Urbach-Wiethe Research Articles

The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1

Lipoid proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in lipoid proteinosis. In this article, we provide an update on the molecular pathology of lipoid proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.

Síndrome de Urbach-Wiethe: relato de caso

We present a case of Urbach-Wiethe syndrome with typical findings, including ocular lesions. A 15-year-old girl was referred to our department complaining of itchy eyelid lesions (moniliform blepharosis) associated with other systemic manifestations. Diagnosis was confirmed by performing skin biopsy. Artificial tears were prescribed, with partial relief of the symptom. The objective of the present study is to describe a typical case of Urbach-Wiethe syndrome attended at the Ophthalmologic Sector of the Medical School of Marília.

The neurology of disgust

Emotions form part of the fabric of our minds, and the scientific attempts to map these dimensions onto the underlying neural substrates date back to the first half of the last century. It has long been suggested that emotional functions are associated with subcortical structures (e.g. Cannon, 1927; Kluver & Bucy, 1937; Hess, 1954). James Papez (1937) was the first to postulate that emotional processing is based on an interconnected cortical-subcortical system, for which later the term ‘Papez circuit’ was coined. The idea of a ‘limbic system’, defined as a functional entity responsible for all emotional experience and emotional expressions, was subsequently put forward by Paul MacLean in the early 1950s. Neuroanatomically, the ‘limbic system’ was associated with neural structures surrounding the midbrain (MacLean, 1993). A different view on the neuroanatomy of emotions emerged during the 1970s, emphasizing the role of the right hemisphere in emotion processing (Schwartz et al ., 1975). However, neither of these conceptual frameworks, dominating the clinical neurosciences well into the mid-1990s, allow for selective impairments of specific emotions. In 1994, Adolphs and colleagues reported an intriguing finding, which changed the way we have to think about how emotions are organized within the brain (Adolphs et al ., 1994). They investigated a person suffering from Urbach–Wiethe disease, a rare hereditary disorder which causes bilateral calcifications of the medial temporal lobes, affecting particularly the amygdala. In this person, a selective deficit in recognizing fearful faces was found, while recognition of other basic emotions such as happiness, surprise, sadness, disgust and anger was preserved. The prominent role of the amygdala in processing …

Nasolacrimal Duct Obstruction With Urbach-Wiethe Syndrome

An 80-year-old woman presented with signs and symptoms consistent with bilateral nasolacrimal duct obstruction. She also was noted to have multiple eyelid margin lesions. She underwent bilateral dacryocystorhinostomy with biopsy of the nasolacrimal ducts and eyelid lesions. Her tearing resolved. Histopathology of the eyelid lesions was consistent with lipoid proteinosis. Nasolacrimal duct obstruction may occur in patients with lipoid proteinosis (Urbach-Wiethe syndrome).

Epilepsy and migraine in a patient with Urbach–Wiethe disease

We report the clinical, neuroradiological, and molecular genetic findings in a patient with lipoid proteinosis or Urbach-Wiethe disease. Interestingly, in this patient epilepsy and migraine were the symptoms leading to the diagnosis of the disease, contrary to most patients in whom skin abnormalities are the first recognized symptoms.

Maladie d’Urbach-Wiethe (lipoïdo-protéinose) avec manifestations neurologiques

Lipoid proteinosis is a rare autosomal recessive disease that has recently been shown to result from mutations in the ECM1 gene. Some cases are associated with a more severe mucocutaneous phenotype. We report the case of a 38-year-old woman who had clinical and histological skin features typical of Urbach-Wiethe disease. Physical examination revealed neurological abnormalities including dizziness, ataxia, slight psychomotor retardation and amnesic impairment. The patient reported sudden left brachiofacial paralysis one month earlier that regressed spontaneously after one week. CT scan and MRI were normal. Cerebral scintigraphy displayed bilateral hypoperfusion of the frontal areas, of the anterior and internal right temporal lobe (which includes amygdala), and of the left thalamic core. We considered these abnormalities as neurological features of lipoid proteinosis in the absence of evidence of any other cause. Our observation as well as other recent reports suggests the need for neurological and neuropsychological investigations in patients with Urbach-Wiethe disease.

