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Novel SOD1 mutation discovered in atypical ALS by whole exome sequencing
  1. Christopher J Klein1,2,
  2. Yanhong Wu3,
  3. Xiaohui Duan1,
  4. Sumit Middha4,
  5. Brian D Dawson3,
  6. Jean-Pierre Kocher4,
  7. Peter J Dyck1
  1. 1 Department of Neurology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  2. 2 Department of Medical Genetics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  3. 3 Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  4. 4 Department of Bioinformatics and Statistics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Christopher J Klein, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; klein.christopher{at}mayo.edu

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Patients with familial amyotrophic lateral sclerosis (f-ALS) typically have asymmetric onset weakness, upper motor neuron signs, absent sensory involvement and relatively rapid disease progression with fatality typically in 2–5 years of onset.1 In contrast, distal hereditary motor neuropathies (dHMNs) and hereditary motor and sensory neuropathies type-2 (HMSN2) have symmetric length-dependent motor axonal loss and slow disease onset and progression. Hereditary motor neuropathies and motor neuron diseases have extremely diverse genetic causes,1 ,2 and within each group, distinct phenotype–genotype correlations are uncommon for f-ALS, dHMN and HMSN2.

This report illustrates a varied phenotypic presentation from SOD1-associated f-ALS and illustrates whole exome sequencing (WES) as an effective approach for diagnosing genetically heterogeneous disorders with atypical phenotypes.

Case report

The proband was evaluated at ages 39, 40, 43, 65, 67 and 73 years. He had symmetrical progressive distal weakness of legs with foot drop and foot paraesthesias. Weakness progressed to his hands. Ankle reflexes were absent, and vibration sensation was reduced at the toes. Babinski and Chaddock signs were absent. From 39 to 65 years of age, he was suspected to have dHMN or HMSN. By age 67, spinobulbar muscular atrophy (SBMA) and HMSN2C were also considered in the differential diagnosis because of weakness in bulbar musculature, flaccid dysarthria and dysphagia. His reflexes became brisk at patellar and biceps brachii tendons despite the prominent weakness in the subserved muscles. At the age of 73, he has severe flaccid dysarthria and diet restriction from aspiration risk. …

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