#613744
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-51 (SPG51) is caused by homozygous mutation in the AP4E1 gene (607244) on chromosome 15q21.
Spastic paraplegia-51 (SPG51) is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity. Affected individuals also have global developmental delay with impaired intellectual development and poor or absent speech (summary by Moreno-De-Luca et al., 2011).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Moreno-De-Luca et al. (2011) reported a consanguineous Palestinian Jordanian family in which 2 sibs had spastic quadriplegia. Both sibs presented at birth with microcephaly and hypotonia, followed by delayed psychomotor development. The sister was more severely affected, developing spastic tetraplegia and hyperreflexia by the first year of life, and seizures at age 5. She never developed language or independent walking. At age 23 years, she was profoundly impaired and showed dysmorphic facial features. Brain MRI showed enlarged ventricles, cortical and cerebellar atrophy, and diffuse white matter loss. Her brother was similarly but less severely affected. He had delayed psychomotor development, learned a few words, could walk with support until age 9, and developed seizures at age 15. At age 22, he had spastic tetraplegia, nystagmus, and dysmorphic facial features.
Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR071) in which 2 individuals had a phenotype consistent with SPG51. They presented with hypotonia in the neonatal period that later progressed to muscular hypertonia, especially of the lower limbs. Physical examination showed contractures, talipes equinovarus, decreased muscle mass of the shanks, short stature, and microcephaly. Both had severe mental retardation and absent speech, as well as dysmorphic prominent and bulbous nose, a wide mouth, and coarse features. One patient had seizures. Both had a shy, amicable, and calm character, and smiled or laughed for no obvious reason, but there were no bursts of laughter.
Kong et al. (2013) reported monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51 apparent from infancy. The girls showed hypotonia, global developmental delay with inability to walk or speak by age 3 years, and microcephaly. They smiled, laughed inappropriately, and drooled. Neurologic examination showed spastic paraplegia of the lower limbs, and brain imaging showed atrophy of the cerebellar vermis and cortical atrophy. The girls had a facial gestalt with prominent bulbous nose, wide mouth, and coarse features, as well as short stature and low body weight. In addition to SPG51, the infants presented at 9 months of age with enlarged and inflamed lymph nodes after BCG vaccination. The lymph nodes were surgically removed, and biopsy confirmed a mycobacterial infection. The patients did not have subsequent mycobacterial infections. In these twins, Kong et al. (2018) identified a homozygous splice site mutation in the SPPL2A gene (608238.0001) as the cause of the mycobacterial disease (IMD86; 619549). These findings indicated that the patients had 2 distinct genetic diseases, SPG51 and IMD86, and confirmed that susceptibility to mycobacterial infection is not part of the SPG51 phenotype.
The transmission pattern of SPG51 in the family reported by Moreno-De-Luca et al. (2011) was consistent with autosomal recessive inheritance.
In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic quadriplegia, Moreno-De-Luca et al. (2011) identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171, NCBI36) that included the 5-prime end of the AP4E1 gene (607244) and the 5-prime end of the SPPL2A gene (608238). Noting that mutation in the AP4M1 gene (602296), which forms a complex with AP4E1, causes a similar phenotype (SPG50; 612936), Moreno-De-Luca et al. (2011) concluded that disruption of the AP4E1 gene was responsible for the phenotype in their family, although they could not exclude a possible role for disruption of the SPPL2A gene. The authors proposed the designation 'AP4 deficiency syndrome' to refer to disorders caused by disruption of any of the 4 subunits of the AP4 complex.
By linkage analysis followed by candidate gene sequencing in a consanguineous Syrian family with mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4E1 gene (607244.0002). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a frameshift mutation in the AP4E1 gene (607244.0003) in 3 affected members of a consanguineous family segregating SPG51.
In a pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51, Kong et al. (2013) identified a homozygous nonsense mutation in the AP4E1 gene (R1105X; 607244.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls.
Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88: 788-795, 2011. [PubMed: 21620353, images, related citations] [Full Text]
Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S. A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. PLoS One 8: e58286, 2013. [PubMed: 23472171, images, related citations] [Full Text]
Kong, X.-F., Martinez-Barricarte, R., Kennedy, J., Mele, F., Lazarov, T., Deenick, E. K., Ma, C. S., Breton, G., Lucero, K. B., Langlais, D., Bousfiha, A., Aytekin, C., and 29 others. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nature Immun. 19: 973-985, 2018. [PubMed: 30127434, images, related citations] [Full Text]
Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J. Med. Genet. 48: 141-144, 2011. [PubMed: 20972249, related citations] [Full Text]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 280763; DO: 0110803;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.2 | Spastic paraplegia 51, autosomal recessive | 613744 | Autosomal recessive | 3 | AP4E1 | 607244 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-51 (SPG51) is caused by homozygous mutation in the AP4E1 gene (607244) on chromosome 15q21.
