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. 2012 Nov;22(11):934-43.
doi: 10.1016/j.nmd.2012.05.001. Epub 2012 Jun 27.

Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients

Affiliations

Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients

Francesca Magri et al. Neuromuscul Disord. 2012 Nov.

Abstract

Limb-girdle muscular dystrophy (LGMD) 2L, caused by mutations in the anoctamin 5 (ANO5) gene, is the third most common LGMD in Northern and Central Europe, where the c.191dupA mutation causes the majority of cases. We evaluated data from 228 Italian LGMD patients to determine the prevalence of LGMD2L and the c.191dupA mutation, and to describe the clinical, muscle biopsy, and magnetic resonance imaging findings in these patients. Forty-three patients who lacked molecular diagnosis were studied for ANO5 mutations, and four novel mutations were found in three probands. Only one proband carried the c.191dupA mutation, which was compound heterozygous with c.2516T>G. Two probands were homozygous for the c.1627dupA and c.397A>T mutations, respectively, while a fourth proband had a compound heterozygous status (c.220C>T and c.1609T>C). Therefore occurrence and molecular epidemiology of LGMD2L in this Italian cohort differed from those observed in other European countries. ANO5 mutations accounted for ∼2% of our sample. Affected patients exhibited benign progression with variable onset and an absence of cardiac and respiratory impairment; muscle biopsy generally showed mild signs, except when performed on the quadriceps muscles; MRI showed predominant involvement of the posterior thigh. Overall these common clinical, morphological and imaging findings could be useful in differential diagnosis.

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Figures

Fig. 1
Fig. 1
Schematic representation of the intron/exon organisation of ANO5 and distribution of mutations along the gene. (A) Mutations already described in the literature. In the box, the mutations that are reported more than once are highlighted. (B) Mutations found in our cohort. Homozygous or compound heterozygous mutations in blue, and heterozygous mutations in green.
Fig. 2
Fig. 2
Pedigrees of the mutated families. Familiars that were tested for ANO5 mutations are specified in each pedigree. WT: wild-type.
Fig. 3
Fig. 3
Muscle biopsy. (A and B) Light microscopy histology (250X) with Gomori’s Trichrome. Patient II.2: skeletal muscle fibres show some centrally located nuclei, and the connective tissue is slightly increased (A). Patient IV: skeletal muscle shows polygonal fibres with a moderate increase in the central nuclei and slight fibre size variability (B). (C–F) Electron microscopy demonstrates defects in the plasma membranes and basal lamina in non-necrotic muscle fibres with focal loss of plasma membranes in (C) (30,000 X; higher magnification in the box) and (D) (25,000 X). Basal lamina overlying the plasma membrane defects is normal in (C), but it is altered in (D) with thickened and flocculent aspects. The basal lamina is replicated, forming more layers in (E) and (F) (12,000 X).
Fig. 4
Fig. 4
Clinical aspects (A) Patient I: vastus medial hamstrings and calf atrophy. (B) Patient II.1: mild sural hypertrophy and atrophy of the posterior compartment of the thigh. (C) Patient II.2: marked sural hypertrophy with mild atrophy of the hamstrings. (D) Patient IV: severe asymmetric quadriceps and posterior compartment atrophy.
Fig. 5
Fig. 5
Muscle imaging. (A–D) Muscle CT imaging of patient I at 29 years of age (A and B) and 43 years of age (C and D). The first study demonstrated only mild atrophy of the biceps femoris, whereas during the following years progressive involvement of the quadriceps femoris, gastrocnemius, and soleus muscles was observed. (E and F) MRI of the muscle of patient II.2, demonstrating bilateral adipose substitution of the posterior compartment of the thigh with partial atrophy of the quadriceps.
Fig. 6
Fig. 6
Molecular analysis. (A–D) In each box, the electropherogram showing the mutation. For missense mutations, the conservation among species. (A) Family I, (B) Family II, (C) Family III, (D) Family IV. (E) Structure of anoctamin 5 and position of mutations. Mutations in our sample are indicated in red (missense mutation) and in violet (frameshift mutation). Full circles indicate homozygous or compound heterozygous mutations, empty circles indicate single heterozygous mutations.
Fig. 7
Fig. 7
Relative frequency of different forms of LGMD in our sample of diagnosed patients. LGMD2L accounts for 2% of LGMDs.

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