Neurodegeneration, Childhood-Onset, Stress-Induced, With Variable Ataxia And Seizures

A number sign (#) is used with this entry because of evidence that stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is caused by homozygous mutation in the ADPRHL2 gene (610624) on chromosome 1p34.

Description

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. Patient have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy (summary by Ghosh et al., 2018).

Clinical Features

Ghosh et al. (2018) reported 6 unrelated families, 5 of which were determined to be consanguineous and 1 with parents who originated from the same small village in Sicily, with a neurodegenerative disorder apparent in childhood after normal early development with some speech and motor acquisition. In most cases, the neurodegeneration was associated with a physiologic stress, such as infection or seizures. The most severely affected family (family 1) included 9 children from the United Arab Emirates, 7 of whom died between 2 and 15 years of age. All patients in this family presented with seizures between 1 and 2 years of age, followed by developmental stagnation and loss of milestones. A detailed history of one of the patients noted that he had cyclic episodes of depressed consciousness and hypoventilation with further loss of milestones. Additional features in this patient included type II fiber atrophy on muscle biopsy, axonal loss on nerve biopsy, and cerebral and cerebellar atrophy. He ultimately required a ventilator and feeding tube and died of respiratory failure at age 9 years. Several other affected children in this family died suddenly during normal activities, such as eating, playing, or sleeping. Seven additional patients from 5 families were subsequently identified. These patients ranged from 2 to 16 years of age; 1 had died in his sleep at age 6. Three of these patients developed generalized multifocal seizures in the first years of life, but 4 patients did not have seizures. Notably, in 1 family (family 4), 1 sib had seizures and the other sib did not. These patients had cerebellar signs with ataxia, dysarthria, dysmetria, tremor, and abnormal eye movements such as strabismus, nystagmus, hypometric saccades, and external ophthalmoplegia, suggesting brainstem dysfunction. Less common features included type II fiber atrophy and fiber type variation on skeletal muscle biopsy, extensor plantar responses, muscle weakness, tongue fasciculations, hearing loss, and axonal or demyelinating sensorimotor polyneuropathy. Most patient had mild global developmental delay with mildly delayed intellectual development, although 1 had patient had normal cognition at age 15. Most patients had cerebellar atrophy on brain imaging; some had spinal cord atrophy and nonspecific white matter abnormalities.

Danhauser et al. (2018) reported 12 patients from 8 unrelated families, 4 of which were consanguineous, with CONDSIAS. The patients ranged from 22 months to 32 years of age, and 7 had died between 1 and 30 years of age. Following early normal development, most patients presented in the first years of life with developmental delay or speech delay, although a few patients presented late in the first decade. The patients had episodic infection- or stress-associated neurologic deterioration affecting motor and cognitive function. Features included gait disturbances, ataxia, dystonic posturing, muscle weakness, hypotonia, facial grimacing, and respiratory insufficiency sometimes requiring mechanical ventilation. Many showed developmental regression and loss of ambulation, as well as variable cognitive decline and dysarthria. Five patients had ophthalmologic abnormalities, such as visual impairment, nystagmus, or strabismus, 1 had sensorineural hearing loss, 6 had seizures, and 8 had cerebellar atrophy on brain imaging. Electrophysiologic testing showed an axonal polyneuropathy in 6 patients. Other more variable features included acquired microcephaly and short stature.

Inheritance

The transmission pattern of CONDSIAS in the families reported by Ghosh et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected individuals from 6 unrelated mostly consanguineous families with CONDSIAS, Ghosh et al. (2018) identified homozygous mutations in the ADPRHL2 gene (610624.0001-610624.0006). There were 2 nonsense mutations, 1 frameshift mutation, and 3 missense mutations affecting highly conserved residues in the ADP-ribosyl-glycohydrolase domain. The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Expression of one of the nonsense mutations (Q334X; 610624.0001) in E. coli resulted in no detectable protein, and analysis of patient cells showed absence of the protein, consistent with a complete loss of function. Expression of one of the missense mutations (T79P; 610624.0003) in E. coli showed that it caused protein destabilization, suggesting that the missense mutations can have a loss-of-function effect. Further functional studies of the variants and studies of patient cells were not performed. Ghosh et al. (2018) suggested that accumulation of poly-ADP ribose (PAR) or failure of reversal of PAR modification could trigger a cell-death response cascade, resulting in progressive neurodegeneration.

In patients from 8 unrelated families with CONDSIAS, Danhauser et al. (2018) identified 5 different homozygous mutations in the ADPRHL2 gene (see, e.g., 610624.0007 and 610624.0008). There was 1 missense mutation (V335G; 610624.0007), 1 nonsense, 2 frameshift, and a splice site mutation. The mutations, which were found by exome sequencing, segregated with the disorder in the families. Fibroblasts derived from 2 unrelated patients showed undetectable ADPRHL2 protein as well as impaired cellular removal of ADP-ribose, accumulation of PAR, and reduced viability compared to wildtype when stressed with hydrogen peroxide. The reduced viability and PAR accumulation could be rescued with wildtype ADPRHL2 and with a PARP1 (173870) inhibitor. These findings were consistent with the mutations causing a loss of function and implicated disturbed posttranslational protein ADP-ribosylation as a pathogenetic mechanism.

Animal Model

Ghosh et al. (2018) demonstrated that knockdown of the Drosophila ADPRHL2 paralog, Parg, resulted in decreased fly survival under oxidative conditions with a similar detrimental effect on neuronal survival when expressed in neurons. Flies with a partially inactivated Parg could survive, but showed progressive neurodegeneration, reduced locomotion, and a reduced lifespan. Expression of wildtype Parg and wildtype human ADPRHL2 rescued the phenotype. Treatment of mutant flies with minocycline, which inhibits PARP (PARP1; 173870) activity, resulted in a dose-dependent rescue of the phenotype.