Advances in treatment for lipoid proteinosis (Urbach-Wiethe disease): a case report and systematic review.

BACKGROUND: Lipoid proteinosis (LP), also known as Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis, caused by mutations in the ECM1 gene. This results in the deposition of periodic acid-Schiff (PAS)-positive, hyaline-like material on the skin, mucosae and internal organs. OBJECTIVES: To present a case report of LP and a systematic review to synthesize the scientific literature on the management of this uncommon and frequently missed diagnosis. METHODS: We present a case report of a 48-year-old man with LP who exhibited significant improvement after oral acitretin therapy. To address the lack of large case-control studies on LP treatment, we performed a systematic review of the literature following the PRISMA 2020 criteria. The search was conducted in PubMed, Web of Science, Cochrane and Scopus databases from inception until June 2023. To assess the methodological quality of case reports and case series, we used the Joanna Briggs Collaboration critical appraisal tool. RESULTS: We included 25 studies that met eligibility criteria. Data from 44 patients with a histopathologically confirmed diagnosis were analysed. Treatment ranged from systemic therapies (acitretin, etretinate, dimethyl sulfoxide, corticosteroids, penicillamine) to surgical or laser procedures. Regarding methodological quality, the main discrepancies arose in the reporting of participant characteristics and treatment interventions. CONCLUSIONS: Low-dose oral acitretin could have potential in managing LP, exhibiting fewer side-effects compared with other therapeutic agents. Further research is needed to establish more comprehensive and evidence-based treatment guidelines.

Lipoid proteinosis: Novel ECM1 pathogenic variants and intrafamilial variability in four unrelated Arab families.

BACKGROUND/OBJECTIVES: Lipoid proteinosis (LP) is a rare autosomal recessive multisystem disorder that is caused by loss-of-function pathogenic variants in the extracellular matrix protein-1 (ECM1) gene. The typical clinical manifestations of LP include hoarseness of voice, beaded papules on the eyelids, infiltration and scarring of the skin and mucosa, as well as neuropsychological abnormalities. Currently, more than 70 pathogenic variants have been reported, including nonsense, missense, splice site, deletion and insertion pathogenic variants, and more than half of them occurred in exons 6 and 7. METHODS: Clinical evaluation and Sanger sequencing were performed on eight patients from four unrelated Arab families. RESULTS: We identified two novel ECM1 variants, one nonsense pathogenic variant in exon 6 (c.579G>A, p.Trp193*) and a deletion of three nucleotides (c.1390_1392del, p.Glu464del) in exon 9, and two previously reported frameshift variants; c.692_693delAG, in exon 6 and c.11dupC in exon 1. CONCLUSIONS: Although all patients had characteristic manifestations of lipoid proteinosis, we observed intrafamilial phenotypic variability. Our data expand the pathogenic variant spectrum of ECM1 and also supports the fact that exon 6 is one of the most common hot spots of pathological variants in ECM1.

Pulmonary storage.

Interstitial lung diseases (ILDs) are not just a matter of scarring or inflammation in the lung tissue. The lungs can also serve as a repository for products that can be produced in excessive amounts in the human body as a result of disease. Geneticaly based dysfunctions of lysosomal enzymes, which leads to an unefficient degradation and transport of various macromolecules from lysosomes, are considered to be storage diseases sensu stricto. ILDs were described in patients with Gaucher disease, Niemann-Pick disease and Fabry disease. In a broader context, however, the accumulation of various substances in the lung tissue is also encountered in cases of pediatric pulmonary interstitial glycogenosis (PIG), alveolar lipoproteinosis or pulmonary amyloidosis. The cause of PIG is not clear. The disease was first described in 2002 and a lung tissue sample is required to establish this diagnosis. Even though PIG usually goes well in childhood and the patients difficulties spontaneously subside over time, the long-term prognosis of the patients is unknown. Alveolar lipoproteinoses can be acquired (e.g. after massive exposure to silica dust), autoimmune, but also genetically determined. Unlike lysosomal storage diseases, in the case of pulmonary alveolar lipoproteinosis, accumulation of abnormal macromolecules occurs only in the lungs of affected individuals. Similarly, amyloidosis is not a single disease, but a group of diseases with different etiopathogenesis, as a result of which amyloid - a group of different proteins with a distinctvive conformation, which can be deposited in various organs, including the lungs - is formed. The diagnosis of pulmonary alveolar lipoproteinosis is based on the typical appearance and biochemical composition of the fluid obtained by bronchoalveolar lavage, the diagnosis of amyloidosis is histological.

