On a snowy April morning in 2013, our daughter Hayden was born. It was a scheduled caesarean section, as the little lazy bones would not roll over. She had a full head of dark curly hair, was a quiet baby, slept through the night very early and didn't feed very well from day one. Looking back now, I realise that some of her characteristics were indicative of her epilepsy that hadn't reared its ugly head yet; but in the early months with our first baby, we thought she was just "a good baby."
When Hayden was approximately three months of age, I remember calling my mother, reporting Hayden having exaggerated "startle reflexes." When lying down, her arms would jerk outwards, accompanied by blinking. Sometimes the jerks were strong enough that she would have a look of fright in her eyes. In my heart I knew something was wrong. When visiting my parents, my father, an optometrist for over 30 years, noted Hayden had strabismus, episodes of nystagmus, and that she had difficulty tracking objects. We got a referral to an ophthalmologist, but never made it to the appointment.
One night in the bath, Hayden's jerks were so big and aggressive they made her cry out. As new parents, we were still filming her bathtime, and my husband recorded it. We went to the local emergency department with phone in hand. We are ever so grateful for the emergency physician and locum paediatricians that were on shift that night. Instead of passing us off as nervous new parents, they took the time to hear our story and watch the video. The paediatrician believed there was a possibility that the movements were a seizure, as part of a diagnosis of Infantile Spasms or West Syndrome. She referred us to The Hospital for Sick Children, in Toronto, Ontario for follow up.
Over the next 17 months, Hayden underwent every test available in the neurology department, cardiology, genetics and metabolics. Her seizures were relentless. Her bad days consisted of myoclonic jerks up to 200 per day. Her best days were small clusters of myoclonics, about 20-40 per day. Hayden also had prolonged status seizures a few times a month that would land her in the local emergency department. She developed multiple seizure types: myoclonic, generalized tonic clonic, clonic, absence, apneic, and activity arrest. The diagnosis of Infantile Spasms was ruled out with her first EEG, which was a relief at the time. However, they couldn't find a genetic cause for her epilepsy. They said she was one in a million.
She lost her ability to eat and had a feeding tube inserted into her belly for nutrition, fluids and medications. She had so many needle pokes and intraosseous accesses, she had a port-a-cath inserted for easy, safe and consistent intravenous access. After failing five antiepileptic medications, we attempted the ketogenic diet.
Finally!! Some improvement!! But unfortunately, with some seizure control, and even a few seizure-free days, came a cardiac arrhythmia. During a prolonged seizure, Hayden's heart rate would climb into the 200s and stay there for hours. Her arrhythmia did not respond to the usual medications and she was often airlifted to the paediatric hospitals hours away. So we tried two more antiepileptic drugs, begged for cannabidiol oils, and enjoyed the good days when we had them.
On a snowy January morning, our daughter Hayden left our world. She left a hole in the heart of everyone she met in her short life. She had the best laugh. She would laugh so hard, a giggle would get caught in the back of her throat and erupt like a volcano. Her laugh was deep and hearty, not a "little girl laugh." Her beautiful thick, dark curly hair turned blonde and went for miles; the only one year old I've ever met that could sport a top knot. She remained our "lazy girl", not rolling or moving very much. She loved to cuddle and would sit on your lap for hours. After treasuring our daughter for 22 months, it turned out my husband and I were wrong, she wasn't "a good baby": she was the best.
hayden's genetics results
Sequencing analysis has shown that Levi is compound heterozygous for the C.254_257delACAG likely Pathogenic Variant and the p.(C192Y) Variant of Uncertain Significance in the CRELD1 gene.
c.254_257delACAG: p.Asp85ValfsX6 in exom 2 in the CRELD1 gene (NM_015513.4). The normal sequence with the bases that are deleted in brackets is: AAAG(delACAG)gtaa, where upper case letters denote exonic sequence and lower case letters denote intronic sequence.
p.Cys192Tyr (TGT>TAT): c.575 G>A in exon 5 in the CRELD1 gene (NM_015513.4).
For this gene, 100% of the coding region was covered at a minimum of 10x. There is no indication of a multi-exon deletion/duplication involving this gene in the sequencing data.
Levi's mother and sibling Levi are heterozygous for the c.254_257delACAG variant in the CRELD1 gene. Hayden's father and sibling Levi are heterozygous for the p.(C192Y) variant in the CRELD1 gene.
The c.254_257delACAG variant in the CRELD1 gene has not been reported previously as a pathogenic variant nor as a benign variant. The c.254_257delACAG variant causes a frameshift starting with codon Aspartic acid 85, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Asp85ValfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.254_257delACAG variant is not observed in large population cohorts and is likely a pathogenic variant.
The C192Y variant in the CRELD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant. The C192Y variant is observed in 47/1266)) (0.037%) alleles from individuals of non-Finnish European background in large population cohorts, and no individuals are reported as homozygous. The C192Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret C192Y as a variant of uncertain significance.