Hereditary primary lateral sclerosis and progressive nonfluent aphasia
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To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia.
Patients and methods
Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another.
Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results.
A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.
KeywordsPrimary lateral sclerosis Motor neuron disease Progressive nonfluent aphasia Cerebellar ataxia Parkinsonism Dominant inheritance Argyrophylic grain disease Primary age-related tauopathy Central distal axonopathy
Our thanks to Dr. Antonio Oliveros-Juste for remission of patients; Drs. Ana Vela and Jordi Aldomá for MR images; Mr. Juan Ramón Solans, Drs. Ariadna Fernández-Sanz and Jesús Aladrén-Sangrós for help with the videtapes; Mrs. María Jesús Chopo for obtention of DNA samples; Mrs. Teresa Sopeña Biarge and Mrs. Mar González-Cantalejo from the Medical Library of Hospital Universitario Miguel Servet, for bibliographical research; and Dr. Jorge Alfaro for assistance in the pathological studies.
Compliance with ethical standards
Conflicts of interest
All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
Supplementary material 1 (MP4 15897 KB)
Supplementary material 2 (MP4 34972 KB)
- 15.Dupré N, Valdmanis PN, Bouchard JP, Rouleau GA. Autosomal dominant primary lateral sclerosis. Neurology 68:1156–7Google Scholar
- 18.Erb W (1902) Spastic and syphilitic spinal paralysis. Lancet 2:969–974Google Scholar
- 32.Josephs KA, Murray ME, Tosakulwong N, Whitwell JL, Knopman DS, Machulda MM et al (2017) Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART). Acta Neuropathol 133:705–715CrossRefGoogle Scholar
- 38.Lamarche JB, Lemieux B, Lieu HB. The neuropathology of “typical” Friedreich’s ataxia in Quebec (1984). Can J Neurol Sci 11(4 Suppl): 592–600Google Scholar
- 42.Mackenzie IR, Feldman H (2004) Neurofilament inclusion body disease with early onset frontotemporal dementia and primary lateral sclerosis. Clin Neuropathol 23:183–193Google Scholar
- 44.Medical Research Council (1976) Aids to the examination of the peripheral nervous system. Her Majesty’s Stationery Office, LondonGoogle Scholar
- 61.Schut JW, Haymaker W (1951) Hereditary ataxia. A pathologic study of five cases of common ancestry. J Neuropathol Clin Neurol 1:183–213Google Scholar
- 66.Tan CF, Kakita A, Piao YS, Kikugawa K, Endo K, Tanaka M et al (2003) Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. Acta Neuropathol 105:615–620Google Scholar