New MFSD8 mutation identified in girl with CLN7 disease

Multidisciplinary approach led to diagnosis of this form of late-infantile Batten disease

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A new mutation in the MFSD8 gene was identified as the cause of CLN7 disease, a form of late-infantile Batten disease, in a young Italian girl with developmental regression and a smaller-than-normal head, a case report shows.

“Our case is discussed to highlight the pivotal role of clinical genetics, and of a multidisciplinary evaluation, in driving a linear, unequivocal and not time-consuming diagnostic procedure” for CLN7 disease, the researchers wrote.

The case study, “Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in MFSD8,” was published in the journal Genes.

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Batten disease comprises a group of inherited, progressive conditions characterized by the toxic buildup of a material called lipofuscin inside cells, which is particularly damaging to brain and eye cells. There are different types of Batten disease, each caused by mutations in different genes.

CLN7 disease is a form of late-infantile Batten caused by mutations in both copies of the MFSD8 gene, which impair the function of lysosomes, the cells’  recycling centers.

“Since the initial identification of the causative gene in 2007, more than 50 different MFSD8 variants responsible for CLN7 [disease] have been reported in the literature,” the researchers wrote.

CLN7 disease patients usually develop symptoms when they are 2 to 7 years old, including developmental delay, motor and coordination problems, cognitive impairment, vision problems, and seizures.

Now, a team of researchers in Italy described the case of a 5-year-old girl whose CLN7 disease was found to be caused by a previously unknown MFSD8 mutation.

She was born to healthy and apparently unrelated parents from a village on the island of Sicily. She had an older brother who was healthy.

The girl first visited a neurologist when she was about 1 year old due to episodes of tremor in her left lower limb. Later, at age 3, her motor skills began to decline and she showed balance difficulties, slowness of movement, and walking problems. Speech had not progressed beyond the first words.

“As reported by parents, she also developed mild behavioral abnormalities, including poor interest in peers and occasional motor [stereotypies],” the researchers wrote. A motor stereotypy is a rhythmic, purposeless movement with a fixed pattern.

Condition worsened

Her worsening condition required hospitalization in the researchers’ child neurology department, where “she immediately underwent a multidisciplinary assessment, including neuroimaging, neuro-cognitive scale grading, metabolic disease screening and clinical genetic evaluation,” the team wrote.

Magnetic resonance imaging of the brain showed shrinkage in both sides of the cerebellum, a brain region that helps coordinate motor movement. It also revealed lesions in an area that relays motor and sensory information between the brain [here] and spinal cord, and in the thalamus, a region that helps transmit signals through different parts of the brain.

An electroencephalogram, which measures the brain’s electrical activity, revealed discharges indicative of atypical absence seizures, which can involve a period of staring with some minor responses or additional movements.

The results of blood and urine testing came back normal, but an eye examination revealed poor vision “without any identifiable reason,” the team wrote.

At the time of the first genetic counseling, when she was about 4.5 years old, the girl clearly presented a smaller-than-normal head, or microcephaly, and other “peculiar characteristics,” such as “rounded nasal tip, thin nasal bridge and deep-set eyes,” the researchers wrote.

Two copies of MFSD8 mutation

Genetic testing revealed that the girl carried two copies of a MFSD8 mutation that had never been reported before in the literature. Both parents carried one copy of the same mutation, called c.863+2dup.

Further molecular analyses showed that the mutation resulted in exon 8 absence from messenger RNA (mRNA), an intermediate molecule derived from DNA that guides protein production. Exons are the sections of genetic information needed to make proteins; much like in a puzzle, they are pieced together in mRNA.

Exon 8 absence prevented the production of a full-length, working protein, prompting the researchers to classify the genetic variant as likely disease-causing.

“In describing the diagnostic procedure, we aim to highlight the pivotal role of clinical genetics, integrated with a multidisciplinary assessment and mRNA analysis, in reaching a linear and unequivocal diagnosis of CLN7,” the researchers wrote.