#614066
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-47 (SPG47) is caused by homozygous mutation in the AP4B1 gene (607245) on chromosome 1p13.
Spastic paraplegia-47 (SPG47) is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Abou Jamra et al., 2011).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Abou Jamra et al. (2011) reported a consanguineous Israeli Arab family (ID01) in which 3 sibs had severe mental retardation and spasticity. All presented at birth with microcephaly and muscular hypotonia, which later developed to hypertonia. Physical examination showed hyperreflexia, spastic paraplegia, and an inability to walk unaided. All had a severe cognitive deficit, marked speech delay, and adaptive impairment. Other features included high palate, broad nasal bridge, short stature, hyperlaxity, genu recurvatum, pes planus, and a waddling gait. They had stereotypic laughter and markedly shy character. None had seizures, vision or hearing impairments, or any anomalies of inner organs.
Blumkin et al. (2011) reported 2 sibs, born of consanguineous Arab parents, with a severe neurodegenerative disorder beginning in infancy. The patients had delayed psychomotor development, mental retardation, and spastic paraplegia with increased tone in the lower limbs, hyperreflexia, and extensor plantar responses. Both had febrile seizures in early childhood. One child had dysarthria at age 5.5 years, and the other showed spastic tongue protrusion and jaw opening with hypersalivation. Brain imaging of both patients showed thinning of the corpus callosum and periventricular white matter changes. Dysmorphic features were not observed, although 1 had microcephaly.
Tuysuz et al. (2014) reported 2 Turkish sisters with SPG47. The patients had delayed psychomotor development, severe intellectual disability with impaired speech, spastic tetraplegia with hypertonia and inability to walk independently, and infantile-onset seizures. Dysmorphic features included microcephaly, facial hypotonia, coarse face, bitemporal narrowing, broad nasal bridge with bulbous nose, short philtrum, everted upper lip, wide mouth, and high-arched palate. Brain imaging showed ventriculomegaly, thin corpus callosum, and white matter loss.
Abdollahpour et al. (2015) reported 2 sibs, born of unrelated parents, with SPG47. The patients were 12 and 14 years old, respectively, at the time of the report. Both showed delayed psychomotor development in early infancy, followed by spasticity of the lower limbs and hyperreflexia. Both patients became wheelchair-bound around 12 years of age and had contractures. Additional features included poor or absent speech, microcephaly, short stature, valgosity of the hips with acetabular dysplasia, clubfoot, and dysmorphic facial features, including open mouth, tongue protrusion, and broad nasal root. Both patients developed febrile seizures at ages 10 and 12 years, respectively.
The transmission pattern of SPG47 in the family reported by Tuysuz et al. (2014) was consistent with autosomal recessive inheritance.
By homozygosity mapping analysis of 2 sibs with complicated spastic paraplegia, Blumkin et al. (2011) found linkage to a 7.3-Mb region on chromosome 1p13-p12, which they designated SPG47.
By linkage analysis followed by candidate gene sequencing of an Israeli Arab family with autosomal recessive mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4B1 gene (607245.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
In 2 sibs, born of consanguineous Arab parents, with SPG47, Bauer et al. (2012) identified a homozygous truncating mutation in the AP4B1 gene (607245.0002). The mutation was found by exome sequencing of the candidate region on chromosome 1p13-p12 identified by linkage analysis (Blumkin et al., 2011). Bauer et al. (2012) noted the phenotypic similarities to the patients reported by Abou Jamra et al. (2011).
In 2 Turkish sisters with SPG47, Tuysuz et al. (2014) identified a homozygous truncating mutation in the AP4B1 gene (607245.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies on patient cells were not reported.
In 2 sibs, born of unrelated parents, with SPG47, Abdollahpour et al. (2015) identified a homozygous truncating mutation in the AP4B1 gene (607245.0004). Functional studies of the variant and studies on patient cells were not reported.
Abdollahpour, H., Alawi, M., Kortum, F., Beckstette, M., Seemanova, E., Komarek, V., Rosenberger, G., Kutsche, K. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. Europ. J. Hum. Genet. 23: 256-259, 2015. [PubMed: 24781758, images, related citations] [Full Text]
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]
Bauer, P., Leshinsky-Silver, E., Blumkin, L., Schlipf, N., Schroder, C., Schicks, J., Lev, D., Riess, O., Lerman-Sagie, T., Schols, L. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics 13: 73-76, 2012. [PubMed: 22290197, related citations] [Full Text]
Blumkin, L., Lerman-Sagie, T., Lev, D., Yosovich, K., Leshinsky-Silver, E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J. Neurol. Sci. 305: 67-70, 2011. [PubMed: 21440262, related citations] [Full Text]
Tuysuz, B., Bilguvar, K., Kocer, N., Yalcinkaya, C., Caglayan, O., Gul, E., Sahin, S., Comu, S., Gunel, M. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am. J. Med. Genet. 164A: 1677-1685, 2014. [PubMed: 24700674, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 280763; DO: 0110799;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p13.2 | Spastic paraplegia 47, autosomal recessive | 614066 | Autosomal recessive | 3 | AP4B1 | 607245 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-47 (SPG47) is caused by homozygous mutation in the AP4B1 gene (607245) on chromosome 1p13.
