Batten Disease May Share Features of Rett Syndrome

Genetic testing confirmed Batten in two girls, case report shows

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Some cases of Batten disease may present with clinical features of Rett syndrome, including Rett’s hallmark repetitive hand movements, according to a recent case report concerning two young girls.

Features that helped distinguish Batten disease in these girls included vision loss, early brain shrinkage (atrophy), and evidence of disease-specific deposits in the skin, according to researchers.

Genetic testing eventually confirmed that girls had mutations in either CLN1 or CLN6 genes, both of which are known causes of Batten disease, but lacked mutations in MECP2, the cause of Rett syndrome.

“Physicians should suspect and investigate for [Batten] disease in patients with Rett-like [features] who are negative for MECP2 mutation, especially in patients with visual impairment and early prominent brain atrophy,” the researchers wrote.

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New Model for Classifying Types of Batten Disease Proposed

The case study, “Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand,” was published in Pediatric Neurology.

Batten disease, also called neuronal ceroid lipofuscinosis (NCL), refers to a group of inherited neurological diseases marked by the buildup of fat and protein deposits called lipofuscins in the body’s cells, especially nerve cells.

Mutations in one of 14 genes — CLN1 through CLN14 cause the different types of Batten. Common symptoms include vision loss, motor and cognitive decline, and seizures.

There is some overlap between Batten symptoms and those of other neurodevelopmental disorders, including Rett syndrome.

Like Batten, Rett is characterized by developmental regression and seizures. However, a hallmark of Rett is the presence of repetitive hand movements such as hand-wringing or squeezing. The disease is caused by mutations in the MECP2 gene, and usually seen in girls.

A few studies have reported symptoms of Rett syndrome in people with Batten disease, specifically the CLN1 and CLN7 types.

Case reports from Thailand

Now, researchers in Bangkok, Thailand, described the cases of two girls who presented with Rett-like symptoms, but were found to have Batten.

The first case involved a girl who was 19 months old. Her parents, who were related, reported she was developing normally up to 13 months of age, when she got the flu and started to show motor and cognitive declines.

Symptoms included a loss of fine motor skills, walking and speaking problems, as well as repetitive hand-wringing — Rett’s hallmark feature.

Upon examination, the researchers found she also had progressive microcephaly, or a smaller-than-normal head, and was unable to visually fixate or follow an object. Abnormally high muscle tone (hypertonia) and overactive reflexes (hyperreflexia) also were present.

While her symptoms were suggestive of Rett syndrome, genetic testing showed no mutations in the MECP2 gene.

Further examination revealed signs of Batten disease, including impairments in the eye’s retina (the thin layer that senses light), early brain shrinkage, and skin deposits consistent with lipofuscin buildup.

More genetic testing

Additional genetic testing revealed the girl had a previously unknown mutation (c.629_630dupGT) in both copies of the CLN1 gene, also known as PPT1, confirming a CLN1 disease diagnosis after other potential conditions were ruled out.

She developed seizures at age 2.5 years that progressed in severity. She was treated with three anti-seizure medications, but was bedridden and experiencing daily seizures as of her last follow-up.

The other girl, age 7.5 years, also was born of related parents. She had similarly experienced developmental regression over the past two years, including progressive ataxia, or poor muscle control, leading to problems with voluntary movement.

By age 5, she was experiencing multiple seizure types, and in the following year she showed a gradual loss of motor and cognitive skills.

Clinical examination revealed microcephaly, visual impairments, hypertonia, hyperreflexia, muscle jerking during movement, and repetitive hand-wringing. Notably, her sister and cousin had similar symptoms.

As with the first patient, abnormal retinal function, generalized brain shrinkage, and evidence of lipofuscin buildup under the skin hinted at a Batten diagnosis.

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EEG or MRI Alone Not Enough to Diagnose CLN2, Panel Agrees

Genetic testing in both the girl and her affected sister revealed a known disease-causing mutation (c.794_796delCCT) in both copies of the CLN6 gene, confirming a diagnosis of CLN6 disease. Notably, Rett-like symptoms, including hand-wringing, have not been reported previously in this Batten type, the researchers noted.

The girl later lost her ability to walk, and developed more muscle stiffness and spasms, with multiple contractures since age 8. She received treatment for seizures and muscle spasms.

“These findings emphasize the consideration of CLN in Rett syndrome with negative MECP2 mutation, especially when the patient has visual impairment,” the researchers wrote, noting that visual impairment and early, prominent brain shrinkage are distinguishing features of Batten.

“Further investigations, such as [retinal activity test] and skin biopsy, are also helpful for supporting a diagnosis of CLN before confirmation by genetic testing,” they added.

“Even though there is no definitive treatment for the diseases, a definitive diagnosis with overlapping clinical features is crucial because it is required to provide genetic counseling and family planning,” the team concluded.