Case Presentation: A 33-year-old male with alcohol use disorder presented with progressive bilateral proximal arm weakness and muscle twitching for months. MRI of his brain and cervical spine were unremarkable. Electromyography (EMG) demonstrated mild diffuse fasciculations and changes consistent with denervation, which were attributed to alcohol-related polyneuropathy. The patient planned to abstain from alcohol and follow-up EMG was scheduled to exclude motor neuron disease, but the patient did not return. Two years later, despite abstinence, he returned with worsening upper extremity weakness, muscle atrophy, diffuse fasciculations, myalgias, joint pains, and worsening anxiety with panic attacks. EMG showed worsening diffuse motor neuron dysfunction and examination revealed reduced power, brisk reflexes, and an intention tremor in the upper extremities, with diffuse fasciculations. Sensation was intact throughout. Vital signs were normal. Laboratory results showed a creatine kinase of 3,518 U/L (20-232 U/L), but were otherwise normal. All antibodies tested were negative. A right deltoid muscle biopsy showed chronic myopathic changes with few scattered inflammatory cells. Genetic testing revealed intermediate repeats in C9ORF72 suggestive of amyotrophic lateral sclerosis (ALS) as the primary diagnosis. A separate genetic mutation, LARGE1, was found to potentially explain elevated levels of CK.Treatment commenced with riluzole for newly diagnosed ALS, prednisone for potential inflammatory myositis, escitalopram and diazepam as needed for anxiety, and dextromethorphan with quinidine sulfate for emotional lability. Follow-up was arranged and a referral to an ALS clinic was made to explore potential clinical trials.
Discussion: ALS is a neurodegenerative disorder characterized by progressive motor neuron dysfunction, typically presenting with asymmetric muscle weakness and atrophy. ALS exhibits considerable clinical heterogeneity and may co-occur with other conditions, including frontotemporal dementia (FTD). This case underscores the challenges in diagnosing ALS, particularly when complicated by genetic variants and atypical clinical features.A repeat expansion in the genetic mutation C9ORF72, as observed in this case, is believed to be the most common cause of adult-onset FTD and ALS (also known as the FTD-ALS complex). This expansion has been shown to restrict neural stem cell growth as well reduce both cortical and thalamic size in early utero development. These changes can lead to consequences in behavior, personality, and language that often precede the symptoms of ALS. This patient’s diagnosis of ALS followed a lengthy history of behavioral and personality changes involving addiction, severe anxiety, and panic attacks. In the context of a C9ORF72 mutation, these symptoms were likely sequelae of the FTD-ALS complex. Unexplained elevation in serum CK with an abnormal muscle biopsy further complicated the clinical picture.
Conclusions: ALS is a heterogeneous disease with multiple genetic variants that can lead to atypical presentations. The C9ORF72 genetic mutation can result in FTD-ALS complex, leading to behavioral, personality, and language changes that often precede symptoms of ALS. A thorough understanding of these genetic complexities is crucial for accurate and early diagnosis as well as treatment planning.