Two young sisters who carry a unique combination of mutations in their CLN8 developed a mild but atypical type of Batten disease, according to a case study.
Both sisters had different mutations in each of their CLN8 genes – one from their mother and one from their father, a pattern of inheritance called a compound heterozygote.
The case study, “CLN8 Heterozygous variants composed of genes: a new case and bioinformatics analyzes of proteinswas published in the journal Genoa.
Mutations in the CLN8 can cause the late infantile form of Batten disease, which occurs in children between the ages of about 2 and 4 years old. It is characterized by convulsions and loss of vision and motor and intellectual abilities.
Epilepsy with progressive mental retardation (PMRE), sometimes called northern epilepsy, is a less severe form of illness caused by CLN8 malformations, the first signs appearing between 5 and 10 years. Symptoms include seizures, intellectual decline, and behavioral changes. Seizure frequency tends to increase until puberty, when cognitive decline will become more rapid.
So far, at least 25 mutations in the CLN8 have been shown to be involved in diseases of the nervous system.
A new combination of CLN8 mutations
In this report, Israeli researchers describe the cases of two sisters carrying a new combination of CLN8 mutations and developed mild but atypical features of the disease.
Both sisters’ parents were otherwise healthy but were first cousins: the mother’s grandfather and the father’s grandmother were siblings. In particular, other parents had been diagnosed with illnesses related to CLN8 malformations, and two siblings from a local but unrelated family also had CLN8 disease.
The older sister, 14,’s early development was normal, except for a diagnosis of attention deficit hyperactivity disorder (ADHD) at age 6. At age 8, she was admitted to hospital due to epileptic seizures. Brain MRI and electroencephalogram (EEG), which measured electrical activity in the brain, were normal.
She was treated with anti-epileptic drugs, but started having absence seizures – sudden brief blackouts. Although his EEG was normal, additional brain imaging showed mild atrophy (shrinking) of the cerebellum, a part of the brain that helps control movement.
Four months later, she began to experience learning difficulties and behavioral problems at school. At age 11, sleep onset attacks developed and MRI showed further cerebellar shrinkage and other abnormalities. Eventually, his gait was unsteady, which worsened over time to a staggering gait at age 13.
Her 12-year-old younger sister also reached early developmental milestones until she was 7 years old when she was diagnosed with a learning disability and ADHD. Shortly after, she had her first seizure with no abnormal EEG findings but with mild cerebellar atrophy.
Months later, she had difficulty walking but had yet to develop staggering walking or other neurological signs.
Genetic analysis of the two sisters revealed two different mutations in each of their CLN8 genes, one inherited from their mother and the other from their father. One mutation, inherited from the mother, was previously identified locally, while the other, inherited from the father, was previously unreported and thought to be pathogenic.
Further genetic testing showed that each parent carried a CLN8 mutation, but both were unaffected.
“We concluded that these compound variants in the CLN8 are most likely the cause of this atypical clinical presentation of CLN8 disease,” the researchers wrote.
To understand the impact of these mutations, the team conducted modeling studies on the protein encoded by the CLN8 embarrassed. Although little is known about the structure and function of the CLN8 protein, it is thought to be involved in protein production, processing and transport.
The previously identified mother CLN8 the mutation resulted in the change from an amino acid glutamine to an amino acid glutamate, two building blocks of proteins, at position 256. Modeling suggested that this change, which introduced a negative electrical charge to an essential part of the protein , affects the stability of the protein or its interactions with other molecules.
the father CLN8 the mutation resulted in the transformation of a tyrosine amino acid into a cysteine amino acid at position 158 of the CLN8 protein. However, the impact of this change on protein function was less clear.
“We report a new case study of two patients (siblings) who present with atypical clinical features of CLN8 disease,” the authors wrote, “caused by a novel heterozygous variant composed of the same gene.”
“The cases in our study confirmed and extended the effect of compound heterozygous variants in CLN8 disease,” they added.
The researchers noted that there is a high rate of consanguineous marriages – unions between related people – in the area where this family lives.
“Therefore, we recommend screening for carriers of the CLN8 genetic variant, as well as the establishment of genetic counseling as a preventive measure, especially in this village”, they concluded.