Clinical and ultrastructural findings in an ataxic variant of Kufor-Rakeb syndrome

Abstract

Introduction: Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive neurodegenerative disorder manifesting as juvenile-onset atypical parkinsonism with pyramidal signs, supranuclear gaze palsy, dementia and characteristic minimyoclonus, with a notable phenotype variability. The responsible gene ATP13A2 was also associated with hereditary spastic paraplegia, uncomplicated early-or late-onset parkinsonism and a form of neuronal ceroid lipofuscinosis. We present clinical and ultrastructural findings in a 28-year-old woman with novel biallelic ATP13A2 mutations. Material and methods: An ultrastructural study of the skin and muscle sample was carried out. Sequence analysis of all protein coding exons and exon-intron boundaries of genes was performed on patient's genomic DNA. A proprietary oligonucleotide-selective sequencing method was used for capturing genomic targets and sequencing was performed using Illumina sequencing system. Results: The patient presented with juvenile-onset progressive parkinsonian syndrome and cognitive deterioration, accompanied by mild spastic paraplegia, supranuclear gaze palsy, cerebellar syndrome, peripheral neuropathy and fine myoclonus. Plentiful and varied osmiophilic deposits were found in skin and muscle biopsy. Sequence analysis identified two novel heterozygous variants in ATP13A2: a nonsense variant c.2209C>T, p.(Gln737*) and a 2-bp deletion c.2366_2367delTC, p.(Leu789Argfs*15) causing a frameshift leading to a premature stop codon. Oral levodopa treatment was initiated resulting in marked improvement of bradykinesia, rigidity, speech and swallowing. Conclusions: We report two novel ATP13A2 pathogenic mutations, further expanding the phenotype of Kufor-Rakeb syndrome with the unusual features of ataxia and polyneuropathy. We thoroughly describe ultrastructural findings and document a meaningful response to levodopa.

Neurodegeneration with Brain Iron Accumulation Disorders and Retinal Neurovascular Structure

“…A postmortem histopathological study revealed lipofuscinosis with whorled lamellar deposits in neurons and the retina, cerebrum, and cerebellum glia. 47 The widespread neuronal and glial lipofuscin aggregation has suggested that this disease is similar to neuronal ceroid lipofuscinosis. 32 Loss of brain and retinal nerve cells is characteristic of neuronal ceroid lipofuscinoses, categorized as lysosomal storage diseases.…”

“…Although further indocyanine green angiography (ICGA) is guided, studies for observation of vortex vein ampullae are needed to corroborate this hypothesis. A postmortem histopathological study revealed lipofuscinosis with whorled lamellar deposits in neurons and the retina, cerebrum, and cerebellum glia 47 . The widespread neuronal and glial lipofuscin aggregation has suggested that this disease is similar to neuronal ceroid lipofuscinosis 32 .…”

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

“…One salient aspect of our literature review is the combination of chorea and developmental delay. Indeed, several entities characterized by motor, language, [318][319][320] and action myoclonus [318][319][320][321][322][323] 606695 (PARK), 617225 (HSP) AR MxMD-MYORG-(PFBC) [324][325][326][327] 923…”

Ataxia and Action Myoclonus Related to Novel Mutations in ATP13A2 Gene

“…6 Cerebellar signs were very uncommon however action myoclonus, ataxia and seizures have been reported together with parkinsonism in a single Iranian family carrying ATP13A2 mutation. [7][8][9] More recently, a phenotype with lateonset ataxia and action myoclonus without parkinsonism has been reported. 10 We report a 47-year-old male presenting with late-onset myoclonic ataxia syndrome related to heterozygous variants in the ATP13A2 gene.…”

“…According to published cases, this phenotype does not seem to be related to a specific type of mutation. [7][8][9][10] Author Roles…”