Neuronal ceroid lipofuscinoses type 8: Expanding genotype/phenotype diversity-first report from Saudi Arabia

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases that presents in childhood and are characterized by seizures and progressive neurological deterioration, which results in dementia, ataxia, visual failure, and various forms of abnormal movement. The most common form of neuronal ceroid lipofuscinoses is late infantile (LI-NCL), in association with the genes CLN2, CLN5, CLN6, and CLN8. We report the cases of neuronal ceroid lipofuscinoses type 8 in 3 patients from 2 unrelated families, which was confirmed by molecular testing in 2 of them. Multiple spontaneous abortions, early death, and early onset of motor disability were observed in our cases, reflecting a possible association of NCL 8 with other unrecognized neurodegenerative diseases. Our results expand the genotypic/phenotypic background of variant late Infantile-NCL in Arabic ethnicity.

CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report

“…The onset is between 2 and 7 years of age, with rapid developmental regression, ataxia, myoclonus and epilepsy, and a prompt visual failure. Subsequent cases were reported in Turkey [ 18 , 22 ], Italy [ 28 ], Germany [ 29 ], Israel [ 30 ], Ireland [ 31 ], Pakistan [ 22 ], Japan [ 32 ], China [ 33 ], and Saudi Arabia [ 34 ], some showing a milder phenotype. A few highly atypical presentations reported thus far include a congenital NCL in an Argentinian female [ 35 ] and a seizure disorder with retinitis pigmentosa but normal cognition in Hispanic siblings [ 36 ].…”

“…A progressive background slowing is consistently reported. Interictal discharges include a spike-slow wave or polyspike-slow wave complexes and polyspikes [ 29 , 30 , 31 , 32 , 33 , 34 ]. Notably, epileptiform activity is scant in EPMR.…”

“…Our patient’s recordings were dominated by background slowing, and she only recently developed unequivocal epileptiform transients. In imaging studies, cerebellar atrophy is the rule and involves both cerebellar vermis and hemispheres in the majority of cases [ 20 , 24 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Our patient is no different.…”

“Atypical” Phenotypes of Neuronal Ceroid Lipofuscinosis: The Argentine Experience in the Genomic Era

“…DNA variants in the congenital phenotype cause deleterious effects on the sequence or expression of CLN8, such as loss of initial codon, small exonic indels, frameshifts, stop-gain variants, and large chromosomal deletions. [22,51,[68][69][70][71][72] CLN8 forms the EGRESS complex together with protein CLN6, which participates in the lysosomal biogenesis by transporting soluble lysosomal enzymes to the ERGIC compartment. [73,74] In addition, it is involved in the regulation of key proteins for cellular metabolism.…”

“…Interestingly, all these "atypical" cases share pathogenic significant variants (such as c.66_66delG, p.Ile23Serfs*5; c.544-2566_590del2613, p.0; c.562_563delCT, p.Leu188Valfs*58; c.298C>T, p.Gln100*; and c.551G>A, p.Trp184*), suggesting a genotype/phenotype correlation for the CLN8 disease. [22,61,[68][69][70][71][72]…”