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Gene & Protein in Disease Clinical findings of RYR1 mutation

(OMIM:180901) located on chromosome 19q13. Four the ability to walk. He began speaking at approximately
6
types of multiminicore disease with distinguishable the same time as his siblings. No mental retardation was
characteristic signs and symptoms have been identified detected. He was referred to the Department of Pediatric
so far, namely the antenatal form with arthrogryposis, Genetics at the age of 4 years and was followed up in the
classic form, progressive form with hand involvement, Pediatric Neurology Department because of neuromotor
and ophthalmoplegic form. 1,7,8 Herein, we present developmental delay. The patient’s pedigree was drawn
the case of a patient with multiminicore disease who at our clinic (Figure 1). The patient’s weight was 13.7 kg
exhibited a homozygous variant of RYR1 and discuss (−1.51 SD), height was 93 cm (−2.39 SD), and head
the clinical differences between family members with circumference was 51.5 cm (+0.31 SD). Furthermore,
homozygous and heterozygous variants of RYR1 to we observed relative macrocephaly; dolichocephaly;
highlight the genotype-phenotype correlation. posteriorly rotated ears; retrognathia and myopathic

2. Case presentation face; pectus excavatum; joint contractures in the elbows,
knees, and left-hand fingers; simian line on the left hand;
A mother with a factor V Leiden mutation and a healthy partial cutaneous syndactyly on the second and third
father, who were first-degree cousins, had nine natural toes of the left foot; clinodactyly on the second, fourth,
pregnancies. The first five pregnancies were aborted. The and fifth toes of both feet; and cryptorchidism (Figure 2).
sixth pregnancy resulted in the birth of a male infant On neurological examination, the muscle strength was
(weight, 2930 g [−0.7 standard deviation (SD)]; length, 3 – 4/5 in the upper extremities and 2/5 in the lower
47.5 cm (−1.05 SD); and occipitofrontal circumference, extremities. Deep tendon reflexes were diminished in the
35.5 cm [+0,73 SD]) at 38 weeks through cesarean section upper extremities and absent in the lower extremities.
due to decreased fetal movements. He was referred to the No pathological reflexes were observed. There was no
neonatal intensive care unit (NICU) because of respiratory restriction of lateral vision or swallowing dysfunction.
difficulties. However, he did not require mechanical Only one measurement of the creatine kinase level was
ventilation and was kept in the NICU for 39 days. The 377 U/L; the others ranged between 90 and 100 U/L. The
initial examination revealed macrocephaly, micrognathia, alanine aminotransferase, aspartate aminotransferase,
poor sucking reflex, hypotonia, and flexion contracture in and alkaline phosphatase levels were 43, 48, and 189 U/L,
the third finger of both hands. The child was fed through respectively. No pathogenic findings were observed on
an orogastric tube throughout his hospital stay, and he the echocardiogram. MRI of the brain revealed a mega
was discharged home in the same condition. Magnetic cisterna magna malformation. Ultrasound revealed
resonance imaging (MRI) of the brain revealed mega widespread increased echogenicity of the muscles
cisterna magna and a Dandy–Walker malformation. The and decreased volume in the anterior and posterior
child passed away at the age of 1.5 years due to difficulty muscle groups of both thighs as well as in both biceps.
in swallowing, recurrent pneumonia, and respiratory Furthermore, electromyography revealed myogenic
distress. A karyotype analysis of the child’s genes yielded changes. Thus, the family members were advised to
a result of 46, XY. The parents’ seventh and eighth undergo a muscle biopsy. However, they declined it due to
pregnancies yielded two healthy daughters. During the its invasive nature. The child’s previous karyotype analysis
ninth pregnancy, increased nuchal lucency was observed yielded a 46, XY result. The patient’s genomic DNA was
on a prenatal ultrasound. However, aneuploidy was not analyzed using a 40-gene neuromuscular gene panel
detected during amniocentesis. Due to decreased fetal on the Illumina Next Generation Sequencing platform.
movements, the child was born at 37 weeks through a The c.115G>A variant, located on the second exon of
planned cesarean section (weight, 3030 g [+0.17 SD]; RYR1 (NM_000540.3), was homozygous. This missense
length, 47 cm [−0.87 SD]; and head circumference, 35 cm variant, previously reported as heterozygous and of
[+0.7 SD]). He was transferred to the NICU due to a femur uncertain clinical significance, results in the substitution
fracture and subdural hemorrhage that resulted from a of glutamate with lysine at position 39 (Glu39Lys).
fall during the delivery. He did not require mechanical
ventilation. However, he had a poor sucking reflex and was In the segregation analysis, the c.115G>A variant of
fed through an orogastric tube. This feeding method RYR1 was heterozygous in the mother, father, and sister
was continued for 2 months after discharge. Thereafter, (Figure 1; II-2, II-3, and III-7, respectively). The father
he was fed with a bottle. Physical therapy was initiated and sister had not undergone any surgery. The mother
because of the flexion contractures in both hands. He had previously undergone four cesarean sections and one
achieved head control at 5 months and was able to sit tonsillectomy without experiencing any complications
without support at 10 months. However, he never acquired related to general anesthesia.

Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.4748