Spastic Paraplegia 78, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-78 (SPG78) is caused by homozygous or compound heterozygous mutation in the ATP13A2 gene (610513) on chromosome 1p36.

Description

Autosomal recessive spastic paraplegia-78 is an adult-onset neurodegenerative disorder characterized predominantly by spasticity and muscle weakness of the lower limbs, resulting in gait difficulties and loss of ambulation in some patients. Affected individuals also have cerebellar signs, such as dysarthria, oculomotor disturbances, and limb and gait ataxia; brain imaging shows cerebellar atrophy. Some patients may have mild cognitive impairment or frank dementia. The phenotype is highly variable (summary by Estrada-Cuzcano et al., 2017).

Biallelic mutation in the ATP13A2 gene also causes Kufor-Rakeb syndrome (KRS; 606693), a neurodegenerative disorder with overlapping features. Patients with KRS have earlier onset and prominent parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017).

Clinical Features

Kara et al. (2016) reported a 46-year-old man, born of consanguineous Pakistani parents, with onset of spastic quadriplegia and cognitive decline at age 18 years. He also showed bilateral pes cavus, ataxia, and oculomotor abnormalities, including nystagmus, squint, and reduced upgaze. Brain imaging showed cerebral atrophy and subtle abnormalities in the basal ganglia. The patient had no features of parkinsonism. Treatment with L-DOPA did not result in lasting clinical improvement.

Estrada-Cuzcano et al. (2017) reported 5 patients from 3 unrelated families with complicated spastic paraplegia. The mean age at onset was 32 years, and the patients presented with abnormal gait, spastic paraplegia, weakness of the lower limbs, and dysarthria; 1 patient had neurogenic bladder dysfunction. Physical examination showed hyperreflexia in the upper and lower limbs, and 4 patients had extensor plantar responses. Three patients lost ambulation 8 to 18 years after disease onset. Additional features included oculomotor disturbance and limb and gait ataxia, indicating cerebellar involvement, as well as axonal motor and sensory polyneuropathy. Only 1 patient had mild resting tremor and bradykinesia; the others did not have clinical evidence of involvement of the extrapyramidal motor system. Of 3 affected brothers in a family of Belgian origin, 2 had mild verbal memory deficits, whereas the third had no cognitive impairment. The 2 other unrelated patients, both female, had severe dementia with supranuclear gaze palsy, and 1 also had acoustic hallucinations. Brain imaging showed cerebellar and cortical atrophy in all patients, thin corpus callosum and periventricular white matter changes in 1 patient, and abnormalities of the anterior fornix of the corpus callosum in 2 patients. Dopamine transporter scintigraphy performed in 1 patient who had no clinical signs or symptoms of extrapyramidal involvement showed a drastic decrease in dopamine transporter density that was most pronounced in the putamen. Estrada-Cuzcano et al. (2017) also reported the clinical features of a Lebanese man with a similar phenotype. He presented with rapidly progressive parkinsonism, supranuclear gaze palsy, perioral myokymia, and cognitive decline at age 44 years. He had pyramidal involvement with marked spasticity and hyperreflexia, most pronounced in the lower limbs. He did not have ataxia.

Inheritance

The transmission pattern of SPG78 in the families reported by Estrada-Cuzcano et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 46-year-old man, born of consanguineous Pakistani parents, with SPG78, Kara et al. (2016) identified a homozygous mutation in the ATP13A2 gene (610513.0009). Functional studies of the variant and studies of patient cells were not performed. The patient was 1 of 97 probands with complicated spastic paraplegia who underwent molecular analysis.

In 5 patients from 3 unrelated families with SPG78, Estrada-Cuzcano et al. (2017) identified homozygous or compound heterozygous mutations in the ATP13A2 gene (610513.0010-610513.0013). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent patients were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. Studies of selected patient cells and in vitro studies of some of the mutations showed abnormal intracellular localization of the mutant proteins, transcript or protein instability in some cases, and impaired lysosomal and mitochondrial function, all consistent with a loss of function.