Lipoid Proteinosis Of Urbach And Wiethe

A number sign (#) is used with this entry because of evidence that lipoid proteinosis is caused by homozygous or compound heterozygous mutation in the ECM1 gene (602201) on chromosome 1q21.

Description

Lipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane (summary by Hamada et al., 2002 and Hamada et al., 2003).

Clinical Features

This disorder was first reported by Urbach and Wiethe (1929). The association of early hoarseness with an unusual skin eruption suggests the diagnosis.

Meenan et al. (1978) reported multiple cases in 2 closely related Irish families. Characteristics included a history of progressive hoarseness since birth; thick, yellowish skin on the face and neck with several white scars on the cheeks; infiltration of the larynx; small nodules on the edges of the upper eyelids, giving a beaded appearance; and red and verrucose skin over the elbows and knees. Additional features included patchy alopecia, mental retardation, and epilepsy. Meenan et al. (1978) indicated that bilateral intracranial calcifications are common in this disorder.

Neuropsychologic/Neuropsychiatric Manifestations

Newton et al. (1971) reported an affected brother and sister of Lebanese extraction, born to second-cousin parents, who manifested neuropsychiatric symptoms, including seizures, memory defects, and rage attacks. The authors stressed the presence of specific intracranial calcifications, which they considered pathognomonic of the disease. By electron microscopy they found filamentous-like material in skin lesions, but its composition could not be defined.

Emsley and Paster (1985) reported 2 unrelated patients with lipoid proteinosis. One was a 51-year-old man who presented to psychiatry with paranoia, mistrustfulness, suspicion, and aggressive attitude. He reported hoarseness since childhood and impaired memory for 10 years. Physical examination showed yellow papular lesions on the lower lip, soft palate, and pharynx. Brain CT scan showed bilateral symmetric calcification in the medial temporal lobe in the region of the amygdala. A brother reportedly had poor memory and experienced episodic 'absences.' The second patient was an 18-year-old girl who presented to psychiatry with abnormal behavior. She had hoarse voice since childhood and raised lesions on her face and around her mouth. She also had poor memory. Psychiatric evaluation showed that she was agitated with persecutory delusions and verbal hallucinations. Physical examination showed acneform facial lesions and scarring, with fine nodules along the palpebral fissures. There were yellow-white papules on the lips and tongue, and laryngeal infiltration. Brain CT scan showed calcification of the medial temporal lobes. Emsley and Paster (1985) emphasized the psychiatric presentation of these patients.

Adolphs et al. (1994) studied a 30-year-old woman (SM) with Urbach-Wiethe disease which had caused a nearly complete bilateral destruction of the amygdala, while sparing the hippocampus and all neocortical structures, as revealed by detailed neuroanatomic analysis of her CT and MRI scans. Studies in animals had shown that the amygdala receives highly processed visual input, contains neurons that respond selectively to faces, and participates in emotion and social behavior. From a study of this unusual patient, Adolphs et al. (1994) obtained results suggesting that the human amygdala may be indispensable to recognize fear in facial expressions and to recognize multiple emotions in a single facial expression, but may not be required to recognize personal identity from faces. Patient SM, reported by Adolphs et al. (1994), was also studied in detail by Tranel and Hyman (1990), Tranel et al. (2006), and Feinstein et al. (2011). The diagnosis of lipoid proteinosis was based on the presence of typical beaded papules along the edges of her eyebrows, thickening of the tongue, thickening of the skin over her elbows and knuckles, papules along the sides of her fingers, and relative skin fragility. She had marked hoarseness since birth. Biopsy of affected skin showed deposition of neutral mucopolysaccharides. She presented with occasional absence-like spells every few months and had poor day-to-day memory. Extensive neuropsychologic investigations by Tranel and Hyman (1990) showed that the patient had significant defects in nonverbal visual memory, in social behavior, and in executive control function. Intellect was low-average, but consistent with her environmental circumstances. She also showed difficulty in geographical navigation in her hometown, but no defects in remote memories. Socially, she was very cooperative, outgoing, and even flirtatious at times. There were no defects in electrodermal activity in the skin conductance response test. The findings suggested that the amygdala plays a role in memory and in the modulation of social and emotional behavior. Tranel et al. (2006) reported the results of a detailed neuropsychologic assessment of patient SM. She showed a normal range of affect and emotion, but was remarkably dispassionate when relating highly emotional and traumatic life experiences. This was accompanied by a strong positive affect, with a defect in recognizing negative emotions in external stimuli. She also seemed not to have a normal sense of distrust or danger, suggesting impaired recognition of social and emotional information. Tranel et al. (2006) concluded that the amygdala is necessary for linking external stimuli to the elicitation of appropriate social behavior and to the appropriate experience of emotion, particularly negative emotions. Feinstein et al. (2011) observed that patient SM did not show fear when exposed to several evocative scary stimuli, including spiders and snakes, a haunted house, and clips of emotionally evocative films. She also showed an absence of overt fear manifestations and an impoverished experience of fear across a battery of self-report questionnaires and despite a personal history of adverse and traumatic events. The findings suggested that the amygdala plays a pivotal role in triggering a state of fear, and that the absence of such a state precludes the experience of fear itself.

Inheritance

In the family reported by Rosenthal and Duke (1967), a mother, 3 sons, and a daughter were affected, but the father was a first cousin of the mother. Thus, a quasidominant pedigree pattern resulting from consanguinity is likely.

Recessive inheritance is well documented by the study of Gordon et al. (1969) of numerous cases in an inbred South African community.

Stine and Smith (1990) estimated the coefficient of selection for the lipoid proteinosis gene to be 0.07 in the Afrikaner population of South Africa. However, the observed decrease in allele frequency could not be explained solely on the basis of selection against the homozygote. Therefore, they suggested that this may be a pleiotropic gene that has a dominant effect in terms of selection even though its known clinical effect is recessive.

Pathogenesis

A disturbance in mucopolysaccharide metabolism was suggested by Moynahan (1966).

Bauer et al. (1981) presented evidence that this is a lysosomal storage disease. Dermal fibroblasts demonstrated marked cytoplasmic vacuolization. Cultured skin fibroblasts by phase contrast microscopy showed strikingly abnormal cells with many inclusions, which by electron microscopy were delimited by a single membrane.

Mapping

Using DNA from 6 consanguineous families, Hamada et al. (2002) mapped the disorder to chromosome 1q21 at D1S498 (lod = 21.85 at theta = 0.0), within a 2.3-cM critical region.

Molecular Genetics

Using a candidate gene approach, Hamada et al. (2002) identified 6 different homozygous loss-of-function mutations in the extracellular matrix protein-1 gene (see, e.g., 602201.0001-602201.0003).

Genotype/Phenotype Correlations

Hamada et al. (2003) sequenced the ECM1 gene in 10 unrelated patients with lipoid proteinosis. They concluded that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid proteinosis and that clinically it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid proteinosis phenotype. However, they were unable to demonstrate any specific genotype-phenotype correlation for neurologic features.

Population Genetics

Lipoid proteinosis occurs worldwide, but is more common in certain areas such as the Northern Cape province of South Africa (Hamada et al., 2002).