Spastic paraplegia-51 (SPG51) is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity. Affected individuals also have global developmental delay with impaired intellectual development and poor or absent speech (summary by Moreno-De-Luca et al., 2011).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Moreno-De-Luca et al. (2011) reported a consanguineous Palestinian Jordanian family in which 2 sibs had spastic quadriplegia. Both sibs presented at birth with microcephaly and hypotonia, followed by delayed psychomotor development. The sister was more severely affected, developing spastic tetraplegia and hyperreflexia by the first year of life, and seizures at age 5. She never developed language or independent walking. At age 23 years, she was profoundly impaired and showed dysmorphic facial features. Brain MRI showed enlarged ventricles, cortical and cerebellar atrophy, and diffuse white matter loss. Her brother was similarly but less severely affected. He had delayed psychomotor development, learned a few words, could walk with support until age 9, and developed seizures at age 15. At age 22, he had spastic tetraplegia, nystagmus, and dysmorphic facial features.
Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR071) in which 2 individuals had a phenotype consistent with SPG51. They presented with hypotonia in the neonatal period that later progressed to muscular hypertonia, especially of the lower limbs. Physical examination showed contractures, talipes equinovarus, decreased muscle mass of the shanks, short stature, and microcephaly. Both had severe mental retardation and absent speech, as well as dysmorphic prominent and bulbous nose, a wide mouth, and coarse features. One patient had seizures. Both had a shy, amicable, and calm character, and smiled or laughed for no obvious reason, but there were no bursts of laughter.
Kong et al. (2013) reported monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51 apparent from infancy. The girls showed hypotonia, global developmental delay with inability to walk or speak by age 3 years, and microcephaly. They smiled, laughed inappropriately, and drooled. Neurologic examination showed spastic paraplegia of the lower limbs, and brain imaging showed atrophy of the cerebellar vermis and cortical atrophy. The girls had a facial gestalt with prominent bulbous nose, wide mouth, and coarse features, as well as short stature and low body weight. In addition to SPG51, the infants presented at 9 months of age with enlarged and inflamed lymph nodes after BCG vaccination. The lymph nodes were surgically removed, and biopsy confirmed a mycobacterial infection. The patients did not have subsequent mycobacterial infections. In these twins, Kong et al. (2018) identified a homozygous splice site mutation in the SPPL2A gene (608238.0001) as the cause of the mycobacterial disease (IMD86; 619549). These findings indicated that the patients had 2 distinct genetic diseases, SPG51 and IMD86, and confirmed that susceptibility to mycobacterial infection is not part of the SPG51 phenotype.
The transmission pattern of SPG51 in the family reported by Moreno-De-Luca et al. (2011) was consistent with autosomal recessive inheritance.
In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic quadriplegia, Moreno-De-Luca et al. (2011) identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171, NCBI36) that included the 5-prime end of the AP4E1 gene (607244) and the 5-prime end of the SPPL2A gene (608238). Noting that mutation in the AP4M1 gene (602296), which forms a complex with AP4E1, causes a similar phenotype (SPG50; 612936), Moreno-De-Luca et al. (2011) concluded that disruption of the AP4E1 gene was responsible for the phenotype in their family, although they could not exclude a possible role for disruption of the SPPL2A gene. The authors proposed the designation 'AP4 deficiency syndrome' to refer to disorders caused by disruption of any of the 4 subunits of the AP4 complex.
By linkage analysis followed by candidate gene sequencing in a consanguineous Syrian family with mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4E1 gene (607244.0002). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a frameshift mutation in the AP4E1 gene (607244.0003) in 3 affected members of a consanguineous family segregating SPG51.
In a pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51, Kong et al. (2013) identified a homozygous nonsense mutation in the AP4E1 gene (R1105X; 607244.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls.
Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am. J. Hum. Genet. 88: 788-795, 2011. [PubMed: 21620353] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.019]
Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S. A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. PLoS One 8: e58286, 2013. [PubMed: 23472171] [Full Text: https://doi.org/10.1371/journal.pone.0058286]
Kong, X.-F., Martinez-Barricarte, R., Kennedy, J., Mele, F., Lazarov, T., Deenick, E. K., Ma, C. S., Breton, G., Lucero, K. B., Langlais, D., Bousfiha, A., Aytekin, C., and 29 others. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nature Immun. 19: 973-985, 2018. [PubMed: 30127434] [Full Text: https://doi.org/10.1038/s41590-018-0178-z]
Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J. Med. Genet. 48: 141-144, 2011. [PubMed: 20972249] [Full Text: https://doi.org/10.1136/jmg.2010.082263]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM