Alopecia‐mental retardation syndrome: Molecular genetics of a rare neuro‐dermal disorder

Abstract

Alopecia‐mental retardation syndrome (APMR) is a rare autosomal recessive neuro‐dermal disorder. It is characterized by heterogeneous phenotypic features, that is, absence of hair on the scalp, eyelashes, and eyebrows and mild to severe intellectual disability. So far, approximately 14 families (i.e., Iranian, Pakistani, and Swiss) with APMR have been reported in the scientific literature. Its precise prevalence is still unknown, but according to a predictive estimate, it prevails with the ratio of 1 in 1,000,000 persons worldwide. Until now, only four loci (two characterized and two uncharacterized) have been reported to be involved in APMR. The pathogenic variants in alpha‐2‐HS‐glycoprotein [AHSG; APMR1 (MIM#203650)] and lanosterol synthase [LSS; APMR4 (MIM#618840)] are the characterized genetic factors associated with APMR. Among them, AHSG was reported in a consanguineous Iranian family and LSS gene in a Swiss origin family, while the remaining two uncharacterized loci, that is, APMR2 and APMR3, are reported in the Pakistani population. The current mini‐report discusses the molecular genetics and mutational spectrum of APMR syndrome, its differential diagnosis from related disorders, and prediction of plausible candidate genes in two uncharacterized loci.

Expanding the Phenotypic Spectrum of APMR4 Syndrome Caused by a Novel Variant in LSS Gene

“…The cardinal signs of the syndromes are loss of scalp hair and eyelashes as well as intellectual disability (ID). APMR are four types classified based on the degree of ID, as well as associated clinical manifestations (Muzammal et al 2021 ). Clinical heterogeneity was observed among types of APMR.…”

“…However, alopecia intellectual disability syndromes 4 (APMR4) (OMIM# 618,840) has a wider degree of affection when describing ID ranging from mild to severe (Besnard et al 2019 ; Sailani Reza et al 2017 ). APMR disorder predictive estimated prevalence is < 1:1,000,000 worldwide (Muzammal et al 2021 ).…”

“…A few numbers of families with APMR have been reported worldwide (Muzammal et al 2021 ) . The first affected family with APMR was described with alopecia and epilepsy in 1962 (Moynahan 1962 ).…”

Defect of LSS Disrupts Lens Development in Cataractogenesis

“…Consequently, the mutations located at the C-terminus of LSS are more likely to cause cataract, whereas the mutations located at the N-terminus of LSS tends to cause hair loss. In addition, mutations of LSS can cause alopecia-mental retardation syndrome (APMR), which is a rare autosomal recessive neuro-dermal disorder ( Muzammal et al, 2021 ). Thus, the studies on LSS mutations suggested that dysfunctions of LSS are far more complex and lead to autosomal-recessive diseases.…”

Novel LSS variants in alopecia and intellectual disability syndrome: New case report and clinical spectrum of LSS‐related rare disease traits

“…1 APMR is classified into four subtypes based on the degree of intellectual disability and the associated clinical manifestations. 1 Alopecia-intellectual disability syndrome type 4 (APMR4, OMIM #618840) is a very rare, neuro-ectodermal syndrome caused by biallelic variants in LSS located on chromosome 21q22. 2 Lanosterol synthase (LSS) is an enzyme involved in the biosynthesis of cholesterol, steroid hormones, and vitamin D. 3 It catalyzes the rate-limiting step in the conversion of (S)-2,3-oxidosqualene into lanosterol.…”