Panic Attacks in an Individual With Bilateral Selective Lesions of the Amygdala

To describe the unique case of a patient with panic attacks and bilateral selective amygdala lesions due to Urbach-Wiethe disease. Case report. Epilepsy Monitoring Unit, Medical University of Vienna. Patient A 38-year-old man with Urbach-Wiethe disease developed spontaneous panic attacks and depressive mood, which ceased after antidepressive treatment. Video electroencephalography monitoring, magnetic resonance imaging, and neuropsychological testing. Extended video electroencephalography monitoring excluded an epileptic etiology of the panic attacks. Results of cranial magnetic resonance imaging showed bilateral selective calcifications of the whole amygdaloid complex. Neuropsychological testing revealed selective memory impairment of autobiographic episodes with preserved memory for autobiographic facts. Our findings indicate that the occurrence of panic attacks does not critically depend on the integrity of the amygdala. Furthermore, the neuropsychological findings in our patient suggest that the amygdala represents an essential neural substrate for the processing of episodic autobiographic memories.

Role of the amygdala in decisions under ambiguity and decisions under risk: Evidence from patients with Urbach-Wiethe disease

Various neuropsychological studies have shown that decision-making deficits can occur in a wide range of patients with brain damage or dysfunctions. Decisions under ambiguity, as measured with the Iowa Gambling Task, primarily depend on the integrity of the ventromedial prefrontal cortex and the amygdala, as well as on further brain regions such as the somatosensory cortex. However, little is known about the specific role of these structures in decisions under risk measured with tasks that offer explicit rules for gains and losses and winning probabilities, for example, the Game of Dice Task. We aimed to investigate the potential role of the amygdala for decisions under risk. For this purpose, we examined three patients with Urbach-Wiethe disease—a rare syndrome associated with selective bilateral mineralisation of the amygdalae. Neuropsychological performance was assessed with the Iowa Gambling Task (decisions under ambiguity), the Game of Dice Task (decisions under risk), and an extensive neuropsychological test battery focussing on executive functions. Furthermore, previous studies found relationships between generating skin conductance responses and deciding advantageously in the Iowa Gambling Task. Accordingly, we recorded skin conductance responses during both decision tasks as a measure of emotional reactivity. Results indicate that patients with selective amygdala damage have lower scores in both decisions under ambiguity and decisions under risk. Decisions under risk are especially compromised in patients who also demonstrate deficits in executive functioning. In both gambling tasks, patients showed reduced skin conductance responses compared to healthy comparison subjects. The results suggest that deciding advantageously under risk conditions involves both the use of feedback from previous trials, as required by decisions under ambiguity, and in addition, executive functions.

Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease

When presented in a neutral context, emotional items interfere with episodic encoding of temporally contiguous non-emotional items, resulting in dissociable valence-dependent retrograde and arousal-dependent anterograde modulatory effects. By studying two rare patients with congenital lipoid proteinosis (Urbach-Wiethe) and a focal disease emphasis on the basolateral amygdala (BLA), we demonstrate that this bidirectional modification of episodic encoding by emotion depends on the integrity of the amygdala, as both retrograde and anterograde modulatory effects are absent. Our findings implicate the amygdala in a neural circuitry that orchestrates rapid retrograde and anterograde regulation of episodic memory access upon criteria of behavioral significance.

