#615683
Table of Contents
A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-64 (SPG64) is caused by homozygous mutation in the ENTPD1 gene (601752) on chromosome 10q24.
Spastic paraplegia-64 (SPG64) is a neurologic disorder characterized by childhood onset of progressive spastic paraplegia with impaired intellectual development, gait impairment, dysarthria, and white matter abnormalities on brain imaging. Some individuals show neurocognitive regression (Calame et al., 2022).
For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Novarino et al. (2014) performed whole-exome sequencing network analysis to identify mutations in consanguineous families with hereditary spastic paraplegia. In 1 family with a complicated form of spastic paraplegia (family 1242), 2 brothers presented between 3 and 4 years of age with abnormal gait. When last examined, one brother, aged 12, was nonambulatory, and the other, aged 6, could walk with support. Both brothers had deep tendon reflexes, dysarthria, and spasticity. Neither had had an MRI, but both had borderline IQ, aggressiveness, delayed puberty, and microcephaly. In another family with a complicated form of spastic paraplegia (family 1800), a brother and sister presented at age 1 year with unsteady gait. When last examined, one at age 11 years and the other at age 21 years, they could still walk without support. Both sibs had dysarthria and spasticity; 1 had absent reflexes, and the other had normal reflexes. Both had mild white matter changes on brain MRI and moderately impaired intellectual development.
Calame et al. (2022) reported 27 individuals with SPG64 from 17 unrelated families from diverse countries and reviewed the literature on an additional 9 affected individuals from 5 unrelated families. Phenotypic features among the 36 patients included an early childhood age of onset, developmental delay or impaired intellectual development, progressive spastic paraplegia, and gait impairment in all patients. Weakness was observed in 28 patients, and dysarthria and abnormal reflexes were each found in 27 patients. Neurocognitive regression was present in 21 patients, and behavioral abnormalities in 22 patients. Cerebral white matter abnormalities were present in 15 of 28 patients for whom brain imaging was available. Dysmorphic features included low anterior hairline, synophrys, low-set ears with fleshy lobes, prominent philtrum, and mild micrognathia. Features present in the authors' cohort that had not previously been reported included dysmorphic facies (13 patients), hypotonia (7 patients), epilepsy (7 patients), scoliosis (5 patients), and cerebellar atrophy (2 patients).
In affected members of 2 consanguineous families segregating autosomal recessive spastic paraplegia, Novarino et al. (2014) identified homozygosity for a missense mutation (G217R; 601752.0001) and a nonsense mutation (E181X; 601752.0002).
In 27 individuals with SPG64 from 17 unrelated families from diverse countries, Calame et al. (2022) identified biallelic mutations in the ENTPD1 gene. These included 12 novel mutations, of which 10 were associated with loss of function and predicted to result in nonsense-mediated decay or premature termination. Two other mutations were not associated with loss of function; one was a missense mutation and the other was a 2-bp deletion-insertion mutation, resulting in a single amino acid substitution. Four recurrent mutations were identified, including one found in 4 families (L370X; 601752.0003) and one found in 3 families (4-bp intronic deletion; 601752.0004). All but 1 of the mutations were absent from the gnomAD database; the exception was the L370X mutation, which was found in 2 heterozygotes of non-Finnish European descent. Functional studies showed that biallelic ENTPD1 mutations impaired ATP hydrolysis and reduced ENTPD1 expression.
Calame, D. G., Herman, I., Maroofian, R., Marshall, A. E., Donis, K. C., Fatih, J. M., Mitani, T., Du, H., Grochowski, C. M., Sousa, S. B., Gijavanekar, C., Bakhtiari, S., and 53 others. Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia. Ann. Neurol. 92: 304-321, 2022. [PubMed: 35471564, related citations] [Full Text]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476, images, related citations] [Full Text]
SNOMEDCT: 726609005; ORPHA: 401810; DO: 0110815;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
10q24.1 | Spastic paraplegia 64, autosomal recessive | 615683 | Autosomal recessive | 3 | ENTPD1 | 601752 |
A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-64 (SPG64) is caused by homozygous mutation in the ENTPD1 gene (601752) on chromosome 10q24.
