FamilyLabel: Pineda-Trujillo_Family_1
Family#PresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)
FamilyHPOFreeText: Onset was at age 9 in all family members, with the first presenting phenotype being visual failure rather than mental retardation (as reported elsewhere). Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at ages 10-12. EEG specifically showed a generalized
pattern of high-voltage polyspike–slow waves.
FamilyNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)
FamilyNotHPOFreeText: N/A
CountryOrigin: Colombia
Ethnicity: Family is reported to have mixed Spanish, Native American, and African ancestry, but no documented northern European ancestry.
Race: Admixture, combining Spanish, Native American, and African ancestry.
Family#PreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. CLN5 PCR products were additionally subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.
Family#Method1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.
Family#Method2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.
Family#GenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.
Affected: 2
Unaffected: 9
Segregations: 1 segregation is reported in the pedigree from Figure 1, with no individuals inconsistent with an autosomal recessive mode of inheritance. The family in question reportedly has multiple consanguinity loops.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Pineda-Trujillo_Patient_NCL-22
Variant: Both affected patients are homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).
ClinVar: 2567
gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals).
https://gnomad.broadinstitute.org/variant/13-77569212-G-A
FamilyAddInfo: N/A
FamilyPMIDs: N/A