Missense Variation in <em>TPP1</em> Gene causes Neuronal Ceroid Lipofuscinosis Type 2 in a Family from Jammu and Kashmir-India

Abstract

We report diagnosis of Neuronal Ceroid Lipofuscinosis Type 2 (CLN2), a rare, hereditary neurodegenerative disease of childhood, in a four and a half year old girl, the first child of non-consanguineous parents with no family history. Despite extensive efforts by the parents, her clinical condition remained undiagnosed and without management, until recently. Our published &amp;ldquo;Bottom-up Approach&amp;rdquo;, based on comprehensive and multidisciplinary clinical, pathological, radiographical and genetic evaluations, played key role in diagnosis of the disease. Detailed analyses involving Next Generation Sequencing confirmed a missense variation NC_00011.10:g.6616374C&amp;gt;T (NP_000382.3:p.Arg339Gln; rs765380155) in exon 8 of TPP1 gene. In silico analyses predicted it to be highly pathogenic. Further family screening (including her both unaffected parents and asymptomatic, one year old younger sister) of the identified variation through Sanger Sequencing, revealed a perfect autosomal recessive segregation in the family. This study is the first case report on classic CLN2 from Jammu and Kashmir-India. This study is also indicating the effectiveness of our &amp;ldquo;Bottom-up Approach&amp;rdquo; in understanding rare disorders in low resource regions and the importance of timely diagnosis. Like in the proband, had diagnosis been established a bit early, the family might have benefitted at least with reference to their second child through counselling programmes.

Identification of a TPP1 Q278X Mutation in an Iranian Patient with Neuronal Ceroid Lipofuscinosis 2: Literature Review and Mutations Update

“…Likely, alleles causing spinocerebellar ataxia result on proteins with some residual function, hence the hypomorphic phenotype in comparison to CLN2 disease alleles with later age of onset and an overall less severe clinical picture [ 40 ]. In line with this, missense alleles can be frequently identified in Spinocerebellar Ataxia 7, while approximately 60% of patients with CLN2 carry two common LOF mutations: the splice acceptor site mutation (c.509-1G > C) and the stop-gain mutation in exon 6 (c.622C > T, p.R208X), which may occur homozygously or heterozygously in trans (compound-heterozygously) with other disease alleles [ 1 , 8 , 41 ]. In the present study, we report a novel homozygous pathogenic stop-gain variant (p.Arg278*) in an Iranian family.…”

“…Neuronal ceroid lipofuscinoses (NCLs) represent a group of rare clinically and genetically heterogeneous progressive neurodegenerative lysosomal storage disorders (LSD), mainly affecting children aged 2–6 years, caused by loss-of-function mutations in CLN-genes. With the exception of CLN4 which is autosomal-dominantly inherited, all other forms follow an autosomal-recessive mode of inheritance [ 1 , 2 , 3 ]. Children mostly show normal psychomotoric development until progressive development of seizures, vision loss, intellectual and motor decline, cognitive impairment, and eventually premature death.…”

“…Despite the rarity of this disease, 300–350 cases of NCLs are reported annually in the US, and its global incidence is one per 100,000 live births (orphaned; ORPHA 79264). The highest incidence rates have been reported in some Nordic countries (one per 14,000 in Iceland) [ 1 , 4 , 5 ], while incidence is unknown for many other countries, including Iran.…”