Arginase 1 Deficiency: using genetic databases as a tool to establish global prevalence.

BACKGROUND/OBJECTIVE: Arginase 1 Deficiency (ARG1-D) is a rare inherited metabolic disease with progressive, devastating neurological manifestations with early mortality and high unmet need. Information on prevalence is scarce and highly variable due to limited newborn screening (NBS) availability, variability of arginine levels in the first days of life, and high rates of misdiagnosis. US birth prevalence was recently estimated via indirect methods at 1.1 cases per million live births. Due to the autosomal recessive nature of ARG1-D we hypothesize that the global prevalence may be more accurately estimated using genetic population databases. METHODS: MEDLINE and EMBASE were systematically searched for previously reported disease variants. Disease variants in ARG1-D were annotated wherever possible with allele frequencies from gnomAD. Ethnicity-specific prevalence was calculated using the Hardy-Weinberg equation and applied to generate country-specific carrier frequencies for 38 countries. Finally, documented consanguinity rates were applied to establish a birth prevalence for each country. RESULTS: 133 of 228 (58%) known causative alleles were annotated with ethnic-specific frequencies. Global birth prevalence for ARG1-D was estimated at 2.8 cases per million live births (country-specific estimates ranged from 0.92 to 17.5) and population prevalence to be 1.4 cases per million people (approximately 1/726,000 people). Birth prevalence estimates were dependent on population demographics and consanguinity rate. CONCLUSION: Birth prevalence of ARG1-D based on genetic database analysis was estimated to be more frequent than previous NBS studies have indicated. There was a higher degree of confidence in North American and European countries due to availability of genetic databases and mutational analysis versus other regions. These findings suggest the need for greater disease education around signs and manifestations of ARG1-D, as well as more widespread testing and standardization of screening for this severe disease in order to appropriately identify patients prior to disease progression.

[Aortic thrombosis in a calf]. / Aortenthrombus bei einem Kalb.

A two month-old female Simmental calf was presented with sensomotoric dysfunction and recumbency. Neurologic examination revealed dysfunction of the cerebral cortex and paralysis of both hind limbs. Examination of the skeletal system revealed a marked reduction of the skin temperature of both hind limbs and the absence of femoral pulse. Examination of cerebrospinal fluid yielded physiological parameters. The radiographic examination of the vertebral column, hip and femur on both sides revealed no evidence of alteration of the bone structures. Thiamine pyrophosphate test indicated thiamine deficiency. Based on these findings a tentative diagnosis of cerebrocortical necrosis and aortic thrombosis were made and the animal was euthanised. Post mortem examination yielded thrombosis of the abdominal aorta cranial to the branching of the iliac arteries and consecutive necrosis of the skeletal muscle of the hind limbs. Possible causes of pathogenesis are discussed.