Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis–frontotemporal dementia phenotypes

Jennifer C Schymick ,Wim Robberecht ,Jenny Gass ,Neill R Graff‐Radford ,Rosa Rademakers ,Parastoo Momeni ,Joshua W Elder ,Jeffrey D Rothstein ,Yi Yang ,Caroline L Dahlberg ,John Hardy ,Ashley Cannon ,Peter M Andersen ,Odity Mukherjee ,Adriano Chiò ,Gabriella Restagno ,Orla Hardiman ,Richard J Caselli ,Matthew Greenway ,Jean Paul Vonsattel ,Michael Hutton ,Andrew Singleton ,Alison M Goate ,Bryan J Traynor

doi:10.1136/jnnp.2006.109553

Abstract

Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD...

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3–5 years from symptom onset
Sequence analysis of the PGRN gene identified novel heterozygous genetic variants in a single patient diagnosed with ALS– Frontotemporal dementia (FTD) (2.0%, 1 of 49) and in a single case of limb onset sporadic ALS (0.4%, 1 of 272 sporadic cases)
S120Y and T182M were not identified in 818 North American control chromosomes, in public databases of single nucleotide polymorphisms or in any of the other 361 ALS/ALS– FTD samples screened as part of this study, or in 523 previously published FTD samples.[7 8 11]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3–5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.[1] Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.[2] Approximately 5% of ALS patients have FTD (ALS– FTD)[3] and approximately half of patients with ‘‘classical’’ ALS have subtle frontal and temporal lobe cognitive impairment.[4] Many FTD cases develop symptoms of motor neuron involvement during the course of their illness[5] and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy.[6]

Methods

Results

Conclusion