Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (446 page)
Authors: Mary A. Williamson Mt(ascp) Phd,L. Michael Snyder Md
The initial hallmark sign in ALS is muscle weakness, occurring in approximately 60% of patients. The onset and nature of symptoms in ALS is very variable, but since it is a disease of upper and lower motor neurons, the senses of touch, hearing, taste, smell, and sight are not affected. Although therapy can in some cases slow the progression of disease, as the disease progress, weakness and paralysis spread to the muscles of the trunk, speech, swallowing, chewing, and breathing, and ultimately patients require permanent breathing support to survive.
Relevant Tests and Diagnostic Value
Mutation detection by analysis of the entire coding regions by single-strand conformation polymorphism (SSCP) or sequence analysis of genes associated with FALS, including SOD1, TARDBP (TDP-43), FUS, C9ORF72, and UBQLN2
Suggested Readings
ALS Association. Available from:
http://www.alsa.org/about-als/genetic-testing-for-als.html
McKinnon WC, Baty BJ, Bennett RL, et al. Predisposition testing for late-onset disorders in adults: a position paper of the National Society of Genetic Counselors.
JAMA.
1997;278:1217–1220.
Turner MR, et al. Controversies and priorities in amyotrophic lateral sclerosis.
Lancet Neurol.
2013;12(3):310–322.
CHARCOT MARIE TOOTH HEREDITARY NEUROPATHY (CMT)
MIM #118220
At least 27 types of CMT can be identified by DNA testing, but a negative result does not rule out the diagnosis as some mutations remain to be identified. More than 40 different genes/loci are associated with CMT, and inheritance can be autosomal recessive, autosomal dominant, or X-linked dominant. Clinical diagnosis is based on family history, neurologic examination, EMG/NCV testing, and in some cases sural nerve biopsy.
Charcot-Marie-Tooth disease (CMT) typically presents during adolescence and early adulthood with distal muscle weakness and atrophy often accompanied by sensory loss, depressed tendon reflexes, and high-arched feet.
Suggested Readings
England JD, et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review): report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation.
Neurology.
2009;72:185–192.
Saifi GM, Szigeti K, Snipes GJ, et al. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies.
J Investig Med.
2003;51:261–283.
Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies.
Ann Neurol.
2011;69:22–33.
MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD
MIM #310200
MUSCULAR DYSTROPHY, BECKER TYPE; BMD
MIM #300376
Duchenne muscular dystrophy (DMD)
is an X-linked disorder resulting from mutations in the dystrophin gene (Xq21.2-Xq21.1). Onset of gait difficulty usually occurs by age 3 years, with patients developing cardiomyopathy, wheelchair limited by age 12, and dying by age 20 years. Female heterozygotes of a mutation can develop progressive cardiac abnormalities.
Becker muscular dystrophy (BMD)
presents with a similar but milder and more slowly progressive course compared to DMD. Age of onset can be as early as age 12 years or much later, with loss of ambulation occurring in adolescence onward, and survival into the fourth or fifth decade.