Case report:
A five-year-old middle eastern female of healthy and consanguineous (first cousin) parents with no family history, and unremarkable perinatal history. At the age of 4 months, parents noted generalized tonic seizures with up rolling eyes and cyanosis lasted 4 minutes. Similar episodes reoccur two to three times a month. However, routine electroencephalogram (EEG) was normal. Given the frequency of these episodes, she was started on levetiracetam, but ultimately achieved anti-seizure medication (ASM)-free seizure by the age of 1 year. She had hip imaging in newborn period showing shallowing of left acetabulum, and repeated images at 1 year of age showed clearly bilateral developmental dysplasia of the hip (DDH). Her early gross motor development was normal up to one year apart of her tip-toeing. Around 15 months, the patient’s mother noted gross motor regression of unclear etiology. She became unable to stand or walk alone. She eventually regains her ability to stand alone but not walking independently. At two years, bilateral cataracts were identified and removed surgically, with intraocular lens implementation. At that time, she was also referred to orthopedics and neurology clinics but not until the age of 3 she was evaluated by both specialty and diagnosed with spastic diplegia and repeated hip x-ray showed bilateral subluxed hip with acetabular dysplasia. Physical therapy and gait training were immediately initiated, and brace was applied. However, she had no improvement and bilateral pelvic osteotomy and hamstring and adductor release at four years were required. She consistently held an appropriate language development; babbling at six months, said her first word at 13 months, and spoke in two-word sentences at two. Currently, she can stand alone and walk using walker, her speech, cognitive and fine motor development are continuing to be appropriate for her age, and she is performing well in kindergarten. Faltering growth was noted around the age of five, when she drops from the 42nd percentile for weight to the 2nd percentile over 9 months period, despite adequate caloric intake and no evidence of loss or malabsorption. Her height continues to range between 11th-18thpercentile, and her head circumference is above 85thpercentile.
Neurological examination showed grade 2 spastic Achilles tendon based on Ashworth scale, mild weakness (4/5) in her upper and lower limbs, and clonus in both ankles. She had scissoring gait with toe walking.
Brain MRI, magnetic resonance spectroscopy (MRS) and spin MRI were normal. Basic metabolic work up was unremarkable and mitochondrial genome was negative. Exome Sequencing (ES) analysis showed heterozygous de novo pathogenic variant c.1438C>T (p.Arg480Cys) inFAR1 gene. The de novo status confirmed based on trio diagnostic settings.
Discussion :
Here we report the first middle eastern patient with confirmed autosomal dominant form of FAR1-related disease. Ferdinandusse et al. identified 3 different heterozygous de novo variants affecting the same arginine at amino-acid position 480, of FAR1 , underlying the newly described autosomal dominant CSPSD in 12 patients (Ferdinandusse et al. 2021). Our patient de novo variant was found again at the 480 site, confirming a markedly increased degree of mutability of this site. The heterozygous variant c.1438C>T (p.Arg480Cys) in our patient has been reported in seven patients, heterozygous variants, c.1439G>A (p.Arg480His) in four patients, and c.1439G>T (p. Arg480Leu) in one patient.
Including our patient, we bring the total number in the literature to 13 patients with CSPSD disorder. Pyramidal tract dysfunction is uniformly involved (100%), including spastic features (13/13), axial hypotonia (7/13), and clonus in (6/7). All 13 patients exhibit bilateral cataracts; 5 patients were diagnosed since birth and 8 patients were undetected until later in childhood, demonstrating the importance of baseline ophthalmological evaluation at the time of diagnosis and continuous follow up thereafter. Early onset epilepsy occurred in 9/13 patients and appeared well controlled with ASM. Out of the 9 patients, 5 were achieved ASM-free seizure. Gross motor skills were the mostly affected in all patients, followed by speech delay in (11/13) patients, and dysarthria in 5 patients. Eventually, walking with assistance was achieved in (12/13) patients, and 6 patients achieved fluency in speech. Cognitive impairment was identified in (3/13), though below average IQ, and memory impairment were identified in 1 patient each. Faltering growth was noted only in our patient, although feeding difficulties, and dysphagia have been reported in 1 patient each. Further, constipation was diagnosed in 5/13 patients. Given the small number of cases, it is difficult to determine if gastrointestinal and growth problems is a possible feature for this condition. In addition, DDH and worsening spasticity failed medical management due to delayed diagnosis and access to orthopedic care in our case, highlighting the importance of early diagnosis and referral to initiate early intervention. Physical therapy to control spasticity and medical management to treat pre-existing conditions may minimize long-term patient disability and the need for surgical intervention. Macrocephaly was identified in two patients, and our patient showed relative macrocephaly. Neuroimaging was obtained for all 13 patients with only mild findings identified inform of ventricular prominence and abnormal temporal lobe morphology, and benign enlargement of subarachnoid spaces in 1 patient each. Dysmorphic facial features were only seen in 1 patient including a flat facial profile, full cheeks, deep-set eyes and absence of incisors. Summary of the clinical manifestations of the 13 patients presented in Table1.
In summary, it is important to report and discuss new cases in rare newly described syndromes to delineate the phenotype of the condition. Mutations in FAR1 should be considered in patients with infantile seizure, and spasticity even in the absence of a family history to ensure early diagnosis and intervention.
Table 1. Summary of the clinical manifestations of the 13 patients with CSPSD