ABSTRACT
CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
Subject(s)
DNA-Directed RNA Polymerases/genetics , Endocrine System Diseases/genetics , Growth Disorders/genetics , Hereditary Central Nervous System Demyelinating Diseases/genetics , Mitochondrial Diseases/genetics , Adolescent , Adult , Biological Variation, Population , Child , Child, Preschool , Cohort Studies , Cross-Sectional Studies , Endocrine System Diseases/epidemiology , Endocrine System Diseases/etiology , Female , Genetic Heterogeneity , Growth Disorders/epidemiology , Growth Disorders/etiology , Hereditary Central Nervous System Demyelinating Diseases/complications , Hereditary Central Nervous System Demyelinating Diseases/epidemiology , Humans , Hypogonadism/epidemiology , Hypogonadism/etiology , Infant , Infant, Newborn , Male , Mitochondrial Diseases/complications , Mitochondrial Diseases/epidemiology , Mutation , RNA Polymerase III/genetics , Retrospective Studies , Young AdultABSTRACT
As the mechanisms for learning and memory are elucidated, modulation of learning and memory becomes a central issue. We studied the modulation of learning and memory by investigating the circadian regulation of short- and long-term sensitization of the siphon withdrawal reflex in Aplysia. We found that Aplysia exhibited diurnal and circadian rhythms of long-term sensitization (LTS) with significantly greater LTS occurring when animals were trained and tested during the day relative to those trained and tested at night. In contrast to the modulation of LTS, short-term sensitization was not regulated by the circadian clock. Time of training rather than time of testing determined the circadian rhythm of LTS. Animals trained during the subjective day demonstrated LTS when tested during either the day or the night. Conversely, when animals were trained during the night, LTS was not observed when animals were tested either at night or during the day. Thus, the circadian rhythm of LTS is a rhythm in learning rather than a rhythm in recall. The threshold required to elicit siphon withdrawal and the duration of siphon withdrawal were not regulated by the circadian clock. These results indicate that the circadian oscillator exerts strong modulatory influences on one form of long-term memory in Aplysia.