Anti-PL12 Anti-Synthetase Syndrome and Amyotrophic Lateral Sclerosis: A Case Report of a Rare Comorbidity.

BACKGROUND Anti-PL-12 syndrome is a rare form of myositis. Amyotrophic lateral sclerosis (ALS) is the commonest of the motor neuron disorders. However, the 2 conditions have not been reported to occur together in a single individual. This case report describes a patient who was diagnosed with anti-PL-12 anti-synthetase syndrome and then subsequently was diagnosed with ALS. CASE REPORT A 55-year-old male patient had anti-PL-12 syndrome and ALS occurring together. The patient initially presented with musculoskeletal complaints and was diagnosed with anti-PL-12 syndrome. He later went on to develop shortness of breath. Neurophysiological testing subsequently confirmed ALS as the patient experienced worsening muscle weakness over a 2-year period. A muscle biopsy performed showed neurogenic and myopathic process. The patient eventually lost the ability to ambulate without mobility assistance and suffered cardiac arrest due to complications from ALS, specifically diaphragmatic dysfunction. CONCLUSIONS This case report represents the first documented case of a patient having both anit-PL-12 syndrome and ALS together. It has been suggested that having an autoimmune disease (AID) may increase the subsequent risk of developing ALS. Previous studies did not conduct evaluation to ascertain serological markers for AS antibodies. Lab tests were rechecked and revalidated multiple times in separate facilities for confirmation of results in case of initial lab error. This may suggest a common etiology for both anti-PL-12 syndrome and ALS.

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD.

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.

Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat-containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-α, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.