Mollie presented with episodes starting at age 1.5 years. Episodes occurred every 6-8 weeks, lasted about 2 days each, and included vomiting up to every 10 minutes, nausea, discomfort with light and sound, extreme lethargy, weakness (whole body), drooling, and thirst. All episodes in early life necessitated hospitalization. Amitriptyline was started at age 13 years, which stretched the episode frequency to every 8-10 weeks, and decreased episode length by about ½ of a day. About ages 18-25 years, her episodes transitioned to headache with less vomiting. At age 41 years, Mollie began seeing an increase in episodes to once or twice a week. At that time, she had been on the same dose of amitriptyline, 50 mg per night, for over 20 years. Clinical manifestations between episodes included chronic fatigue, constipation, and dizziness on standing. Neuropsychiatric issues include mild-to-moderate intellectual deficits, ADHD, social skill impairment beyond that expected based on intellectual disabilities, and severe anxiety. The family history is significant for hyperemesis gravidarum (nausea and vomiting) in all her mother’s pregnancies, and headaches/migraine in the maternal grandmother.
Mitochondrial-targeted supplements had been provided for years, but at age 40 years the supplement regimen was escalated in the number of agents and dosing by providing SpectrumNeeds® (33 active ingredients), the ubiquinol form of coenzyme Q10, additional B vitamins, (“B100”) including extra riboflavin, vitamin D, magnesium, and fish oil. On this regimen, maintaining the same dose of amitriptyline, episodes dramatically declined, and now consist only of ½ day of headache alone, no more frequent that once a month. Anxiety responded well to the recent addition of sertraline (Zoloft).
Whole genome sequencing (WGS) of Mollie and her parents revealed one copy (heterozygous) of a de novo (not present in either parent)DNA variant, p.Tyr401fs, in the PPM1D gene. The variant causes a frameshift that results in an inactive or absent protein. This gene encodes for a protein in the stress-response pathway. Similar sequence variants in this gene have been associated with Jansen-de Vries syndrome. This syndrome is an excellent match for Mollie, given the features of cyclic vomiting, reflux, longstanding constipation, developmental delay, low tone, broad-based gait, anxiety, myopia, wide mouth with thin upper lip, small hands and feet, small nails, and short stature relative to her family. Gastrointestinal disorders were present in 10/14 cases reported by Jansen et al, 2017 [PMID 28343630], including cyclic vomiting, feeding difficulties, constipation, and reflux.
*RICHARD G. BOLES, M.D.
MEDICAL GENETICIST
CHIEF MEDICAL & SCIENTIFIC
OFFICER, NEURO NEEDS, LLC
DIRECTOR, NEUROABILITIES
NEURO GENOMICS PROGRAM
Disclosure: Dr. Boles is the Chief Medical & Scientific Officer for NeuroNeeds LLC, the start-up company that makes SpectrumNeeds®, EnergyNeeds®, QNeeds®, and CalmNeeds®. You are under no obligation to purchase this or any products, whether recommended by Dr. Boles or another health care provider. As always, it is recommended that you contact your physician regarding these products and all other changes to disease management.
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