ORPHA: 168491; DO: 0110722;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q28.2 | Ceroid lipofuscinosis, neuronal, 7 | 610951 | Autosomal recessive | 3 | MFSD8 | 611124 |
A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-7 (CLN7) is caused by homozygous or compound heterozygous mutation in the MFSD8 gene (611124), which encodes a putative lysosomal transporter, on chromosome 4q28.
The neuronal ceroid lipofuscinoses (NCL, or CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally (summary by Mole et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Topcu et al. (2004) reported the so-called Turkish variant of late-infantile CLN in 17 of 28 Turkish patients. Most of the families were consanguineous. The mean age at disease onset was 5.1 years (range, 2 to 7 years), with seizures or motor impairment as the most common presenting symptom. As the disease progressed, mental regression, myoclonus, speech impairment, loss of vision, and personality disorders developed, and most of the patients became nonambulatory within 2 years after onset. The features distinguishing the Turkish variant from CLN2 and CLN3 included a more severe course regarding seizures, the presence of condensed fingerprint profiles on electron microscopic examination of lymphocytes, and lack of vacuolated lymphocytes.
Mole et al. (2005) stated that the clinical phenotype of CLN7 is considered to be the same as Turkish patients with CLN8 (600143).
Stogmann et al. (2009) reported a consanguineous Egyptian family in which 5 members had late-infantile CLN. The average age at onset was 5 years, and all patients presented with seizures, including complex partial, secondary generalized tonic-clonic, and myoclonic jerks. All showed gradual deterioration and loss of psychomotor skills about 1 year after the seizures started. Three patients showed aggressive behavior, memory impairment, and language abnormalities with substantial loss of speech function. The disorder was progressive, with motor impairment ultimately resulting in disability of sitting and walking and eventual bedridden status. Two patients died at age 13 years. One patients developed extrapyramidal signs, including axial rigidity, hesitation in initiation of movement, and coarse postural tremor, and also showed frontal manifestations including bilateral positive grasp, paratonia, and positive snout reflexes. None of the patients had visual impairment. Skin biopsies were not informative, likely due to lack of proper sampling.
Aldahmesh et al. (2009) reported a consanguineous Saudi family in which 3 individuals had variant late infantile-onset NCL. The proband developed poor vision at age 6 years and had onset of focal seizures with secondary generalization 1 year later. His vision deteriorated to blindness by age 7.5, and he had declining cognitive function. By age 10, he had minimal verbal communication and retinitis pigmentosa. There was no evidence of ultrastructural deposits of NCL on conjunctival biopsy. Brain MRI showed atrophic changes which were more in the occipital lobe. A 14-year-old brother and an 18-year-old half-sister had a similar presentation, with onset of poor vision around age 7 years, progression to blindness, seizures, and cognitive decline. The 14-year-old brother had a rapidly progressive course and has been in a vegetative state since age 11. The 18-year-old half-sister has significant impairment of cognitive functions comparable to the index case and intractable seizures. Her EEG showed diffuse slowing with frequent, multifocal sharp waves. Aldahmesh et al. (2009) commented that the phenotype in this family was similar to that reported in other patients with this form of CLN.
Clinical Variability
Kousi et al. (2009) reported a Dutch patient with a protracted course of CLN7. The patient presented at age 11 years with visual failure. He had motor impairment and seizures in his mid-twenties, followed by mental and speech regression in his thirties, and loss of independent ambulation at age 39. Genetic analysis identified a homozygous mutation in the MFSD8 gene (A157P; 611124.0007) that resulted in the substitution of a neutral nonpolar alanine with a neutral nonpolar proline. Kousi et al. (2009) postulated that the mild impact of the mutation on amino acid substitution may have contributed to the later onset and milder course of the disorder in this patient. Importantly, patients with later onset of CLN should still be considered to have mutations in the MFSD8 gene.
Kim et al. (2019) reported the development and use of a patient-specific antisense oligonucleotide (ASO) drug, milasen, to treat a patient with CLN7. From diagnosis to initiation of therapy took just under a year, during which the patient continued to lose skills. Nevertheless, after starting intrathecal injection of escalating doses of the ASO, the patient experienced a decrease in frequency and duration of seizures. There were no significant adverse events. This study provided a template for and showed the feasibility of rapid development of patient-customized treatment.
Wheeler et al. (1999) referred to a group of patients with the so-called Turkish variant of late-onset infantile CLN as having CLN7. Although some of these patients have been found to carry mutations in the CLN8 (607837) or CLN6 (606725) genes, the underlying molecular defect in other Turkish patients had not been determined. Ranta et al. (2004) and Siintola et al. (2005) excluded 7 Turkish families with late-onset infantile CLN from all known CLN loci, including CLN8; these patients had previously been reported by Topcu et al. (2004). Siintola et al. (2005) concluded that these Turkish families may still represent a distinct genetic entity, CLN7.
