#614067
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-52 (SPG52) is caused by homozygous or compound heterozygous mutation in the AP4S1 gene (607243) on chromosome 14q12.
Spastic quadriplegia-52 (SPG52) is an autosomal recessive neurodevelopmental 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). Some patients may have seizures (Hardies et al., 2015).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Abou Jamra et al. (2011) reported a consanguineous Syrian kindred (MR061) in which 5 individuals had severe mental retardation and spasticity. They had delayed motor development in infancy, but lost the ability to walk in early childhood due to spasticity. Physical examination showed muscular hypertonia, especially of lower limbs, contractures, talipes equinovarus, decreased shank muscle mass, short stature, and microcephaly. All had a severe cognitive deficit and absent speech and could only express basic needs. Dysmorphic features included a prominent and bulbous nose, wide mouth, and coarse features. All were markedly shy, amicable, and calm, and kept smiling or laughing for no obvious reason, but did not have laughter bursts. None of the patients had seizures, a hearing impairment, or any anomalies of inner organs.
Hardies et al. (2015) reported 2 sisters, born of unrelated Caucasian parents, with developmental delay, febrile seizures, and spastic paraplegia. The patients were 14 and 13 years old at the time of the report. The older sister had 5 brief generalized febrile seizures between 5 months and 5 years of age, and seizure onset was associated with a stagnation in development. The seizures were well controlled and then remitted without treatment between 10 and 13 years. They subsequently recurred as afebrile focal tonic and tonic-clonic seizures with partial response to treatment. Her sister had apneic episodes until the age of 3 months and then showed delayed psychomotor development. She had 2 simple febrile seizures at the age of 1 and 2 years, followed by partially controlled afebrile focal seizures after age 9 years. Both girls had profound intellectual disability, axial hypotonia, and spastic diplegia; one had microcephaly (-3 SD). Brain MRI of the older sister showed dilation of the lateral ventricles and hypoplasia of the posterior portion of the corpus callosum. Brain MRI of the younger sister showed nonprogressive hydrocephalus due to congenital stenosis of the aqueduct of Sylvius with severe reduction of subcortical white matter, absence of the corpus callosum, and a lack of white-gray matter differentiation in basal ganglia. Both girls also had facial hypotonia and dysmorphic features, including broad nasal bridge, hypertelorism, arched eyebrows, bulbous nose, short philtrum, wide mouth with full lips, and high palate.
The transmission pattern of SPG52 in the family reported by Hardies et al. (2015) was consistent with autosomal recessive inheritance.
By linkage analysis followed by candidate gene sequencing of a Syrian family with autosomal recessive mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4S1 gene (607243.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
In 2 sisters, born of unrelated Caucasian parents, with SPG52 and seizures, Hardies et al. (2015) identified compound heterozygous truncating mutations in the AP4S1 gene (607243.0002 and 607243.0003). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of cells derived from 1 sister showed absence of the AP4S1 protein and a substantial reduction in all other AP4 subunits compared to controls. Immunoprecipitation studies confirmed the reduction of AP4 subunits and also showed impaired assembly of the complex. The findings implicated a defect in endosomal trafficking in both epilepsy and spastic paraplegia.
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]
Hardies, K., May, P., Djemie, T., Tarta-Arsene, O., Deconinck, T., Craiu, D., AR Working Group of the EuroEPINOMICS RES Consortium, Helbig, I., Suls, A., Balling, R., Weckhuysen, S., De Jonghe, P., Hirst, J. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum. Molec. Genet. 24: 2218-2227, 2015. [PubMed: 25552650, images, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 280763; DO: 0110804;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q12 | Spastic paraplegia 52, autosomal recessive | 614067 | Autosomal recessive | 3 | AP4S1 | 607243 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-52 (SPG52) is caused by homozygous or compound heterozygous mutation in the AP4S1 gene (607243) on chromosome 14q12.
Spastic quadriplegia-52 (SPG52) is an autosomal recessive neurodevelopmental 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). Some patients may have seizures (Hardies et al., 2015).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Abou Jamra et al. (2011) reported a consanguineous Syrian kindred (MR061) in which 5 individuals had severe mental retardation and spasticity. They had delayed motor development in infancy, but lost the ability to walk in early childhood due to spasticity. Physical examination showed muscular hypertonia, especially of lower limbs, contractures, talipes equinovarus, decreased shank muscle mass, short stature, and microcephaly. All had a severe cognitive deficit and absent speech and could only express basic needs. Dysmorphic features included a prominent and bulbous nose, wide mouth, and coarse features. All were markedly shy, amicable, and calm, and kept smiling or laughing for no obvious reason, but did not have laughter bursts. None of the patients had seizures, a hearing impairment, or any anomalies of inner organs.
Hardies et al. (2015) reported 2 sisters, born of unrelated Caucasian parents, with developmental delay, febrile seizures, and spastic paraplegia. The patients were 14 and 13 years old at the time of the report. The older sister had 5 brief generalized febrile seizures between 5 months and 5 years of age, and seizure onset was associated with a stagnation in development. The seizures were well controlled and then remitted without treatment between 10 and 13 years. They subsequently recurred as afebrile focal tonic and tonic-clonic seizures with partial response to treatment. Her sister had apneic episodes until the age of 3 months and then showed delayed psychomotor development. She had 2 simple febrile seizures at the age of 1 and 2 years, followed by partially controlled afebrile focal seizures after age 9 years. Both girls had profound intellectual disability, axial hypotonia, and spastic diplegia; one had microcephaly (-3 SD). Brain MRI of the older sister showed dilation of the lateral ventricles and hypoplasia of the posterior portion of the corpus callosum. Brain MRI of the younger sister showed nonprogressive hydrocephalus due to congenital stenosis of the aqueduct of Sylvius with severe reduction of subcortical white matter, absence of the corpus callosum, and a lack of white-gray matter differentiation in basal ganglia. Both girls also had facial hypotonia and dysmorphic features, including broad nasal bridge, hypertelorism, arched eyebrows, bulbous nose, short philtrum, wide mouth with full lips, and high palate.
The transmission pattern of SPG52 in the family reported by Hardies et al. (2015) was consistent with autosomal recessive inheritance.
By linkage analysis followed by candidate gene sequencing of a Syrian family with autosomal recessive mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4S1 gene (607243.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.
In 2 sisters, born of unrelated Caucasian parents, with SPG52 and seizures, Hardies et al. (2015) identified compound heterozygous truncating mutations in the AP4S1 gene (607243.0002 and 607243.0003). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of cells derived from 1 sister showed absence of the AP4S1 protein and a substantial reduction in all other AP4 subunits compared to controls. Immunoprecipitation studies confirmed the reduction of AP4 subunits and also showed impaired assembly of the complex. The findings implicated a defect in endosomal trafficking in both epilepsy and spastic paraplegia.
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]
Hardies, K., May, P., Djemie, T., Tarta-Arsene, O., Deconinck, T., Craiu, D., AR Working Group of the EuroEPINOMICS RES Consortium, Helbig, I., Suls, A., Balling, R., Weckhuysen, S., De Jonghe, P., Hirst, J. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum. Molec. Genet. 24: 2218-2227, 2015. [PubMed: 25552650] [Full Text: https://doi.org/10.1093/hmg/ddu740]
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