HELLO!
If you are a caregiver of a child impacted by PACS2 mutation, you will find here handy information on the syndrome which - hopefully - will help you work on your child development.
If you are an "experienced" caregiver, a scientist or a physician caring for PACS2 children and you would like to correct any of the information below or enrich it, please do not hesitate to contact us!
We aim to ensure the best & most current data for caregivers of children with PACS2 mutation.
PACS2 mutation
First publication on PACS2 mutation comes from 2018. Since then, ca. 20 cases were covered in publications and around 40-50 people (mainly children) around the globe have heard diagnosis connected with this mutation. Nevertheless, it is hard to diagnose PACS2 syndrome as the phenotype is not strictly specific and currently the most common way to learn about the mutation is to perform whole exome sequencing.
This is quite exceptional, single variant mutation - in most of the cases it occurs in the same place c.625G>A (p.Glu209Lys) (in just few ones: c.631G>A (p.Glu211Lys)) leading to change of one protein - coding lysine instead of glutamate. At the same time, it is heterozygous variant what means that mutation impacts only one allele while the other one works correctly. Unfortunately, its pattern is autosomal dominant meaning that mutation in just one allele is leading to disease. Almost all the cases are de novo - it is not inherited from parents. Except for one case featured just in February 2022 (LINK). At least it is what we know for now.
PACS2 syndrome phenotype
PACS2 mutation leads to developmental and epileptic encephalopathy (DEEs).
General phenotype:
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neonatal seizures - usually first symptom observed; in most of the cases focal seizures occuring in first two weeks of life; still there are few children having generalized seizures later in life (3rd-4th month)
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varying degree of cerebellar dysgenesis causing hypotonia and potential problems with fine and gross motor skills, such as coordination disorders or delayed and unstable walk
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intellectual disability from low-average intelligence (1 case reported to have IQ = 85 -> see publication from Taiwan, Mar 2023 and 1 case with learning disabilities -> see publication from Italy, Feb 2022) to severe
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psychomotor developmental delay
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facial dysmorphism (in many cases almost unnoticable)
In most of the cases / many of them also:
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autism spectrum disorders
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eyesight problems
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hematology disorders
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growth disturbance (some caregivers reported that the pituitary gland is impacted)
Also reported:
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abnormal heart structure
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submucosal cleft palate (can impact both speech and acceptance of solid food)
PACS2 treatment
Please be aware that below statements are caregivers' experiences mixed with publications' outcomes, not official medical recommendation. As each case is different, it has to be consulted with your physician. Nevertheless we hope it may help in finding right treatment for your child.
Epilepsy management - there is no one treatment scheme and caregivers' experiences heavily vary:
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carbamazepine / oxcarbazepine seams to be efficient solution in many cases, able to control seizures in monotherapy
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recently high dosage of pyridoxine was reported as a solution for uncontrollable seizures LINK
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sodium valproate / valproic acid also is widely used and for some children works well, however those cases require closer observation as it impacts hematology (same as mutation itself) and there are cases reported when valproic acid worsened the situation (LINK)
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levetiracetam gives differential results - tried by many but could not control seizures; in publications usually in polytherapy with valproic acid;
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phenobarbital - some parents reported that they observed negative impact on development
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other medications being a solution in individual cases (often in polytherapies): vigabatrin, topiramate, clobazam, lamotrigine, nitrazepam
Ketogenic diet produces different outcomes - we know only two children who tried it:
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for one being 4 years old it worked very well, controlling seizures (earlier uncontrollable) without medicine
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for the other it was ineffective in the early months - infant case (LINK)
Development support - as the mutation impacts mainly motor skills and speech and can cause autism spectrum disorders, ongoing stimulation of patients' development focuses on:
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speech therapy (if your child is diagnozed as a baby, it is worth to consult speech therapist before introduction of solid food as expanding the diet is a challenge for many of PACS2 children and it impacts later speech development)
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alternative communication - do not worry, it does not interfere with speech therapy or even can support it, while some parents reported that they regret focusing on speech therapy only (fighting for each word), because now their children cannot express what they want
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occupational therapy (especially sensory excercises)
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physical therapy (from our side we can recommend Vojta which is neurological method widely known in Europe and for many children with genetic disorders ensures accelerated development)
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interactions with other children ;) - it can especially stimulate speech, it was recommended to us by experienced neurologist
Other links
Great compendium on molecular biology - if you have just heard diagnosis and would like to understand more of medical statements, it is what helped us a lot at the start: Matt Might’s An Algorithm for Precision Medicine