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C9orf72 Gene

By Kelly Mrachek, MD

Jun 10, 2021

C9orf72 gene, neuronotes, neropathology

The patient is a middle-aged Caucasian male who presents with chief complaint of progressive muscle weakness and muscle cramps of insidious onset. He also reported muscle mass loss and muscle twitching. No muscle pain, no skin rash, or myotoxic medications are reported.  Myositis panel is negative.  CPK levels over the last few months have trended slightly upward, and the most recent CPK is ~800.  EMG/NCS shows denervation-type changes.  No family history of  neuromuscular disorder is reported.  A muscle biopsy of the thigh was pursued to aid in diagnostic work-up, and confirms denervation-type changes that are active and chronic.  A clinical diagnosis of motor neuron disease was made, and genetic testing was pursued.


Using figures 1-4, which of the following gene mutations is most commonly identified in amyotrophic lateral sclerosis?



Answer: C9orf72

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that results in loss of upper and lower motor neurons.

The majority of ALS cases are sporadic, with a mean onset in the mid 50’s, and earlier onset reported in familial cases, about a decade earlier.

The most common genetic cause of ALS is a hexanucleotide G4C2 repeat expansion in chromosome 9 open reading frame 72 gene (C9orf72). See references.

Why were the other answers wrong?

A few gene mutations have been discovered as etiologies for familial amyotrophic lateral sclerosis (FALS).

C9orf72 accounts for approximately less than half of FALS (30%-40%).

SOD1 mutations account for 20% of FALS.

TARDBP, encodes the TDP-43 protein, accounts for ~5% of FALS cases.

Mutations in FUS also account for ~5% of FALS cases.


Baloh RH, Rakowicz W, Gardner R, Pestronk A. Frequent atrophic groups with mixed-type myofibers is distinctive to motor neuron syndromes. Muscle Nerve. 2007 Jul;36(1):107-10. PMID: 17299742.

Mathis S, Goizet C, Soulages A, et al. Genetics of amyotrophic lateral sclerosis: A review. J Neurol Sci. 2019 Apr 15;399:217-226. PMID: 30870681.

Iłzecka J, Stelmasiak Z. Creatine kinase activity in amyotrophic lateral sclerosis patients. Neurol Sci. 2003 Nov;24(4):286-7. PMID: 14658051.

van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017 Nov 4;390(10107):2084-2098. PMID: 28552366.


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