Fear Processing Defect in patients of Urbach-Wiethe

disease

Presentedby: Shalimar Shadeed.Supervisor: Prof. Adnan Al-

Qurashi.

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.

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.

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

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.

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.

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

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

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 .

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.

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.

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.

• 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.

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.

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)

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

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.

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.

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.

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.

References

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