What is the pathophysiology of facioscapulohumeral dystrophy (FSHD)?

Updated: Mar 19, 2019
  • Author: Naganand Sripathi, MD; Chief Editor: Amy Kao, MD  more...
  • Print

It is an autosomal dominant disease in 70-90% of patients and is sporadic in the rest. One of the FSHD genes has been localized to chromosome band 4q35, but the gene or genes that are affected in FSHD are still unknown. Patients with FSHD have a shorter Eco RI digestion fragment detected by the chromosome-4qter DNA marker p13E-11. About 2% of FSHD patients are not linked to the locus at 4q35. [1]

The probe p13E-11 identifies 2 polymorphic loci at 4q35 and 10q26. The Eco R1 fragment of 4q is composed of repetitive DNA sequences that are 3.3-kilobase (kb) Kpn I tandem repeats identified as D4Z4. In control subjects, the D4Z4 repeat consists of 11-100 KpnI units, each 3.3 kb, whereas in FSHD this is shortened; the shortened Eco RI fragment in FSHD is 1-10 units. Diagnostic difficulties arise as these fragments also may come from chromosome 10, as already described. 4-Type units are resistant to Bln I and 10-type units are resistant to Xap I. The combined use of EcoRI, BlnI, and XapI in pulsed-field gel electrophoresis–based DNA separation techniques allows detection of 4q fragments.

  • FSHD is caused by a contraction mutation of D4Z4 macrosatellite repeats in the subtelomeric region of the 4qA161 haplotype of chromosome 4 in 95% of patients.

  • Those without FSHD have approximately 11-100 D4Z4 units, whereas patients with FSHD have 1-10 D4Z4 units. [2]

  • At least 1 copy of D4Z4 is required to develop FSHD.

  • Mosaic males are mostly affected, where as mosaic females with an equal complement of affected cells are more often asymptomatic carriers.

  • A bi-allelic variation of chromosome 4qter is known, designated as 4qA and 4qB. FSHD alleles are exclusively of the 4qter type (4qA161).

  • Although the genetic lesion is well described in FSHD, the causal gene and the protein products are not known.

  • Additional testing may be needed in patients without D4Z4 contraction for a deletion encompassing the region.

  • Patients with FSHD and no contraction of D4Z4 repeats may show loss of DNA methylation and heterochromatin markers of D4Z4 repeat.

  • The most extensively studies candidate genes for FSHD on 4q35 are ANT1, PDLIM3, FRG1, TUBB4q, FRG2, and DUX4.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!