Clinical Guidance

Homozygosity for the pathogenic variant p.Arg367Trp is associated with a relatively consistent phenotype . No clinically relevant genotype-phenotype correlations are available to date in individuals with other YARS1 pathogenic variants.

Source: GeneReviews — "YARS1 Deficiency"

Diagnostic Criteria

No consensus diagnostic criteria for YARS1 deficiency have been published.

Suggestive Findings

YARS1 deficiency should be considered in probands with the following clinical and imaging findings and family history. Clinical findings

• Premature birth (typically 27-31 weeks' gestation)

• Growth

• Intrauterine growth restriction (z score = 2.95 to 1.95)

• Poor postnatal linear growth and weight gain

• Neurologic

• Developmental delay or intellectual disability of variable degree

• Hypotonia with impaired gross motor function

• Impaired fine motor development

• Impaired speech development

• Acquired microcephaly

• Gastrointestinal

• Feeding difficulties

• Gastroesophageal reflux disease

• Recurrent vomiting

• Exocrine pancreatic insufficiency in severely affected individuals

• Liver disease

Source: GeneReviews — "YARS1 Deficiency"

Differential Diagnosis

Given the protean manifestations in affected individuals, the genetic differential diagnosis of YARS1 deficiency is unavoidably broad and includes other early-onset multisystem disorders including the following:

• Mitochondrial disorders (See Primary Mitochondrial Disorders Overview.)

• Metabolic disorders with liver involvement

• Disorders involving members of the aminoacyl-tRNA synthase family of enzymes, almost all of which are associated with developmental delay, hypotonia, and poor growth. Note that liver disease is a prominent feature in MARS1, LARS1, and IARS1 deficiencies .

Note: Congenital cytomegalovirus infection, which is associated with hepatosplenomegaly, microcephaly, poor growth, hearing impairment, vision impairment, and developmental delay, can mimic YARS1 deficiency.

Source: GeneReviews — "YARS1 Deficiency"

Management Guidelines

No clinical practice guidelines for YARS1 deficiency have been published. The following recommendations are based on the authors' personal experience managing individuals with YARS1 deficiency.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with YARS1 deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

YARS1 Deficiency: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Growth

| Eval of weight, height, OFC |

Neurologic

| Comprehensive neurologic exam by pediatric neurologist | • To incl brain MRI if not performed at time of initial eval

• Consider EEG if seizures are a concern.

Gastrointestinal/

Feeding difficulties

| Eval by nutritionist, feeding team, or OT | In case of poor feeding:

• Evaluate total caloric protein intake to assure sufficient protein intake (≥2 g/kg/day and up to 3 g/kg/day);

• Consider eval for gastrostomy tube placement in children w/dysphagia /or aspiration risk.

Hepatic involvement

| By hepatologist | To incl assessment of:

• Liver size echogenicity

• Transaminases

• Liver function

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Evaluate preschool-age children to determine eligibility for an early intervention program school-age children for an IEP.

Speech/Language

| Eval by speech-language pathologist/therapist |

Musculoskeletal

| Orthopedics/ physica...

Source: GeneReviews — "YARS1 Deficiency"

Clinical Guidance

Avoid the following:

• Catabolism and insufficient protein intake (i.e., less than 1.5-2 g/kg/day)

• Prolonged fasting given the increased risk of hypoglycemia

• Fever

Source: GeneReviews — "YARS1 Deficiency"

Therapies Under Investigation

YARS1 deficiency belongs to the group of aminoacyl-tRNA synthetase (ARS) deficiencies. Other ARS deficiencies include MARS1, LARS1, IARS1, SARS1, and FARBSB deficiencies. tested the effect of high-dose supplementation with the respective amino acids (lysine, isoleucine, serine, and phenylalanine) for one individual with LARS1 deficiency, one individual with IARS1 deficiency, one individual with SARS1 deficiency, and one individual with FARBSB deficiency for five to 32 months.

Source: GeneReviews — "YARS1 Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in are recommended. Table 4. YARS1 Deficiency: Recommended Surveillance

Source: GeneReviews — "YARS1 Deficiency"