Genetic Variations and Neuropathologic Features of Patients with PRKN Mutations.

BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.

Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years.

We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.