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