Siintola et al. (2007) performed a genomewide scan with SNP markers and homozygosity mapping in 9 Turkish families, including the families reported by Topcu et al. (2004) and 1 Indian family who were not linked to any known NCL locus, and mapped a variant late infantile-onset NCL (vLINCL) locus to chromosome 4q28.1-q28.2 in 5 families.
The transmission pattern of vLINCL in the families reported by Siintola et al. (2007) was consistent with autosomal recessive inheritance.
In 6 families with vLINCL, 5 of them Turkish families reported by Topcu et al. (2004), Siintola et al. (2007) identified 6 different homozygous mutations in the MFSD8 gene (see, e.g., 611124.0001-611124.0003 and 611124.0010). MFSD8 belongs to the major facilitator superfamily of transporter proteins and is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously reported NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. Analysis of the genome-scan data suggested the existence of at least 3 more genes in the remaining 5 families, further corroborating the great genetic heterogeneity of LINCLs.
In affected individuals of a consanguineous Egyptian family with CLN7, Stogmann et al. (2009) identified a homozygous mutation in the MFSD8 gene (Y121C; 611124.0004).
In 3 affected individuals of a consanguineous Saudi family with CLN7, Aldahmesh et al. (2009) identified a homozygous mutation in the MFSD8 gene (P412L; 611124.0005).
In 32 of 80 patients from 75 families with late-infantile onset CLN, Kousi et al. (2009) identified 10 mutations in the MFSD8 gene, including 8 novel mutations (see, e.g., 611124.0006-611124.0007). Although most of the patients were of Turkish origin, many were from other regions, including India, the Netherlands, Italy, and Czech Republic. The phenotype was mostly homogeneous, with onset between 1.5 and 5 years, developmental regression, seizures, mental and motor regression, speech impairments, ataxia, visual failure, and myoclonus. Most of the mutations were private, found only in a single family. However, all known CLN loci were excluded in Turkish patients from 35 families with late-infantile onset of CLN, indicating genetic heterogeneity.
In 9 (39%) of 23 children with late infantile-onset CLN, 22 of Italian origin and 1 from the southeast of France, who were negative for mutation in known CLN-associated genes, Aiello et al. (2009) identified homozygosity or compound heterozygosity for pathogenic mutations in MFSD8 (see, e.g., 611124.0001, 611124.0009, and 611124.0011-611124.0012). Mutation-positive patients were characterized by early psychomotor regression and seizures, with 7 of 9 developing mental regression, personality disorders, and speech impairment within 3 to 4 years after onset, and 4 becoming unable to walk unaided within 2 years. In 14 of the patients, Aiello et al. (2009) found no mutations in any of the known CLN-causing genes, suggesting further genetic heterogeneity of vLINCL.
Kousi et al. (2009) identified a homozygous mutation in the MFSD8 gene (T294K; 611124.0006) in 14 Roma patients from 12 families with CLN7 from the former Czechoslovakia. The phenotype was characterized by late-infantile onset, developmental regression, seizures, visual failure, and ataxia. Haplotype analysis was consistent with a founder effect.
Ashwini et al. (2016) performed neurologic evaluations on 4 unrelated client-owned Chihuahua dogs from Japan, Italy, and England that exhibited progressive neurologic signs consistent with a diagnosis of NCL. Brain and in some cases also retinal and heart tissues were examined postmortem for the presence of lysosomal storage bodies characteristic of NCL. The affected dogs exhibited massive accumulation of autofluorescent lysosomal storage bodies in the brain, retina, and heart accompanied by brain atrophy and retinal degeneration. The dogs were screened for known canine NCL mutations that had been reported in a variety of dog breeds. All 4 dogs were homozygous for the MFSD8 single-basepair deletion (c.843delT) previously associated with NCL in a Chinese Crested dog and in 2 affected littermate Chihuahuas from Scotland. The dogs were all homozygous for the normal alleles at the other genetic loci known to cause different forms of canine NCL. The MFSD8 c.843delT mutation was not present in 57 Chihuahuas that were either clinically normal or suffered from unrelated diseases or in 1761 unaffected dogs representing 186 other breeds. Based on these data Ashwini et al. (2016) considered it almost certain that the MFSD8 c.843delT mutation is the cause of NCL in Chihuahuas. Because the disorder occurred in widely separated geographic locations or in unrelated dogs from the same country, it is likely that the mutant allele is widespread among Chihuahuas. Ashwini et al. (2016) suggested that genetic testing for this mutation in other Chihuahuas is therefore likely to identify intact dogs with the mutant allele that could be used to establish a research colony that could be used to test potential therapeutic interventions for the corresponding human disease.
