Inspired by a patient
A four-year-old from Inver Grove Heights is one of just a few hundred kids in the world with a rare genetic disorder. Mae Knopik has what is known as CTNNB1 Syndrome, a genetic disorder that is associated with developmental delays and cognitive impairments.
Mae is nonverbal and needs help walking.
“I want to hear her talk. I want to watch her walk unassisted. Will that happen? I don’t know. I’m hopeful, you have to stay hopeful,” said her dad Joe Knopik.
Since CTNNB1 Syndrome is so rare, it is still somewhat of a mystery to doctors and there is no real road map for Mae’s journey.
“It’s such a new diagnosis that we don’t actually know the natural history of what this disease looks like,” said Dr. Amy Authement with Gillette Children’s Specialty Healthcare.
“What I always tell my families is that they are the experts in their child’s disease,” she said.
Which is one of the reasons the Knopiks are sharing their story. They are hoping more awareness will lead to more research, which could one day lead to a cure.
The Knopiks are hoping to take place in a genetic therapy clinical trial in Europe this summer. They will find out in early 2025 if Mae has been selected as a candidate. For more information on Mae’s journey, visit Mae’s Mission. (see below)
https://kstp.com/kstp-news/top-news/inver-grove-heights-parents-hope-to-raise-awareness-spark-research-surrounding-their-daughters-rare-disease/
Mae is a 4 year old Minnesota girl who was diagnosed with a very rare genetic disorder, CTNNB1 Syndrome when she was 1.5 years old. It is so rare that there are just over 430 known diagnosed cases in the world. The CTNNB1 gene is in charge of producing a crucial developmental protein called beta-catenin. Because CTNNB1 Syndrome lacks creating enough beta-catenin, the symptoms that these children experience are detrimental to their development. Many kids including Mae, have developmental delays, intellectual/cognitive disabilities, gross and fine motor delays, sleeping issues, behavioral issues, and struggle with talking or communicating. Since Mae’s diagnosis in December of 2021, she has been in physical therapy, speech therapy, and occupational therapy and has undergone many procedures, tests, and surgeries. With all odds stacked against her, she is one determined little girly with a big personality and contagious laugh to match!
Mae’s Mission is to raise awareness about CTNNB1 Syndrome, bring accessibility to communities, and help fundraise for ongoing research.
https://maesmissionmn.org/
Freeman M, Fakhori N, Monteil D. Progressive spasticity and developmental delay in an infant with a CTNNB1 mutation. BMJ Case Rep. 2024 Jun 13;17(6):e260856. doi: 10.1136/bcr-2024-260856. PMID: 38871641.
Abstract
We present an infant referred to Developmental Paediatrics for delays, slow growth, hypotonia, esotropia and spasticity. Over the course of 2 months, the infant's exam progressed, demonstrating worsening spasticity and tonal changes in the setting of a normal brain MRI with acquired microcephaly. Genetic testing demonstrated a pathogenic CTNNB1 nonsense mutation. Following the discovery of the underlying cause for the child's clinical picture, the child was evaluated by therapeutic services and neurology, which was initially only available via asynchronous telehealth, due to a resource limited area. Cerebral palsy is a nonprogressive neurodevelopmental disorder and, when associated with developmental delay, qualifies for further genetic investigation into the underlying aetiology. Genetic testing recommendations exist for developmental delay, but there is no current algorithm regarding testing for cerebral palsy. Education and clear guidelines on genetic testing allow for better prognostication and potential treatment in cases of cerebral palsy, especially when associated with other disorders.
Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A. 2014 Jun;164A(6):1571-5. doi: 10.1002/ajmg.a.36484. Epub 2014 Mar 25. PMID: 24668549.
Abstract
A girl patient born to healthy nonconsanguineous parents was referred at age 3 years and 2 months to our genetics department for testing due to developmental delay and postnatal microcephaly. Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin. Postnatal microcephaly and progressive ataxia and spasticity appeared later. Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin. β-catenin is a sub-unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report. Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice. Point mutations in CTNNB1 in human have recently been reported but this is the first observation of a new recognizable multiple congenital anomaly/mental retardation syndrome caused by CTNNB1 haploinsufficiency. This clinical report should prompt a search for point mutations in CTNNB1 in patients presenting developmental delay, mild hair, skin and facial anomalies, and neurodegeneration characterized by postnatal microcephaly, and progressive ataxia and spasticity.
Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, van den Boogaard MJ, Bramswig N, Büttner C, Cremer K, Czeschik JC, Engels H, van Gassen K, Graf E, van Haelst M, He W, Hogue JS, Kempers M, Koolen D, Monroe G, de Munnik S, Pastore M, Reis A, Reuter MS, Tegay DH, Veltman J, Visser G, van Hasselt P, Smeets EE, Vissers L, Wieland T, Wissink W, Yntema H, Zink AM, Strom TM, Lüdecke HJ, Kleefstra T, Wieczorek D. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015 Jan;134(1):97-109. doi: 10.1007/s00439-014-1498-1. Epub 2014 Oct 19. PMID: 25326669.
Abstract
Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