Lipoid proteinosis: A case with distinct histopathological and radiological findings.

Lipoid proteinosis is a rare inherited genodermatosis characterized by hyaline deposits in various tissues. Clinically, it manifests with cutaneous as well as extracutaneous features. Periodic acid-Schiff (PAS)-reactive hyaline deposits in the upper dermis, with localization around blood vessels and eccrine sweat glands, in particular, is the histopathological hallmark finding. On brain imaging, bilateral symmetrical temporal lobe calcifications are considered to be pathognomonic of this disorder. We report a case of lipoid proteinosis in which hyaline deposits were present in the papillary and reticular dermis, without being seen at the periphery of eccrine sweat glands, along with dystrophic calcification. Magnetic resonance imaging (MRI) of brain revealed hydrocephalus, subependymal heterotropia and absent splenium of corpus callosum with no evidence of temporal lobe calcification. Thus, our case highlights the inherent diverse nature of lipoid proteinosis.

Translational neuroscience of basolateral amygdala lesions: Studies of Urbach-Wiethe disease.

Urbach-Wiethe disease (UWD) is an extremely rare autosomal recessive disorder characterized by mutations in the extracellular matrix protein 1 gene on chromosome 1. Typical clinical manifestations include voice hoarseness in early infancy and neuropsychiatric, laryngeal, and dermatological pathologies later in life. Neuroimaging studies have revealed a pattern of brain calcification often but not exclusively leading to selective bilateral amygdala damage. A large body of work on amygdala lesions in rodents exists, generally employing a subregion model focused on the basolateral amygdala (BLA) and the central-medial amygdala. However, human work usually considers the amygdala as a unified structure, not only complicating the translation of animal findings to humans but also providing a unique opportunity for further research. To compare data from rodent models with human cases and to complement existing data from Europe and North America, a series of investigations was undertaken on UWD subjects with selective BLA damage in the Namaqualand region, South Africa. This review presents key findings from this work, including fear processing, social-economic behavior, and emotional conflict processing. Our findings are broadly consistent with and support rodent models of selective BLA lesions and show that the BLA is integral to processing sensory stimuli and exhibits inhibitory regulation of responses to unconditioned innate fear stimuli. Furthermore, our findings suggest that the human BLA mediates calculative-instrumental economic behaviors and may compromise working memory via competition for attentional resources between the BLA salience detection system and the dorsolateral prefrontal cortex working memory system.

Extracellular matrix protein 1 gene (ECM1) mutations in nine Iranian families with lipoid proteinosis.

BACKGROUND & OBJECTIVES: Lipoid proteinosis (LP) is an autosomal recessive disease. Clinical characteristics of this disease are hoarse voice, scarring of the skin, brain calcifications, and eyelid papules (moniliform blepharosis). Mutations in the ECM1 gene on 1q21.2 are responsible for this disease. This study was conducted to investigate the mutation spectrum of ECM1 gene in nine Iranian families having at least one LP patient diagnosed clinically. METHODS: The entire ECM1 gene was screened using PCR and direct sequencing in nine Iranian families with 12 suspected LP patients who were referred to the clinic, along with their parents and siblings. Thirty healthy individuals were included as controls. RESULTS: In only one patient a homozygous G>A transition at nucleotide c.806 in exon 7 was detected. A G>A substitution at nucleotide 1243 in exon 8 that changes glycine (GGT) to serine (AGT) was observed in most of our patients. Furthermore, in one patient there was a change in the sequence of intron 8, the A>T transition in nucleotide 4307. In addition, in two cases (one patient and one healthy mother with affected child) there was a C (4249) deletion in intron 8. INTERPRETATION & CONCLUSIONS: Our results indicate that although mutation in ECM1gene is responsible for lipoid proteinosis, it is likely that this is not the only gene causing this disease and probably other genes may be involved in the pathogenesis of the LP disease.

Treatment of lipoid proteinosis with ablative Er:YAG laser resurfacing.

