Dataset Information

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).

ABSTRACT:

Objective

Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious.

Methods

We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1.

Results

In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material.

Conclusions

Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.

SUBMITTER: Hirst J

PROVIDER: S-EPMC5001803 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).

Hirst Jennifer J Madeo Marianna M Smets Katrien K Edgar James R JR Schols Ludger L Li Jun J Yarrow Anna A Deconinck Tine T Baets Jonathan J Van Aken Elisabeth E De Bleecker Jan J Datiles Manuel B MB Roda Ricardo H RH Liepert Joachim J Züchner Stephan S Mariotti Caterina C De Jonghe Peter P Blackstone Craig C Kruer Michael C MC

Neurology. Genetics 20160825 5

<h4>Objective</h4>Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious.<h4>Methods</h4>We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1.<h4>Results</h4>In 4 of the 6 patients, the ...[more]

PMID: 27606357

Similar Datasets

Project description:Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.

Dataset Information

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).

Objective

Methods

Results

Conclusions

Publications

Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).

Similar Datasets

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