Manifestations ophtalmologiques de la hyalinose cutanéo-muqueuse

Lipoid proteinosis (LP), also known as hyalinosis (or lipoidosis) cutis et mucosae or Urbach-Wiethe disease, is a rare autosomal recessive disorder. It is associated with deposits of protein-lipid complexes in various tissues including the skin and mucous membranes. Ophthalmologic manifestations are frequent and can affect visual prognosis. This 28-year-old patient presented vesiculobullous lesions of the face that developed into varioloid scars associated with hoarseness. Ophthalmologic examination revealed unilateral lesions including hyaline deposits on the palpebral margins, iris, and trabecular zone, complicated by uveitis, cataract, and glaucoma, which caused the functional loss of the left eye. Histological examination of a cutaneous biopsy confirmed the diagnosis. Involvement of the eyelids is characteristic, and moniliform blepharosis is pathognomonic and frequent. This case featured a rare intraocular form (uveitis). Deposits may be found on the conjunctiva, cornea, trabecula and Bruch membrane. Conjunctival or cutaneous biopsy confirms the diagnosis. Available treatment is quite limited.

Urbach–Wiethe disease

Objective: Urbach–Wiethe disease (lipoid proteinosis) is a rare, recessively inherited disorder, characterized by infiltration of a hyalin-like material in skin, mucous membranes, brain and other internal organs. We present a case of a child with this rare disease. Case report: A 15-year-old boy was referred to our clinic because of a 10-year history of hoarseness. On clinical examination, waxy papules were seen on the face. The cutaneous lesions appeared early in childhood soon after the development of hoarseness and were located along the margin of both eyelids and on the upper lip on a beaded arrangement. Hyperkeratotic plaques were also found on the elbows and white–yellow infiltrates on the mucosae of the pharynx and the tongue. Full laboratory investigation was unremarkable. A biopsy from oral mucosae confirmed the diagnosis of lipoid proteinosis. Conclusion: Lipoid proteinosis is thought to be a multisystemic disorder due to deposition of hyaline material around the blood vessels in internal organs. Usual manifestations of the disease include recurrent parotitis related to the occlusion of the salivary duct, epilepsy owed to intracranial suprasellar calcification, malfunction of the eyelashes causing corneal ulceration or alopecia of the eyelashes and eyebrows. The most serious manifestation of lipoid proteinosis is the possible respiratory obstruction in infancy because of the enlargement of the tongue and the presence of hyaline infiltrates in pharynx. Otherwise, the disease is compatible with a normal life span. The disfiguring lesions and the permanent hoarseness can seriously impair quality of life. There is no effective therapy at the present time.

Lipoid Proteinosis: An Unusual Presentation with Verruca Vulgaris

Lipoid proteinosis (LP) is a very rare, autosomally recessive, inherited disease. It is also known as Urbach Wiethe disease or Hyalinosis cutis et mucosa. LP usually runs a benign, stable, and slowly progressing course. We present one LP case with additional unusual dermatologic involvement; verruca vulgaris was superimposed on papular lesions of LP. To our knowledge, this case is the first and only one described in the literature. In this presentation, we discuss the possibility of predisposition to Human Papilloma Virus (HPV) infections in LP.

A novel mutation of the extracellular matrix protein 1 gene (ECM1) in a patient with lipoid proteinosis (Urbach-Wiethe disease) from Sicily

Lipoid proteinosis (LP), also known as Urbach-Wiethe disease, is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix protein 1 (ECM1) gene cause LP. We report the molecular analysis of the ECM1 gene in a Sicilian patient with LP in order to extend the mutation spectrum of this genodermatosis. We studied a 32-year-old female born from consanguineous parents who was diagnosed at the age of 11 years as having LP. She has a clinical phenotype corresponding to Urbach-Wiethe disease characterized by papules/nodules, indurated plaques and sometimes ulcerated lesions primarily involving the skin and mucous membranes, and extracutaneous features such as epilepsy, hoarseness of the voice and neuropsychiatric abnormalities. Samples of clinically affected skin obtained by biopsies were analysed after staining with haematoxylin and eosin, periodic acid-Schiff (PAS), and PAS-diastase. The whole ECM1 gene was analysed by direct sequencing. We identified a homozygous nonsense mutation in exon 6 of the ECM1 gene, C589T (Q197Ter). Over 60% of mutations occur in exons 6 and 7. Exon 7 is alternatively spliced and frameshift mutations in exon 7 lead to ablation of the ECM1a transcript, but not the shorter ECM1b transcript that normally lacks this exon. Homozygous nonsense or frameshift mutations in exon 6 are predicted to affect both full-length ECM1a and ECM1b transcripts, whereas ECM1b should be unaffected for similar types of mutation in exon 7. It has been suggested that individuals with mutations in exon 7 have a slightly milder phenotype than those with exon 6 mutations. This is the first report with respect to a novel mutation of the ECM1 gene responsible for recessive LP in Sicily.

