Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (447 page)

   Western blot testing for dystrophin: Absent in DMD; abnormal size; normal amount in BMD

   Sequence analysis of the entire coding region and deletion/duplication analysis of the dystrophin gene

Suggested Readings

Beggs AH, Kunkel LM. Improved diagnosis of Duchenne/Becker muscular dystrophy.
J Clin Invest.
1990;85:613–619.

Emery AEH. The muscular dystrophies.
Lancet.
2002;359:687–695.

Tuffery-Giraud S, et al. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase.
Hum Mutat.
2009;30:934–945.

MYOTONIC DYSTROPHY TYPE 1

MIM #160900

   Definition

Myotonic dystrophy (DM1) clinically presents with myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and an abnormal EKG. In contrast to DMD, DM1 initially affects head and neck muscles, extraocular muscles, and the distal muscles of the extremities, and only later involves proximal musculature. DM1 results from the autosomal dominant inherited expansion of a CTG trinucleotide repeat sequence in the 3′- untranslated region of the dystrophia myotonica protein kinase gene (DMPK; 19q13.3).

   Relevant Tests and Diagnostic Value

Determination of CTG repeat size by polymerase chain reaction (PCR) amplification of the repeat region or by Southern blot analysis. Repeat size of <37 repeats is normal; 36–49 repeats are premutations; and 50 or more repeats are consistent with myotonic dystrophy type 1. A negative result does not rule out this diagnosis, and a diagnosis of myotonic dystrophy type 2 (DM2) associated with an expansion of a CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene should also be considered.

Suggested Readings

Groh WJ, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1.
New Eng J Med.
2008;358:2688–2697.

Modoni A, Silvestri G, Pomponi MG, et al. Characterization of the pattern of cognitive impairment in myotonic dystrophy type 1.
Arch Neurol.
2004;61:1943–1947.

Musova Z, et al. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene.
Am J Med Genet.
2009;149A:1365–1374.

FRIEDREICH ATAXIA (FRDA)

MIM #229300

   Definition

FRDA1 results from mutations in the frataxin gene (FXN; 9q21.11). The most common mutation is a GAA trinucleotide repeat expansion in intron 1 of the FXN gene, and it is found in over 95% of FRDA1 patients. In normal individuals, there are 5–30 GAA repeat expansions, while FRDA1 patients have 70 or more GAA repeats.

   Who Should Be Suspected?

Friedreich ataxia (FRDA1) is an autosomal disorder with onset in the first or second decade characterized by progressive gait and limb ataxia, and limb muscle weakness. Clinical manifestations include lower limb areflexia, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception.

   Relevant Tests and Diagnostic Value

   Polymerase chain reaction (PCR), fragment analysis, and Southern blot for GAA repeat detection

   Sequence analysis of the entire coding region; targeted mutation analysis; deletion/duplication analysis

Suggested Readings

Lodi R, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia.
Proc Natl Acad Sci U S A.
1999;96:11492–11495.

Pandolfo M. Friedreich ataxia
Arch Neurol.
2008;65:1296–1303.

SPINAL MUSCULAR ATROPHY (SMA)

   Definition and Classification