins’ DNA samples. Direct sequencing of the purified PCR products was carried out
on an automatic sequence analyzer, Sequence reads were confirmed manually,
and the sequences were assembled using a software.

12. Continue…
Structural Imaging:
High resolution structural magnetic resonance imaging (MRI) scans of both twins
were acquired to assess the lesion extent. Additionally, the twins were scanned on a
16-row multi-detector x-ray CT device To obtain accurate anatomical information on
the lesion extent and localize intracranial calcifications in both twins. Volumes of
interest (VOIs) were defined and measured in the axial, coronal and sagittal
planes at a fixed threshold , these CT derived lesion contours were superimposed
onto the MRI scans.

13. • The results:
Figure 6: Fragment of the genomic sequence from exon 7 of the extracellular matrix protein 1
gene(ECM1) from patient 1 (left panel) and patient 2 (right panel). The homozygous c.709T>C
missense mutation leading to an exchange of a highly conserved tryptophan at position 237
to arginine is indicated with an orange box.

14. Figure 6: Alignment of proteins of the extracellular matrix protein 1
gene (ECM1) family (PF05782). The position of tryptophan 237 (here
position 310, red mark on the top) is highly conserved among
proteins belonging to the ECM1 family. This is an indication for a
probable functional relevance of Trp237 and pathogenicity of the
novel p.Trp237Arg ECM1 missense mutation detected in the twins.

15. Figure 7: Axial (horizontal) magnetic resonance imaging sect ions of the
anterior medial temporal lobes with color contours delineating twin 1
denoted as patient one ,calcification damage as detected by X-ray
computed tomography scans in 6 situations (fear, anger, disgusted , sad,
happy, neutral respectively)

16. Figure 8: Axial (horizontal) magnetic resonance imaging sections of
the anterior medial temporal lobes with color contours delineating
twin 2 denoted as patient 2.

18. Discussion
Results show that the twins share the same genotype in all sequenced
regions. Specifically, a novel homozygous missense mutation in exon 7 of
ECM1 (c.709T>C; p.Trp237Arg) was found.
In line with evidence that exons 6 and 7 are the most common sites for ECM1
mutations in Urabach-Wiethe disease.
This experiment showed an extensive evidence that patients with focal
bilateral amygdala lesions are impaired in recognizing fear from faces.
Despite their shared genetic profile and common environment as both
children and adults, the twins exhibited markedly different abilities in
recognizing fearful faces.

19. Continue…
In line with previous reports on LP patients with complete bilateral amygdala
damage , patient2 was severely impaired. Patient 1, however, showed preserve
recognition of fearful faces. Using fMRI, they found that patient 1, but not
patient 2,showed a specific enhancement of neural activity in the right premotor
cortex face area (PFA )and bilateral inferior parietal lobule (IPL )in response to
fearful faces .
Lesion mapping by means of CT–MRI revealed an equivalent lesion anatomy
between the twins, suggesting that a greater sparing of amygdala tissue in
patient 1 might not account for her preserved fear recognition abilities.

20. Continue…
The preserved fear-recognition abilities of patient 1, unlike patient 2, are not
based on a greater sparing of amygdala tissue ,but on compensatory
mechanisms enabling patient 1 to recognize fearful faces .
Their findings implicate the PFA and IPL in this functional compensation
respond to emotional faces with the fact that IPL has been shown to specifically
respond to fearful faces and other negatively valenced stimuli.
Finally , patient 1 displayed a fear-selective increase in PFA Activity a recent
transcranial magnetic stimulation study has identified a direct relationship
between PFA activity and facial emotion recognition abilities.

21. Conclusion
The premotor cortex face (PFA) area and inferior parietal lobule(IPL) are both
implicated in the cortical mirror-neuron system.
Which mediates learning of observed actions and may thereby promote both
imitation and empathy.
Findings suggest that despite the preeminent role of the amygdala in
processing social information, the cortical mirror-neuron system may
sometimes adaptively compensate for its pathology.

22. References
1- Salih MA, Abu-Amero KK, Alrasheed S, Alorainy IA, Liu Lu, McGrath JA,
Maldergem LV, Al-Fakey YH, Al-Suhaibani AH, Oystreck DT, Bosley TM (2011).
Molecular and neurological characterizations of three Saudi families with lipoid
proteinosis. BMC Med. Gen., 12: 31.
2- Becker B, DAydin M, Feinstein JS, Hurlemann R ., Kendrick KM, Maier W .,Matusch
A., Mihov Y., Oros-Peusquens AM ., Schlaepfer TE Shah NJ.,Scheele Reich H, Urbach
H, Zilles K. , Fear Processing and Social Networking in the Absence of a Functional
Amygdale. BIOL PSYCHIATRY 2012.
3- Muhammad Nasir, Amir Latif, Muhammad Ajmal, Reem Qamar, Muhammad
Naeem, Abdul Hameed Diagn Pathol. 2011; 6: 69 Molecular analysis of lipoid
proteinosis: Identification of a novel nonsense mutation in the ECM1 gene in a Pakistani
family. Diagnostic Pathology 2011 6:69.
4- Helena B. Thornton , Daan Nel, Dorothy Thornton, ack van Honk, Gus A. Baker, Dan J.
Stein (2008). J Neuropsychiatry Clin Neurosci 20:1.
5- Samdani AJ, Azhar A, Shahid SM, Nawab SN, Shaikh R, Qader SA,Mansoor Q, Khoso
BK, Ismail M: Homozygous frame shift mutation in ECM1 gene in two siblings with lipoid
proteinosis. Journal of Dermatological Case Reports 2010, 4.
6- Syed M. Shahid, Abid Azhar, Syeda N. Nawab, Rozeena Shaikh, Muhammad Ismail
and Azam J. Samdani (2011). African Journal of Biotechnology Vol. 10(53), pp. 10825-
10830.
7- Antonis Kaberos, Dimitrios G. Balatsouras ,Efstathios Rallis , Nicolas C. Economou
,pavlos Papadakis,, Stavros Korres (2006). International Journal of Pediatric
Otorhinolaryngology Extra, 1, 1—4.