PREPL deficiency: delineation of the phenotype and development of a functional blood assay

Abstract

PurposePREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.ResultsFive subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader-Willi syndrome.ConclusionPREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader-Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency.

TP63‐truncating variants cause isolated premature ovarian insufficiency

“…At the time of genetic diagnosis, isolated PREPL deficiency (MIM #616224) had only been described once in the literature with no long‐term follow‐up of the affected patient (Regal et al, ). Recently, endocrine involvement, including hypergonadotropic hypogonadism (POI), has been described in PREPL deficient patients (Regal et al, ). Scoring the PREPL variants using ACMG guidelines (American College of Medical Genetics and Genomes, ), reveals these null‐type compound heterozygous variants that segregate with disease in the family, are pathogenic (Table S2).…”

PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus

“…However, such literature does not refer to the absence of ovaries and hypoplasia of the uterus. Although hypergonadotropic hypogonadism has been observed in some patients with isolated PREPL deficiency (Richards et al, 2015;Régal et al, 2018), this study is the first to report the absence of the ovaries and hypoplasia of the uterus. We also observed other symptoms in our patient including microcephaly and a short neck.…”

“…As previously, subjects with PREPL deficiency often present with growth deficiency. Growth hormone therapy has a positive effect on the cohort of cases that exhibit growth hormone deficiency (Jaeken et al, 2006;Régal et al, 2014Régal et al, , 2018. In our study, the patient suffered congenital myasthenic syndrome, a failure to thrive, severe growth deficiency, and short stature.…”

“…Hypotonia-cystinuria syndrome has been described as a disorder with cystinuria and congenital myasthenic result from the recessive deletions in SLC3A1 and PREPL (Jaeken et al, 2006;Régal et al, 2014;Legati et al, 2016;Tucker et al, 2019). To date, only 10 patients with isolated PREPL deficiency (Jaeken et al, 2006;Régal et al, 2014Régal et al, , 2018Laugwitz et al, 2018;Silva et al, 2018 6 ) and 21 HCS families (contiguous deletion, including the SLC3A1 and PREPL genes) have been reported (Clara and Lowenthal, 1966;Polgár, 2002;Font-Llitjós et al, 2005;Szeltner et al, 2005;García-Horsman et al, 2007;Martens et al, 2007;Boonen et al, 2011;Eggermann et al, 2012;Régal et al, 2012Régal et al, , 2014Bartholdi et al, 2014;Wortmann et al, 2015). The most frequent characteristic features of subjects with PREPL deficiency are severe neonatal hypotonia, growth impairment and cognitive problems.…”

“…This syndrome is caused by recessive deletions of SLC3A1 and PREPL genes on chromosome 2p21 (Régal et al, 2012). In HCS, SLC3A1 deficiency, result in cystinuria (MIM 606407) (Font-Llitjós et al, 2005), while PREPL deficiency causes other symptoms (Jaeken et al, 2006;Régal et al, 2018). Congenital myasthenic syndrome (MIM 616224) is an autosomal recessive disorder caused by isolated PREPL deficiency.…”