Lipoidoproteinose: relato de dois casos

A lipoidoproteinose (doença de Urbach-Wiethe) é doença autossômica recessiva rara, caracterizada pela deposição progressiva de substância hialina na pele, membranas mucosas e órgãos internos. Clinicamente, os pacientes apresentam lesões papulonodulares na face, com áreas de infiltração difusa da pele principalmente nos joelhos, cotovelos e mãos; a língua apresenta consistência firme. Infiltração da laringe produz rouquidão que pode estar presente já ao nascimento. Os autores relatam dois casos dessa doença acometendo indivíduos da mesma família (irmãos).

Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease.

Patients with Urbach-Wiethe disease constitute a unique nature experiment as more than half have bilaterally symmetrical damage in the amygdaloid region. Ten such patients were studied neuropsychologically and, nine of them, neuroradiologically with static (CT) and functional imaging techniques [single-photon emission computed tomography (SPECT) and PET]. Their principal bilateral amygdala damage was confirmed. Neuropsychologically, the patients showed cognitively little deviation from normal subjects, while they differed emotionally. This was evident in their judgement of all emotions in facial expressions, in an odour-figure association test as well as in remembering negative and positive pictures. This suggests that the human amygdala influences both negative and positive emotional processing.

Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.

Bihippocampal Damage with Emotional Dysfunction: Impaired Auditory Recognition of Fear

A right-handed man developed a sudden transient, amnestic syndrome associated with bilateral hemorrhage of the hippocampi, probably due to Urbach-Wiethe disease. In the 3rd month, despite significant hippocampal structural damage on imaging, only a milder degree of retrograde and anterograde amnesia persisted on detailed neuropsychological examination. On systematic testing of recognition of facial and vocal expression of emotion, we found an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger. Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces versus voices). This is consistent with the idea that there may be multiple emotion systems. The study of emotional perception in this unique case of bilateral involvement of hippocampus suggests that this structure may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions and from that of fear in facial expression. In regard of recent data suggesting that the amygdala is playing a role in the recognition of fear in the auditory as well as in the visual modality this could suggest that the hippocampus may be part of the auditory pathway of fear recognition.

Dry Eye Syndrome Associated With Urbach-Wiethe Disease

Dry Eye Syndrome Associated With Urbach-Wiethe Disease

Manifestation of Urbach-Wiethe syndrome in the ENT area

Urbach-Wiethe's syndrome (hyalinosis cutis et mucosae) is a rare genetic defect of probably autosomal recessive origin. The exact nature concerning the pathogenesis of this disorder is still controversial. A characteristic symptom in early childhood might bei hoarseness, later on manifestations with hyalin deposits in the larynx, oral cavity and oropharynx might occur as well as yellowish-white papular deposits in the skin. The overall prognosis of this disease is good, therapeutic intervention might be necessary for functional purposes (narrowing of the laryngeal lumen) and consists of surgical removal of the lesions.

The amygdalaʼs contribution to memory—a study on two patients with Urbach–Wiethe disease

The amygdalaʼs contribution to memory—a study on two patients with Urbach–Wiethe disease