Spastic paraplegia-47 (SPG47) is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Abou Jamra et al., 2011).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Abou Jamra et al. (2011) reported a consanguineous Israeli Arab family (ID01) in which 3 sibs had severe mental retardation and spasticity. All presented at birth with microcephaly and muscular hypotonia, which later developed to hypertonia. Physical examination showed hyperreflexia, spastic paraplegia, and an inability to walk unaided. All had a severe cognitive deficit, marked speech delay, and adaptive impairment. Other features included high palate, broad nasal bridge, short stature, hyperlaxity, genu recurvatum, pes planus, and a waddling gait. They had stereotypic laughter and markedly shy character. None had seizures, vision or hearing impairments, or any anomalies of inner organs.
Blumkin et al. (2011) reported 2 sibs, born of consanguineous Arab parents, with a severe neurodegenerative disorder beginning in infancy. The patients had delayed psychomotor development, mental retardation, and spastic paraplegia with increased tone in the lower limbs, hyperreflexia, and extensor plantar responses. Both had febrile seizures in early childhood. One child had dysarthria at age 5.5 years, and the other showed spastic tongue protrusion and jaw opening with hypersalivation. Brain imaging of both patients showed thinning of the corpus callosum and periventricular white matter changes. Dysmorphic features were not observed, although 1 had microcephaly.
Tuysuz et al. (2014) reported 2 Turkish sisters with SPG47. The patients had delayed psychomotor development, severe intellectual disability with impaired speech, spastic tetraplegia with hypertonia and inability to walk independently, and infantile-onset seizures. Dysmorphic features included microcephaly, facial hypotonia, coarse face, bitemporal narrowing, broad nasal bridge with bulbous nose, short philtrum, everted upper lip, wide mouth, and high-arched palate. Brain imaging showed ventriculomegaly, thin corpus callosum, and white matter loss.
Abdollahpour et al. (2015) reported 2 sibs, born of unrelated parents, with SPG47. The patients were 12 and 14 years old, respectively, at the time of the report. Both showed delayed psychomotor development in early infancy, followed by spasticity of the lower limbs and hyperreflexia. Both patients became wheelchair-bound around 12 years of age and had contractures. Additional features included poor or absent speech, microcephaly, short stature, valgosity of the hips with acetabular dysplasia, clubfoot, and dysmorphic facial features, including open mouth, tongue protrusion, and broad nasal root. Both patients developed febrile seizures at ages 10 and 12 years, respectively.
The transmission pattern of SPG47 in the family reported by Tuysuz et al. (2014) was consistent with autosomal recessive inheritance.
By homozygosity mapping analysis of 2 sibs with complicated spastic paraplegia, Blumkin et al. (2011) found linkage to a 7.3-Mb region on chromosome 1p13-p12, which they designated SPG47.
By linkage analysis followed by candidate gene sequencing of an Israeli Arab family with autosomal recessive mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4B1 gene (607245.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
In 2 sibs, born of consanguineous Arab parents, with SPG47, Bauer et al. (2012) identified a homozygous truncating mutation in the AP4B1 gene (607245.0002). The mutation was found by exome sequencing of the candidate region on chromosome 1p13-p12 identified by linkage analysis (Blumkin et al., 2011). Bauer et al. (2012) noted the phenotypic similarities to the patients reported by Abou Jamra et al. (2011).
In 2 Turkish sisters with SPG47, Tuysuz et al. (2014) identified a homozygous truncating mutation in the AP4B1 gene (607245.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies on patient cells were not reported.
In 2 sibs, born of unrelated parents, with SPG47, Abdollahpour et al. (2015) identified a homozygous truncating mutation in the AP4B1 gene (607245.0004). Functional studies of the variant and studies on patient cells were not reported.
Abdollahpour, H., Alawi, M., Kortum, F., Beckstette, M., Seemanova, E., Komarek, V., Rosenberger, G., Kutsche, K. An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. Europ. J. Hum. Genet. 23: 256-259, 2015. [PubMed: 24781758] [Full Text: https://doi.org/10.1038/ejhg.2014.73]
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]
Bauer, P., Leshinsky-Silver, E., Blumkin, L., Schlipf, N., Schroder, C., Schicks, J., Lev, D., Riess, O., Lerman-Sagie, T., Schols, L. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics 13: 73-76, 2012. [PubMed: 22290197] [Full Text: https://doi.org/10.1007/s10048-012-0314-0]
Blumkin, L., Lerman-Sagie, T., Lev, D., Yosovich, K., Leshinsky-Silver, E. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum. J. Neurol. Sci. 305: 67-70, 2011. [PubMed: 21440262] [Full Text: https://doi.org/10.1016/j.jns.2011.03.011]
Tuysuz, B., Bilguvar, K., Kocer, N., Yalcinkaya, C., Caglayan, O., Gul, E., Sahin, S., Comu, S., Gunel, M. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am. J. Med. Genet. 164A: 1677-1685, 2014. [PubMed: 24700674] [Full Text: https://doi.org/10.1002/ajmg.a.36514]
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