Clinical Guidance

It is difficult to establish a genotype-phenotype correlation in FARS2 deficiency given the limited number of affected individuals and the complication of compound heterozygosity in such studies. All 14 individuals homozygous for the most commonly reported variant, , had the infantile-onset phenotype (see Table 9). Although the number of affected individuals reported to date is small, the infantile-onset and later-onset phenotypes have not shared the same genotypes.

Source: GeneReviews — "FARS2 Deficiency"

Diagnostic Criteria

FARS2 deficiency comprises a spectrum of disease severity that ranges between two phenotypes: infantile-onset epileptic mitochondrial encephalopathy and less severe, later-onset spastic paraplegia. Formal diagnostic criteria for FARS2 deficiency have not been established.

Suggestive Findings

The two phenotypes known to date to be associated with FARS2 deficiency are infantile-onset epileptic mitochondrial encephalopathy and later-onset spastic paraplegia. FARS2-related infantile-onset epileptic mitochondrial encephalopathy should be considered in children from birth to age six months with the following clinical, laboratory, and imaging findings.

Clinical findings

• Seizures

• Developmental delay

• Truncal hypotonia

Laboratory findings

Source: GeneReviews — "FARS2 Deficiency"

Differential Diagnosis

Phenotypic features associated with FARS2 pathogenic variants are not sufficient to diagnose FARS2 deficiency. For children with a phenotype consistent with infantile-onset epileptic mitochondrial encephalopathy, all genes known to be associated with early-infantile epileptic encephalopathy (65 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis. For individuals with later-onset spastic paraplegia, all genes known to be associated with complicated spastic paraplegia (see Hereditary Spastic Paraplegia Overview) should be included in the differential diagnosis.

Source: GeneReviews — "FARS2 Deficiency"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FARS2 deficiency, the evaluations summarized in and (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy

System/Concern | Evaluation | Comment

Constitutional

| Assess height, weight, head circumference. | FTT is a significant issue for all patients.

Neurologic

| Assess for seizures. | Seizures are usually focal but other forms are possible. EEG usually shows multifocal epileptic discharges.

Assess for myoclonus. | Eye facial twitching; myoclonic jerks of extremities

Assess for hypotonia. | Axial hypotonia could be assoc w/appendicular hypertonia.

Development

| Developmental assessment | Incl assessment of age-appropriate motor, speech/language, cognitive skills

Ophthalmologic

| Assess visual acuity. | Central visual impairment (i.e., w/o retinal or optic nerve changes) is common.

Musculoskeletal

| Physical medicine rehab/ PT OT eval | Assess tone spasticity.

Gastrointestinal/

Feeding

| Gastroenterology/ nutrition/ feeding team eval | Assess swallowing, feeding, nutritional status to determine safety of oral vs gastrostomy feeding.

Assess for evidence of hepatic involvement. | Liver enzymes hepatic ultrasound exam

Respiratory

| Assess airway, pulmonary function, secretion mgmt. | Sleep study to assess for apnea

Source: GeneReviews — "FARS2 Deficiency"

Clinical Guidance

Valproic acid can induce liver failure in persons with mitochondrial diseases . Some individuals with FARS2 deficiency received valproic acid and showed no evidence of liver dysfunction or worsening of existing liver disease . Given the limited number of affected individuals reported to date, no general recommendation can be made.

Source: GeneReviews — "FARS2 Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "FARS2 Deficiency"

Surveillance Guidelines

Individuals with FARS2 deficiency should be evaluated periodically by an interdisciplinary team that includes a neurologist, clinical geneticist, physiatrist, and developmental specialist to assess disease progression ( and ), to maximize ambulation and communication skills, and to reduce other manifestations. Table 7. Recommended Surveillance for Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy

Source: GeneReviews — "FARS2 Deficiency"