ABSTRACT
Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.
Subject(s)
Carrier Proteins/genetics , Hereditary Sensory and Autonomic Neuropathies , Intellectual Disability , Nerve Tissue Proteins/genetics , Adolescent , Carrier Proteins/chemistry , Child , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Family , Female , Hereditary Sensory and Autonomic Neuropathies/complications , Hereditary Sensory and Autonomic Neuropathies/diagnosis , Hereditary Sensory and Autonomic Neuropathies/genetics , Hereditary Sensory and Autonomic Neuropathies/pathology , Humans , Infant , Intellectual Disability/complications , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/pathology , Magnetic Resonance Imaging , Male , Models, Molecular , Mutation, Missense , Nerve Tissue Proteins/chemistry , Neuroimaging/methods , Pedigree , Phenotype , Protein ConformationABSTRACT
BACKGROUND AND AIMS: In animal studies, vitamin A deficiency (VAD) during pregnancy has been shown to be associated with a decrease in nephron number and kidney weight of the offspring. At present, it is unclear whether these observations are pertinent to humans. Thus, this study was performed to assess the vitamin A status of a cohort of Egyptian pregnant women and their newborns and to determine the potential effect of maternal VAD during pregnancy on the neonatal kidney size. METHODS: The maternal and cord blood samples were collected for the measurement of serum retinol concentration.Within the first 3 days after delivery, an abdominal ultrasound was performed in all newborns to determine the renal dimensions and volume. RESULTS: Sixteen (20%) mothers had VAD. The newborns delivered to VAD mothers had significantly lower mean values of cord retinol concentrations and dimensions of both kidneys than the newborns delivered to mothers with vitamin A sufficiency. The maternal serum retinol concentrations were positively correlated with the cord retinol concentrations, the dimensions of both kidneys, and the combined renal volume of their respective newborns. CONCLUSION: Maternal VAD during pregnancy may decrease renal size in the infant at birth. The functional implications of this effect warrant further study.
Subject(s)
Kidney/pathology , Pregnancy Complications/blood , Vitamin A Deficiency/complications , Vitamin A Deficiency/pathology , Adult , Cross-Sectional Studies , Egypt/epidemiology , Female , Fetal Blood/metabolism , Humans , Infant, Newborn , Kidney/diagnostic imaging , Male , Maternal-Fetal Exchange , Organ Size , Pregnancy , Pregnancy Complications/epidemiology , Ultrasonography , Vitamin A/blood , Vitamin A Deficiency/epidemiology , Young AdultABSTRACT
Posterior fossa cysts are frequently identified on MR studies. This paper takes a different approach to analyzing these cysts based on the pathology of the cyst wall and the embryology of the hindbrain, choroid plexus, and meninges. The type of cyst depends on the histologic components of the cyst wall. Frequent types of posterior fossa cysts are arachnoid, Blake's pouch, and cysts associated with Dandy Walker malformation. All of these cysts may mimic the others in terms of position of the torcula, vermian abnormalities, and mass effect on the cerebellum and occipital bone. A clue to the nature of the cyst may be the position of the choroid plexus in the fourth ventricle; normal in arachnoid cyst, absent in Dandy Walker malformation, and displaced into the superior cyst wall in Blake's pouch. When the cyst wall histology is not known, it is suggested to use a descriptive term such as "retrocerebellar cyst".