YARS1 Deficiency

Excerpt

Clinical characteristics: YARS1 deficiency is characterized by developmental delay / intellectual disability, poor prenatal and postnatal growth, gastrointestinal (GI) involvement (feeding difficulties, recurrent vomiting, GI bleeding, chronic diarrhea, pancreatic insufficiency), liver involvement (increased transaminases, cholestasis, steatosis, fibrosis, episodes of hepatic failure), chronic anemia, endocrine involvement (hypothyroidism, hypoglycemia), lung disease (cystic disease, interstitial fibrosis), retinitis pigmentosa, and sensorineural hearing loss. Other less frequent findings include kidney disease and primary amenorrhea. The multisystem clinical manifestations of YARS1 deficiency typically vary from individual to individual.

Diagnosis/testing: The diagnosis of YARS1 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in YARS1 identified by molecular genetic testing.

Management: Treatment of manifestations: Multidisciplinary care by specialists in relevant fields including developmental pediatrics, pediatric neurology, gastroenterology, hepatology, pulmonology, medicine, kidney disease, otolaryngology and audiology, ophthalmology, low vision services, hematology, endocrinology, social work, and clinical genetics. General recommendations for urgent treatment of acute episodic illnesses include: increase protein intake (up to 2-2.5 g/kg/day), avoid prolonged fasting, aggressively treat fever with antipyretics, and provide appropriate steroid coverage for individuals with known adrenal insufficiency.

Surveillance: Routinely scheduled visits with treating specialists.

Agents/circumstances to avoid: Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day) and prolonged fasting given the increased risk of hypoglycemia.

Genetic counseling: YARS1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a YARS1 pathogenic variant, at conception each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial YARS1 pathogenic variants. Once the YARS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.