Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis

Abstract

ObjectiveProgressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases.DesignRetrospective, observational.SettingAutopsied patients.ParticipantsWe compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included.Primary outcome measuresClinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles.ResultsClinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology.ConclusionsPMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological profile. The remaining patterns have LMN degeneration with TDP-43 pathology without UMN degeneration, or a combination of UMN and LMN degeneration with FUS-positive basophilic inclusion body disease.

Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

“…PMA neuropathology may show abnormalities of the UMN by way of CD68 staining of the descending corticospinal tract, abnormalities identified in 50% of patients with clinically isolated LMN disease 140 . Distinct pathological change is identified in the motor and extra-motor areas of the brains as well as the spinal cords of patients whose disease was clinically limited to the LMN and these changes seem independent of progression rate 141 Importantly, as is seen in ALS, inclusions positive for ubiquitin, TDP-43, and FUS are frequently present 140, 142 . Thus, the strongest evidence points to PMA being part of disease spectrum, not a different disease.…”

Amyotrophic lateral sclerosis of long clinical course clinically presenting with progressive muscular atrophy

“…Progressive muscular atrophy (PMA), also referred to as spinal progressive muscular atrophy, progressive spinal muscular atrophy, or Aran–Duchenne disease is characterized by isolated signs of lower motor neuron (LMN) dysfunction, loss of anterior horn cells, and preservation of upper motor neuron (UMN) and corticospinal tracts . Phosphorylated TDP‐43‐immunopositive inclusions were also observed in PMA . Therefore, sporadic ALS and PMA are now considered to fall within the same disease spectrum as examples of TDP‐43 proteinopathy.…”

Esclerosis lateral amiotrófica: actualización

“…La forma clásica de esta enfermedad se caracteriza por la mezcla de manifestaciones clínicas de lesión de las neuronas motoras superior e inferior y signos de alteración bulbar y respiratoria (tabla 2) (38 (39). Muchos pacientes con ELA presentan síntomas de déficit cognitivo, conductual y comportamental en el espectro de la DFT; estos son principalmente disfunción ejecutiva, irritabilidad, cambios de la personalidad con impulsividad y mal reconocimiento de la enfermedad; su presencia constituye un marcador pronóstico negativo.…”