This research highlights the importance of an appropriate clinical follow‐up to ensure an accurate diagnosis, as some patients with genetic metabolic diseases may initially show symptoms that resemble those of Rett syndrome.
The study, “Rett and Rett‐like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene,” was published in the journal Molecular Genetics & Genomic Medicine.
Rett syndrome is mostly caused by mutations in the MECP2 gene. Alterations in the CDKL5 and FOXG1 genes have been linked to atypical types of the disease, where symptoms do not meet all the diagnostic criteria for Rett syndrome.
Still, some individuals with overlapping signs and symptoms test negative for genes commonly associated with the disorder.
A team at Peking University First Hospital in China assessed the genetic cause of disease in 44 patients, ages 13 months to 12.5 years, with Rett syndrome or Rett-like features, but without mutations in the MECP2, CDKL5, or FOXG1 genes.
Overall, the group consisted of 21 patients with typical Rett syndrome, 19 with Rett‐like symptoms, and four with atypical Rett syndrome.
Genetic testing on blood samples was done using next-generation sequencing — an advanced technique that allows the rapid DNA sequencing of multiple genes — targeted to 512 gene candidates.
This method allowed the identification of genetic variants causing Rett syndrome in 14 patients (31.8%).
Apart from two MECP2 variants missed by prior conventional sequencing methods, the assessment identified variants in other nine genes.
Two genes were associated with Rett syndrome for the first time. A 13-month-old girl, conceived via in vitro fertilization, had typical Rett syndrome caused by a mutation known as c.275_276ins AA, p. Cys92 in the KIF1A gene.
She had delayed development, could not walk independently, and was unable to speak. She had lost hand skills, made stereotypic (repetitive) movements such as hand clapping, and exhibited sleeping and breathing issues. She also had microcephaly — a smaller-than-normal head.
Another child, a 4-year-old girl with atypical disease, had a mutation referred to as c.2337C > A, p. Val793Phe in the GRIN1 gene. She had epilepsy from 2 months of age, accompanied later by developmental delay, difficulty speaking, stereotypic movements, and gradual loss of hand skills. She also developed breathing problems.
KIF1A provides instructions for making a protein called kinesin family member 1A, which plays a critical role in maintaining viability and function of nerve cells. This gene could also be linked to MECP2 function through a common target gene called BDNF, which may explain their overlap in causing Rett syndrome, the scientists said.
Mutations in KIF1A have been found in people with a variety of neurological manifestations, including autosomal dominant mental retardation type 9.
GRIN1 provides instructions for a protein subunit of the N‐methyl‐D‐aspartate receptor (NMDAR), which plays a key role in the communication between nerve cells.
Variants in NMDAR subunits are associated with a variety of neurodevelopmental problems, such as intellectual disability, epilepsy, and autism spectrum disorders.
Two different genetic variants in the PPT1 gene were detected in a girl who initially had typical symptoms of Rett syndrome — including microcephaly, stereotypic movements, and breathing problems — but was found later to have neuronal ceroid lipofuscinosis (NCL), or infantile Batten disease.
“It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT [Rett syndrome] and Rett‐like profiles,” the scientists wrote.
“Our findings expanded the genetic heterogeneity of Chinese [Rett] or Rett‐like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow‐up is essential for the diagnosis,” they added.