Aiello, C., Terracciano, A., Simonati, A., Discepoli, G., Cannelli, N., Claps, D., Crow, Y. J., Bianchi, M., Kitzmuller, C., Longo, D., Tavoni, A., Franzoni, E., and 10 others. Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 30: E530-E540, 2009. Note: Electronic Article. [PubMed: 19177532] [Full Text: https://doi.org/10.1002/humu.20975]
Aldahmesh, M. A., Al-Hassnan, Z. N., Aldosari, M., Alkuraya, F. S. Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emerging. Neurogenetics 10: 307-311, 2009. [PubMed: 19277732] [Full Text: https://doi.org/10.1007/s10048-009-0185-1]
Ashwini, A., D'Angelo, A., Yamato, O., Giordano, C., Cagnotti, G., Harcourt-Brown, T., Mhlanga-Mutangadura, T., Guo, J., Johnson, G. S., Katz, M. L. Neuronal ceroid lipofuscinosis associated with an MFSD8 mutation in Chihuahuas. Molec. Genet. Metab. 118: 326-332, 2016. [PubMed: 27211611] [Full Text: https://doi.org/10.1016/j.ymgme.2016.05.008]
Kim, J., Hu, C., Moufawad El Achkar, C., Black, L. E., Douville, J., Larson, A., Pendergast, M. K., Goldkind, S. F., Lee, E. A., Kuniholm, A., Soucy, A., Vaze, J., and 36 others. Patient-customized oligonucleotide therapy for a rare genetic disease. New Eng. J. Med. 381: 1644-1652, 2019. [PubMed: 31597037] [Full Text: https://doi.org/10.1056/NEJMoa1813279]
Kousi, M., Siintola, E., Dvorakova, L., Vlaskova, H., Turnbull, J., Topcu, M., Yuksel, D., Gokben, S., Minassian, B. A., Elleder, M., Mole, S. E., Lehesjoki, A.-E. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain 132: 810-819, 2009. [PubMed: 19201763] [Full Text: https://doi.org/10.1093/brain/awn366]
Mole, S. E., Williams, R. E., Goebel, H. H. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6: 107-126, 2005. [PubMed: 15965709] [Full Text: https://doi.org/10.1007/s10048-005-0218-3]
Ranta, S., Topcu, M., Tegelberg, S., Tan, H., Ustubutun, A., Saatci, I., Dufke, A., Enders, H., Pohl, K., Alembik, Y., Mitchell, W. A., Mole, S. E., Lehesjoki, A.-E. Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Hum. Mutat. 23: 300-305, 2004. [PubMed: 15024724] [Full Text: https://doi.org/10.1002/humu.20018]
Siintola, E., Topcu, M., Aula, N., Lohi, H., Minassian, B. A., Paterson, A. D., Liu, X.-Q., Wilson, C., Lahtinen, U., Anttonen, A.-K., Lehesjoki, A.-E. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am. J. Hum. Genet. 81: 136-146, 2007. [PubMed: 17564970] [Full Text: https://doi.org/10.1086/518902]
Siintola, E., Topcu, M., Kohlschutter, A., Salonen, T., Joensuu, T., Anttonen, A.-K., Lehesjoki, A.-E. Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin. Clin. Genet. 68: 167-173, 2005. [PubMed: 15996215] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00471.x]
Stogmann, E., El Tawil, S., Wagenstaller, J., Gaber, A., Edris, S., Abdelhady, A., Assem-Hilger, E., Leutmezer, F., Bonelli, S., Baumgartner, C., Zimprich, F., Strom, T. M., Zimprich, A. A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. Neurogenetics 10: 73-77, 2009. [PubMed: 18850119] [Full Text: https://doi.org/10.1007/s10048-008-0153-1]
Topcu, M., Tan, H., Yalnizoglu, D., Usubutun, A., Saatci, I., Aynaci, M., Anlar, B., Topaloglu, H., Turanli, G., Kose, G., Aysun, S. Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk. J. Pediat. 46: 1-10, 2004. [PubMed: 15074367]
Wheeler, R. B., Sharp, J. D., Mitchell, W. A., Bate, S. L., Williams, R. E., Lake, B. D., Gardiner, R. M. A new locus for variant late neuronal ceroid lipofuscinosis--CLN7. Molec. Genet. Metab. 66: 337-338, 1999. [PubMed: 10191125] [Full Text: https://doi.org/10.1006/mgme.1999.2804]