Neuronal Ceroid Lipofuscinosis 1 via the PPT1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7201 PPT1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7201PPT181479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative lysosomal storage disorders caused by the accumulation of ceroid and lipofuscin in various cell types, mainly cells of the cerebral cortex, cerebellar cortex, and retina (Dyken et al. 1988; Williams and Mole 2012; Bennett and Rakheja, 2013). Characteristic features at onset include clumsiness; deterioration of vision and psychomotor functions; seizures and behavioral changes. Progression of clinical features results ultimately in total disability, blindness and premature death. Although NCL affects primarily children, age of onset of symptoms varies from infancy to adulthood. The incidence of NCL is variable and ranges from 1.3 to 7 per 100,000 (Mole and Williams 2013). However, it is more common in northern European populations, particularly Finland where the incidence may reach 1 in 12,500 individuals and a carrier frequency of 1 in 70 (Rider and Rider 1988; Vesa et al. 1995). NCLs are clinically and genetically heterogeneous. A nomenclature based both on the age of onset of symptoms and the disease-causing gene has been recently developed, which classifies NCLs into thirteen subtypes (CLN1-8, 10-14) (Williams and Mole 2012). The causative gene for the CLN9 phenotype has not been identified yet (Schulz et al. 2004). Of note, NCLs were previously known as Batten disease. However, in recent nomenclature, Batten disease only applies to NCL caused by mutations in CLN3.

CLN1, also known as Haltia-Santavuori disease, was first reported in infant patients from Finland. It is further divided into four subgroups based on the age of onset of symptoms.

1) CLN1 disease, infantile, is the most prevalent of the four subgroups. It is characterized by an early age of onset, usually between 8 and 18 months; rapid progression; blindness by the age of two years; and short life expectancy. Additional features include cerebellar ataxia, muscle hypotonia, myoclonic jerks, and microcephaly (Santavuori et al. 1973; Haltia et al. 1973).

2) CLN1 disease, late infantile variant, begins usually between 18 months and 3.5 years of age. Presenting features include seizures, cognitive and or motor decline and vision impairment (Das et al. 1995).

3) CLN1 disease, juvenile, is characterized by age of onset between 5-7 years and death before the third decade of life. Vision impairment is the most common presenting feature followed by seizures and cognitive decline (Das et al. 1995).

4) CLN1 disease, adult, has been reported in a few cases. In this form of the disease additional features have been reported and include brain atrophy, epilepsy, parkinsonism, decreased verbal fluency, irritability, depression, and hallucinations (Haltia et al. 1973; Becker et al. 1979; Mitchison et al. 1998; van Diggelen et al. 2001; Ramadan et al. 2007).

Genetics

Most CLNs (including CLN1) are inherited in an autosomal recessive manner. Thirteen genes have been implicated in the disorder: PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 (Mole and Williams 2013). CLN1 is caused by pathogenic variants in the PPT1 gene (Vesa et al. 1995; Hofmann et al. 1997). About 70 mutations have been reported in various ethnic populations, and include missense, nonsense, splicing, and small insertions or deletions. Only one large pathogenic deletion was reported in one patient from Italy who is affected with the late infantile variant of the disease (Simonati et al. 2009).

The PPT1 gene encodes palmitoyl-protein thioesterase (PPT), a lysosomal hydrolase involved in several cell functions such as lipid-modification of proteins. PPT1 pathogenic variants result in PPT enzyme deficiency (Das et al. 1998; Mitchison et al. 1998). Accumulation of mutated proteins within a cell is thought to trigger apoptosis (Gupta et al. 2001).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in PPT1 were detected in >98% of patients with NCL and PPT1 enzyme deficiency (Das et al. 1998).

Testing Strategy

This test provides full coverage of all coding exons of the PPT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with a clinical diagnosis of NCL and deficient PTT1 enzyme activity. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PPT1.

