DO: 0070412;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
3p25.3 | Spinocerebellar ataxia, autosomal recessive 31 | 619422 | Autosomal recessive | 3 | ATG7 | 608760 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-31 (SCAR31) is caused by homozygous or compound heterozygous mutation in the ATG7 gene (608760) on chromosome 3p25.
Autosomal recessive spinocerebellar ataxia-31 (SCAR31) is a complex neurodevelopmental disorder characterized by global developmental delay with hypotonia and variably impaired intellectual and language development. Affected individuals have an ataxic gait, tremor, and dysarthria; more severely affected patients also have spasticity with inability to walk. Most have optic atrophy. Brain imaging shows cerebellar hypoplasia, enlarged ventricles, and atrophy of the posterior corpus callosum. Additional features may include retinitis pigmentosa, sensorineural deafness, dysmorphic facial features, and possibly endocrine dysfunction (summary by Collier et al., 2021).
Collier et al. (2021) reported 12 patients from 5 unrelated families with a complex neurodevelopmental disorder. The patients were ascertained internationally through the GeneMatcher Program after undergoing exome sequencing. The patients ranged from 21 months to 71 years of age. From early infancy, they showed axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All patients had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Other brain imaging findings included cerebral atrophy, enlarged ventricles, and atrophy of the posterior part of the corpus callosum. Most patients had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. More severely affected patients had spastic paraplegia and inability to walk. Some patients had dysmorphic facial features, such as long face, smooth philtrum, retrognathia, high-arched palate, and gum hypertrophy. One patient (P3) had seizures, another (P5) had hypertrophic cardiomyopathy, hypogonadotropic hypogonadism, and gynecomastia, and 2 sisters (family 2) had late-onset or absent puberty, suggesting possible endocrine dysfunction. Two sibs (family 4), 71 and 68 years of age, had additional neurodegenerative features, including dementia, schizophrenic psychosis, aggression, self-mutilation behavior, dysphagia, and choreatic hyperkinesia.
The transmission pattern of SCAR31 in the families reported by Collier et al. (2021) was consistent with autosomal recessive inheritance.
In 11 patients from 5 unrelated families with SCAR31, Collier et al. (2021) identified homozygous or compound heterozygous mutations in the ATG7 gene (see, e.g., 608760.0001-608760.0007). The mutations were found by exome sequencing, and the patients were ascertained internationally through the GeneMatcher Program. There were 1 nonsense, 2 splice site, and 6 missense mutations. Only 1 family had biallelic complete loss-of-function mutations, although there was not a clear genotype-phenotype correlation. Patient cells showed decreased levels of ATG7 protein associated with defective protein folding and dimerization, and accumulation of p62 (SQSTM1; 601530) in puncta. Functional studies of patient cells demonstrated impaired autophagic flux and decreased LC3 (MAP1LC3A; 601242) processing compared to controls. Expression of wildtype ATG7 rescued the defects in cells from 1 patient. The mutations were unable to fully rescue the LC3 lipidation and autophagic defects in Atg7-knockout mouse cells, consistent with a functional deficiency. Similar studies in yeast showed that the ATG7 mutations were associated with attenuated autophagy. Collier et al. (2021) concluded that impaired intracellular autophagy resulting from ATG7 mutations underlies the complex neurodevelopmental disorder and other organ system involvement observed in these patients.
Komatsu et al. (2006) reported that loss of Atg7, a gene essential for autophagy, leads to neurodegeneration in mice. Mice lacking Atg7 specifically in the central nervous system showed behavioral defects, including abnormal limb clasping reflexes and a reduction in coordinated movement, and died with 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with aging. Komatsu et al. (2006) commented that there was no obvious alteration in proteasome function. The authors concluded that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
Komatsu et al. (2007) found that conditional knockout mice with Purkinje cell-specific deletion of Atg7 developed abnormal axonal swellings and dystrophy of Purkinje cell axon terminals in the deep cerebellar nuclei. The distal axons of Purkinje cells in the knockout mice accumulated aberrant membranous structures that were different from double-membrane vacuole-like structures found in the distal axons of Purkinje cells from wildtype animals. The findings indicated impaired autophagic activity in the axons of mutant cells, which resulted in cell-autonomous axonopathy and Purkinje cell death. Dendritic spines were comparatively much less affected. Mutant mice subsequently developed deficits in locomotion and motor coordination. Komatsu et al. (2007) concluded that autophagy is required for normal axon terminal membrane trafficking and turnover and plays an essential role in the maintenance of axonal homeostasis and prevention of axonal degeneration.
Collier, J. J., Guissart, C., Olahova, M., Sasorith, S., Piron-Prunier, F., Suomi, F., Zhang, D., Martinez-Lopez, N., Leboucq, N., Bahr, A., Azzarello-Burri, S., Reich, S., and 21 others. Developmental consequences of defective ATG7-mediated autophagy in humans. New Eng. J. Med. 384: 2406-2417, 2021. [PubMed: 34161705] [Full Text: https://doi.org/10.1056/NEJMoa1915722]
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., Tanaka, K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880-884, 2006. [PubMed: 16625205] [Full Text: https://doi.org/10.1038/nature04723]
Komatsu, M., Wang, Q. J., Holstein, G. R., Friedrich, V. L., Jr., Iwata, J., Kominami, E., Chait, B. T., Tanaka, K., Yue, Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Nat. Acad. Sci. 104: 14489-14494, 2007. [PubMed: 17726112] [Full Text: https://doi.org/10.1073/pnas.0701311104]