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis characterized by deposition of amorphous hyaline material in different parts of the body, especially the skin and mucous membranes. Disfiguring lesions predominantly affect facial appearance. There is no curative therapy and treatment options are limited to symptomatic approaches. Facial disfigurement in this disease may have an huge negative effect on the patients' psychology and quality of life. With this regard, the patients may benefit very much from symptomatic treatments. Four patients with LP were treated with Er:YAG laser to ablate disfiguring lesions on the face. Patients were followed up for 14 months to 2 years. We obtained favorable clinical and aesthetic results in all cases with Er:YAG laser treatment and did not observe any recurrences during the follow-up. Depending on our observations Er-YAG laser can be accepted as an effective tool for dermal accumulations and scars of LP with precise ablation capability and favorable esthetic results.

Vocal fold hyalinosis in Urbach-Wiethe disease, a rare cause of hoarseness.

BACKGROUND: Lipoid proteinosis is an autosomal recessive disorder characterized by hyalin deposits in the skin and mucosa of the upper aerodigestive tract; currently, no treatment exists. Nearly all patients experience hoarseness and speech difficulties, due to hyalin deposition in the vocal folds and diminished mobility in infiltrated lips, tongue, and palate. METHODS: We describe a patient with extensive hyalin plaques on the vocal folds, which resulted in near-aphonic hoarseness. Hyalin deposits in the vocal folds and skin were treated with laser resection. RESULTS: Both the vocal folds and skin improved in appearance, with smoother surface epithelium. However, the patient's speech remained impaired, due to extensive hyalin plaques in the mouth, tongue, and lips. The voice improved only temporarily. CONCLUSIONS: Laser resection of hyalin plaques in the vocal folds and skin is a feasible treatment for lipoid proteinosis. However, speech may remain severely limited, due to impaired tongue and lip movement.

Lipoid proteinosis in a Chinese patient.

Lipoid proteinosis is a rare autosomal recessive deposition disorder due to loss-of-function mutations in the gene encoding extracellular matrix protein 1 on chromosome 1q21. There are limited case reports of lipoid proteinosis in the Chinese population. The authors report 1 case of lipoid proteinosis in a Chinese patient with typical clinical and histopathological manifestations. Physical examination in this patient demonstrated hoarse voice, hypertrophy of tongue and lips, inability to fully protrude the tongue, and cutaneous features including moniliform blepharosis, verrucous plaques, and scarring. Biopsies from the eyelid, pharyngeal mucosa, and elbow lesions revealed diffuse amorphous deposits of hyaline material within the dermis and around blood vessels, which stained positively for periodic acid-Schiff, was diastase resistant and stained negatively on Congo red.

Lipoid Proteinosis: a case report in two siblings.

Lipoid proteinosis was first reported by Urbach and Wiethe in 1929. It is also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease. It is a rare autosomal recessive disorder and characterized by the infiltration of hyaline material in the skin, oral cavity, larynx, and internal organs. Lipid proteinosis presents early in life. Hoarseness develops in infancy. The classic sign is beaded eyelid papules along the lid margin, also known as 'Monilform Blepherosis'. In India about 30 cases have been reported to date. We report the following case because of its rarity in the Indian literature.

Keratoconus in a case of lipoid proteinosis.

PURPOSE: To report a patient of lipoid proteinosis (LP) with bilateral keratoconus. METHODS: A 16-year-old boy presented to our institution with a complaint of gradual decrease in vision over the past 4 years in both eyes and a contact lens intolerance. He had a hoarse voice and multiple areas of hyperpigmented lesions over the head and neck region. Slit lamp biomicroscopy of the both eyes showed multiple round solid pearly lesions along the upper and lower lid margins and a mild central corneal ectasia in both eyes. Central corneal thickness and the keratometric values were measured by using Scheimpflug imaging (Pentacam), and the results were compatible with keratoconus. The histopathologic examination of the lesions taken from bilateral eyelid margins showed hyalinosis, papillomatosis, and depositions of eosinophilic material around the blood vessels, which were compatible with LP. CONCLUSIONS: With this report, we describe a case of LP with keratoconus. As seen in our case, LP and its characteristic eyelid margin lesions in keratoconus patients can be associated with a contact lens intolerance.

Lipoid proteinosis presenting with an unusual nonsense Q32X mutation in exon 2 of the extracellular matrix protein 1 gene.

