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.
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).
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 (eg. Lena in 3rd month)
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
intellectual disability from mild to severe, however only two cases with mild / borderline intellectual disability reported in official publications so far
psychomotor developmental delay
facial dysmorphism (in many cases almost unnoticable)
In most of the cases / many of them also:
autism spectrum disorders
growth disturbance (some caregivers reported that the pituitary gland is impacted)
abnormal heart structure
submucosal cleft palate (can impact both speech and acceptance of solid food)
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:
in case of focal seizures, carbamazepine / oxcarbazepine seams to be efficient (popular especially in US)
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)
levetiracetam gives differential results - tried by many but could not control seizures; in publications usually in polytherapy with valproic acid;
phenobarbital - some parents reported that they observed negative impact on development
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:
for one being 4 years old it worked very well, controlling seizures without medicine
for the other it was ineffective in the early months (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:
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)
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
occupational therapy (especially sensory excercises)
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)
interactions with other children ;) - it can especially stimulate speech, it was recommended to us by experienced neurologist
PACS2 syndrome publications
Italy | Feb 2022 | First reported case of an inherited PACS2 pathogenic variant with variable expression
Spain | Nov-Dec 2021 | New case with the recurrent c.625G>A pathogenic variant in the PACS2 gene: expanding the phenotype
China | Oct 2021 | Clinical and genetic analysis of PACS2 gene variant in two child patients with developmental and epileptic encephalopathy 66
China | July 2021 | Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review
Japan | Feb 2021 | Clinical variations of epileptic syndrome associated with PACS2 variant
Italy | May 2020 | A further contribution to the delineation of epileptic phenotype in PACS2-related syndrome
Italy | April 2019 | Expanding the clinical spectrum associated with PACS2 mutations
International | May 2018 | A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
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