Gene

Official Gene Symbol OMIM ID
PPT1 600722
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Ceroid Lipofuscinosis Neuronal 1 AR 256730

Related Test

Name
Neuronal Ceroid Lipofuscinoses (Batten Disease) Panel

Citations

  • Becker K, Goebel HH, Svennerholm L, Wendel U, Bremer HJ. 1979. Clinical, morphological, and biochemical investigations on a patient with an unusual form of neuronal ceroid lipofuscinosis. Eur J Pediatr 132:197-206.
    PubMed ID: 510322
  • Bennett MJ, Rakheja D. 2013. The neuronal ceroid-lipofuscinoses: The Neuronal Ceroid-Lipofuscinoses. Developmental Disabilities Research Reviews 17: 254–259. PubMed ID: 23798013
  • Das AK, Becerra CH, Yi W, Lu J-Y, Siakotos AN, Wisniewski KE, Hofmann SL. 1998. Molecular genetics of palmitoyl-protein thioesterase deficiency in the US. Journal of Clinical Investigation 102: 361-370. PubMed ID: 9664077
  • Dyken PR, Opitz JM, Reynolds JF, Pullarkat RK. 1988. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. American Journal of Medical Genetics 31: 69–84. PubMed ID: 3146331
  • Gupta P, Soyombo AA, Atashband A, Wisniewski KE, Shelton JM, Richardson JA, Hammer RE, Hofmann SL. 2001. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proceedings of the National Academy of Sciences 98: 13566–13571. PubMed ID: 11717424
  • Haltia M, Rapola J, Santavuori P, Keränen A. Infantile type of so-called neuronal ceroid-lipofuscinosis. 2. 1973. Morphological and biochemical studies. J Neurol Sci.18:269-285. PubMed ID: 4121459
  • Hofmann, S.L. et al. 1997. "Palmitoyl-protein thioesterase and the molecular pathogenesis of infantile neuronal ceroid lipfuscinosis. Neuropediatrics 28(1):27-30. PubMed ID: 9151316
  • Mitchison HM, Hofmann SL, Becerra CH, Munroe PB, Lake BD, Crow YJ, Stephenson JB, Williams RE, Hofman IL, Taschner PE. 1998. Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Human molecular genetics 7: 291–297. PubMed ID: 9425237
  • Mitchison HM, Hofmann SL, Becerra CH, Munroe PB, Lake BD, Crow YJ, Stephenson JB, Williams RE, Hofman IL, Taschner PE. 1998. Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Human molecular genetics 7: 291–297.
    PubMed ID: 9425237.
  • Mole S.E., Williams R.E. 2013. Neuronal Ceroid-Lipofuscinoses. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301601
  • Ramadan H, Al-Din AS, Ismail A, Balen F, Varma A, Twomey A, Watts R, Jackson M, Anderson G, Green E, Mole SE. 2007. Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1. Neurology 68: 387–388. PubMed ID: 17261688
  • Rider J.A., Rider D.L. 1988. American journal of medical genetics. Supplement. 5: 21-6. PubMed ID: 3146319
  • Santavuori P, Haltia M, Rapola J, Raitta C. Infantile type of so-called neuronal ceroid-lipofuscinosis. 1. 1973.  A clinical study of 15 patients. J Neurol Sci. 18:257-267. PubMed ID: 4698309
  • Schulz A. et al. 2004. Annals of neurology. 56: 342-50. PubMed ID: 15349861
  • Simonati A, Tessa A, Bernardina BD, Biancheri R, Veneselli E, Tozzi G, Bonsignore M, Grosso S, Piemonte F, Santorelli FM. 2009. Variant late infantile neuronal ceroid lipofuscinosis because of CLN1 mutations. Pediatr. Neurol. 40: 271–276. PubMed ID: 19302939
  • van Diggelen OP, Thobois S, Tilikete C, Zabot MT, Keulemans JL, Bunderen PA van, Taschner PE, Losekoot M, Voznyi YV. 2001. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann. Neurol. 50: 269–272. PubMed ID: 11506414
  • Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL, Peltonen L. 1995. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584-587. PubMed ID: 7637805
  • Williams R.E., Mole S.E. 2012. Neurology. 79: 183-91. PubMed ID: 22778232

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