Spastic paraplegia-64 (SPG64) is a neurologic disorder characterized by childhood onset of progressive spastic paraplegia with impaired intellectual development, gait impairment, dysarthria, and white matter abnormalities on brain imaging. Some individuals show neurocognitive regression (Calame et al., 2022).
For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Novarino et al. (2014) performed whole-exome sequencing network analysis to identify mutations in consanguineous families with hereditary spastic paraplegia. In 1 family with a complicated form of spastic paraplegia (family 1242), 2 brothers presented between 3 and 4 years of age with abnormal gait. When last examined, one brother, aged 12, was nonambulatory, and the other, aged 6, could walk with support. Both brothers had deep tendon reflexes, dysarthria, and spasticity. Neither had had an MRI, but both had borderline IQ, aggressiveness, delayed puberty, and microcephaly. In another family with a complicated form of spastic paraplegia (family 1800), a brother and sister presented at age 1 year with unsteady gait. When last examined, one at age 11 years and the other at age 21 years, they could still walk without support. Both sibs had dysarthria and spasticity; 1 had absent reflexes, and the other had normal reflexes. Both had mild white matter changes on brain MRI and moderately impaired intellectual development.
Calame et al. (2022) reported 27 individuals with SPG64 from 17 unrelated families from diverse countries and reviewed the literature on an additional 9 affected individuals from 5 unrelated families. Phenotypic features among the 36 patients included an early childhood age of onset, developmental delay or impaired intellectual development, progressive spastic paraplegia, and gait impairment in all patients. Weakness was observed in 28 patients, and dysarthria and abnormal reflexes were each found in 27 patients. Neurocognitive regression was present in 21 patients, and behavioral abnormalities in 22 patients. Cerebral white matter abnormalities were present in 15 of 28 patients for whom brain imaging was available. Dysmorphic features included low anterior hairline, synophrys, low-set ears with fleshy lobes, prominent philtrum, and mild micrognathia. Features present in the authors' cohort that had not previously been reported included dysmorphic facies (13 patients), hypotonia (7 patients), epilepsy (7 patients), scoliosis (5 patients), and cerebellar atrophy (2 patients).
In affected members of 2 consanguineous families segregating autosomal recessive spastic paraplegia, Novarino et al. (2014) identified homozygosity for a missense mutation (G217R; 601752.0001) and a nonsense mutation (E181X; 601752.0002).
In 27 individuals with SPG64 from 17 unrelated families from diverse countries, Calame et al. (2022) identified biallelic mutations in the ENTPD1 gene. These included 12 novel mutations, of which 10 were associated with loss of function and predicted to result in nonsense-mediated decay or premature termination. Two other mutations were not associated with loss of function; one was a missense mutation and the other was a 2-bp deletion-insertion mutation, resulting in a single amino acid substitution. Four recurrent mutations were identified, including one found in 4 families (L370X; 601752.0003) and one found in 3 families (4-bp intronic deletion; 601752.0004). All but 1 of the mutations were absent from the gnomAD database; the exception was the L370X mutation, which was found in 2 heterozygotes of non-Finnish European descent. Functional studies showed that biallelic ENTPD1 mutations impaired ATP hydrolysis and reduced ENTPD1 expression.
Calame, D. G., Herman, I., Maroofian, R., Marshall, A. E., Donis, K. C., Fatih, J. M., Mitani, T., Du, H., Grochowski, C. M., Sousa, S. B., Gijavanekar, C., Bakhtiari, S., and 53 others. Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia. Ann. Neurol. 92: 304-321, 2022. [PubMed: 35471564] [Full Text: https://doi.org/10.1002/ana.26381]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476] [Full Text: https://doi.org/10.1126/science.1247363]
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