Molecular and neurological characterizations of three Saudi families with lipoid proteinosis

Abstract

BackgroundLipoid 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.MethodsClinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene.ResultsAll 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.ConclusionsThese 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.

A Novel Association of the Additional Intracranial Calcification in Lipoid Proteinosis: A Case Report

“…The mutations in this gene lead to the deposition of a hyaline like material in the skin and the viscera in abnormal amounts, which is the cause of the clinical manifestations. These deposits stain positive with the Periodic Acid-Schiff stain and they are Diastase resistant and negative for Congo red [10].…”

Prominent corneal nerves: a novel sign of lipoid proteinosis

“…In most genetic reports regarding LP, phenotype–genotype correlations are not obvious 8 9. Hamada and colleagues noted that individuals with mutations outside of exon 7 seemed more affected than individuals with mutations involving exon 7 of the ECM1 gene 8.…”

“…Patients from each family had skin punch biopsies including epidermis, dermis and subcutaneous tissue that were fixed in formalin and stained with PAS and PAS/diastase; in addition, laryngeal biopsies were taken from all except Patient 2B. After obtaining informed consent, the ECM1 gene was directly sequenced in affected individuals, in available first degree relatives and in 100 chromosomes from healthy individuals of matching ethnicity as described previously 3 8 9. Nucleotide numbering for mutations reported in all three families was referenced to the NCBI sequence (NG_012062).…”

Single nucleotide substitution mutations and polymorphisms in ECM1 gene in lipoid proteinosis in siblings of a Pakistani family

“…A number of recent genetic studies reported the involvement of homozygous frame shift, missense, nonsense and single nucleotide substitution, deletion and insertion mutations in ECM1 gene LP which is located on chromosome 1q21.2 (Salih et al, 2011;Samdani et al, 2010;Kumar et al, 2009;Nasir et al, 2009). About 300 cases of LP have been so far reported.…”

“…The precise function of ECM1 is still unknown. Many pathogenic mutations have been reported so far, mostly nonsense, missense or splice site mutations with the majority occurring in exon 6 or 7 of the 10-exon in ECM1 gene encoding a glycoprotein (Salih et al, 2011). LP is histologically characterized by intercellular deposits of periodic acid Schiff (PAS)-positive hyaline material in the skin, mucous membranes and internal organs.…”