#619621
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-84 (SPG84) is caused by compound heterozygous mutation in the PI4KA gene (600286) on chromosome 22q11.
Mutation in the PI4KA gene also causes NEDSPLB (616531), a severe neurodevelopmental disorder.
Autosomal recessive spastic paraplegia-84 (SPG84) is characterized by onset of slowly progressive walking difficulties due to lower limb weakness, stiffness, and spasticity in the first 2 decades of life. Additional features may include nystagmus, urinary urgency, joint contractures, and possible learning disabilities (summary by Verdura et al., 2021).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Verdura et al. (2021) reported 2 unrelated men with spastic paraplegia. Patient 9 was a 42-year-old man, born of unrelated parents of Spanish descent, who developed walking difficulties associated with weakness and stiffness of the lower limbs at age 17. He had an earlier history of frequent falls. The disorder was progressive, evolving to spastic paraplegia with hyperreflexia and extensor plantar responses. He had mild weakness of the distal hand muscles and mild sensory impairment of the distal lower legs. Other features included urinary urgency, horizontal nystagmus, and elongated visual and auditory potentials. At age 21, he was diagnosed with ileocolonic Crohn disease. Cognition was normal. Patient 10 was an 18-year-old man, born of unrelated parents of Latin American descent, who was noted to have frequent falls soon after walking at age 15 months. He developed spastic paraparesis at age 2 years. At age 17, there was mild progression of the spasticity and he showed bilateral cavus feet and lower limb contractures. He had mild cognitive impairment with difficulties in school. Imaging of both patients showed atrophy of the cervical spinal cord with no cerebellar abnormalities.
The transmission pattern of SPG84 in the families reported by Verdura et al. (2021) was consistent with autosomal recessive inheritance.
In 2 unrelated patients (patients 9 and 10) with SPG84, Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene (600286.0006-600286.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed decreased PI4K protein levels compared to controls. Further studies showed that patient cells had decreased PI4KA activity compared to controls, consistent with the mutations being hypomorphic alleles.
Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. Brain 144: 2659-2669, 2021. [PubMed: 34415322, images, related citations] [Full Text]
ORPHA: 631079; DO: 0112347;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | Spastic paraplegia 84, autosomal recessive | 619621 | Autosomal recessive | 3 | PI4KA | 600286 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-84 (SPG84) is caused by compound heterozygous mutation in the PI4KA gene (600286) on chromosome 22q11.
Mutation in the PI4KA gene also causes NEDSPLB (616531), a severe neurodevelopmental disorder.
Autosomal recessive spastic paraplegia-84 (SPG84) is characterized by onset of slowly progressive walking difficulties due to lower limb weakness, stiffness, and spasticity in the first 2 decades of life. Additional features may include nystagmus, urinary urgency, joint contractures, and possible learning disabilities (summary by Verdura et al., 2021).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Verdura et al. (2021) reported 2 unrelated men with spastic paraplegia. Patient 9 was a 42-year-old man, born of unrelated parents of Spanish descent, who developed walking difficulties associated with weakness and stiffness of the lower limbs at age 17. He had an earlier history of frequent falls. The disorder was progressive, evolving to spastic paraplegia with hyperreflexia and extensor plantar responses. He had mild weakness of the distal hand muscles and mild sensory impairment of the distal lower legs. Other features included urinary urgency, horizontal nystagmus, and elongated visual and auditory potentials. At age 21, he was diagnosed with ileocolonic Crohn disease. Cognition was normal. Patient 10 was an 18-year-old man, born of unrelated parents of Latin American descent, who was noted to have frequent falls soon after walking at age 15 months. He developed spastic paraparesis at age 2 years. At age 17, there was mild progression of the spasticity and he showed bilateral cavus feet and lower limb contractures. He had mild cognitive impairment with difficulties in school. Imaging of both patients showed atrophy of the cervical spinal cord with no cerebellar abnormalities.
The transmission pattern of SPG84 in the families reported by Verdura et al. (2021) was consistent with autosomal recessive inheritance.
In 2 unrelated patients (patients 9 and 10) with SPG84, Verdura et al. (2021) identified compound heterozygous mutations in the PI4KA gene (600286.0006-600286.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed decreased PI4K protein levels compared to controls. Further studies showed that patient cells had decreased PI4KA activity compared to controls, consistent with the mutations being hypomorphic alleles.
Verdura, E., Rodriguez-Palmero, A., Velez-Santamaria, V., Planas-Serra, L., de la Calle, I., Raspall-Chaure, M., Roubertie, A., Benkirane, M., Saettini, F., Pavinato, L., Mandrile, G., O'Leary, M., and 23 others. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. Brain 144: 2659-2669, 2021. [PubMed: 34415322] [Full Text: https://doi.org/10.1093/brain/awab124]
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