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Two new mutations in the DNA sequences of children with late childhood Batten disease, a type of neuronal ceroid lipofuscinosis (NCL), were discovered by researchers in Saudi Arabia.

The study with this conclusion, “Neuronal ceroid lipofuscinosis type 8: widening of the diversity of genotypes / phenotypes – first report in Saudi Arabia, ”Was published in Neuroscience.

Batten disease refers to a group of rare inherited neurological diseases that includes 14 known forms, from CLN1 to CLN14. Each form varies with age at onset of symptoms (birth, childhood, or adulthood) and is caused by distinct genetic mutations.

CLN8 disease, a type of late childhood Batten disease, is caused by a deficiency in the CLN8 uncomfortable. The function of the CLN8 protein is unknown, but it appears to reside in a cellular structure called the endoplasmic reticulum (ER), which generates much of the proteins and lipids in cells and may play a role in the transformation of ceramides (a family of lipids that make up cell membranes).

CLN8 disease can be divided into two different subtypes: progressive epilepsy with mental retardation (EPMR) and late infantile variant-NCL (vLI-NCL), with patients classified according to their symptoms.

Three patients of Arab origin, belonging to two unrelated families, were studied based on clinical observations and metabolic tests (such as blood tests and liver function). Magnetic resonance imaging (MRI) – a medical imaging technique that creates detailed images of organs and tissues in the body – has been used to scan patients’ brains. Two of the patients, one from each family, also had DNA samples tested for mutations.

The first patient, a boy, developed normally until the age of 2, after which he began to have seizures which gradually increased in frequency over the next two years. The patient’s seizures were resistant to high doses of two antiepileptic drugs, namely Depakoté (valproic acid) and Keppra (levetiracetam).

At the age of 3, he began to regress in cognition, speech, vision and motor function. He gradually becomes incontinent and develops spastic quadriplegia with ataxic movements (muscle stiffness in all four limbs).

The second patient, a girl, presented with delays in global development, mainly with speech and gross motor skills. At the age of 2, she began to have seizures, an ataxic gait (poor coordination) and falls. The patient’s seizures were refractory even though she was treated with high doses of three antiepileptic drugs, including phenobarbital, Depakote and Keppra.

Subsequently, she began to regress in terms of motor skills, cognition, speech and vision, developing spastic quadriplegia. Four years

The third patient, a boy, was the older brother of the second patient. At the age of 7, he experienced developmental regression, ataxia with frequent falls and seizures. He also suffered from spastic quadriplegia, was bedridden and fed by a gastrostomy tube. He was the only patient who had not undergone genetic testing (he died before genetic testing could be done).

Brain MRI in all patients revealed cerebellar atrophy, a common finding in patients with CNL.

Genetic testing revealed that the children had mutations in the CLN8 gene, so they were diagnosed as having CLN8 disease. One patient had a homozygous deletion in exon 1 (the part of the gene that provides instructions for making a protein) of CLN8 gene, while the second patient had a homozygous mutation in exon 2.

The type of mutation found in both children was homozygous, meaning that there are mutations present in both copies of the gene – the copy inherited from the mother and the copy from the father.

This type of mutation is more common when the parents are closely related. The children in this study were all from first-degree consanguineous marriages (marriage between blood relatives such as siblings), which is more common in Arab regions.

Children in this study were classified as having the disease-specific CLN8 vLI-NCL subset because their symptoms were similar to those of other vLI-NCL cases. The discovery of these two new types of mutations adds to what we already knew about the CLN8 disease.

The authors said their study was unique in that after looking at patient histories, they noted that both families reported multiple miscarriages during the second and third trimesters of pregnancy. One family has also reported premature deaths in the first few months of life with no obvious explanation. This is the first time that miscarriages and premature deaths have been associated with CLN8 disease.

“We stress the importance of early recognition, diagnosis and counseling in NCL patients, especially in Arab regions with a high rate of consanguineous marriages, especially with recent advances in the use of antisense oligonucleotide drugs such as Possible treatment modality for NCL type8 in the future, ”the researchers concluded.

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