Lipoid proteinosis (LP) is a rare disorder characterized by extensive hyaline-like deposits on the skin, mucous membranes and various internal organs with varying clinical manifestations. The disorder has been recently shown to result from loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1) on 1Q21. The two cases reported here had typical clinical and histological features consistent with LP. Direct sequencing of amplified DNA from the second patient showed a single nucleotide substitution (C > T) at nucleotide 94 within exon 2 of the ECM1 gene, nonsense mutation Q32X. This is the second case reported of LP with involvement of exon 2 of ECM1.

Assessment of dynamic thiol-disulfide homeostasis in patients with lipoid proteinosis (Urbach-Wiethe syndrome).

OBJECTIVE: Lipoid proteinosis is a rare autosomal recessive genetic dermatological disease that occurs due to the accumulation of hyaline material in the skin and mucous membranes. This study aimed to investigate whether dynamic thiol-disulfide homeostasis is a new marker of oxidative stress in patients suffering from lipoid proteinosis. METHODS: The study group involved 17 patients with lipoid proteinosis and 17 healthy controls with same gender and age. Native thiol, total thiol, disulfide levels, and thiol-disulfide indexes were measured with the fully automated spectrophotometric method described by Erel and Neselioglu, and the results of the two groups were statistically analyzed. RESULTS: Serum total thiol and native thiol levels were significantly lower in lipoid proteinosis group compared to the control group (p=0.020 and p=0.014, respectively). The disulfide levels were found to be higher in lipoid proteinosis group, but there was no significant difference between two groups. CONCLUSIONS: Impaired dynamic thiol-disulfide homeostasis was observed in lipoid proteinosis patients, suggesting that thiol-disulfide homeostasis may have a role in the pathogenesis of this disease.

Lipoid proteinosis: A systematic presentation of an unusual disease.

BACKGROUND: Lipoid proteinosis (LP) or Hyalinosis Cutis et Mucosae or Urbach-Wiethe disease is a rare autosomal recessive genodermatosis characterized by an amorphous hyaline material deposition in the skin mucosa and viscera. The clinical symptoms of this disease often begin in childhood, which persist throughout life. Skin manifestations include inflammation, scaling, acne, and eventually ulceration, and hyaline amorphous deposits in these areas of the wound cause a waxy and thick appearance on the skin. In addition, wounds leave atrophic scars like chickenpox. AIM: Herein, we present the first case of LP in the north of Iran; although LP is a sporadic disease, it occurs all around the world, with about 400 cases worldwide having been reported thus far. PATIENT: We report the case of a 28-year-old female patient with a history of skin lesions on her face, scalp, extremities, and buttock, as well as hoarse cry, respiratory problems, dysphagia, and migraine since childhood. There was no evidence of other clinical presentations. A biopsy was taken from the lesions, and the patient was diagnosed with LP. A laryngeal laser was performed for the patient, and peeling creams were used for her skin lesions. RESULT: According to previous findings, there has been no case report of LP with systemic symptoms in the north of Iran.

Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.

Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

Molecular and neurological characterizations of three Saudi families with lipoid proteinosis.

BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families. METHODS: Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene. RESULTS: All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8. CONCLUSIONS: These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.

Eyelid lesions in lipoid proteinosis or Urbach-Wiethe disease: case report and review of the literature.

Lipoid proteinosis (LP) or Urbach-Wiethe disease is a recessively inherited disorder not usually seen by ophthalmologists. It is characterized by non-inflammatory, persistent papules on the skin and mucous membranes. The first clinical manifestation of LP is usually progressive hoarseness. The lid lesions, consisting of beaded papules along the lid margins (moniliform blepharosis), are considered almost pathognomonic of the disease. The interesting clinical and histopathological features of LP are described in a 45-year-old man with a history of lipoid proteinosis, who presented to us for evaluation of ocular discomfort and unusual multiple eyelid lesions. We surgically removed all the eyelid lesions. The histologic findings were consistent with LP. Knowledge of the typical eyelid lesions may help to diagnose many typical or atypical cases of LP, although biopsy confirmation is always necessary. In our experience, the surgical removal of the eyelid lesions seems to be curative and due to the amount of eyelid lesions that can be developed, it is recommended to initiate an early treatment as soon as possible to avoid postoperative deformities.