Which clinical history findings are characteristic of myofibrillar myopathies?

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Myofibrillar myopathies, (previously called desmin-storage myopathies because desmin was the first protein found and is the most consistent protein in the aggregates that are characteristic of these disorders) refers to a group of hereditary myopathies with homogeneous morphological features.

The relative frequency of mutations is unknown, but desminopathy is likely the most common and αβ-crystallinopathy is the least common. However, in more than half of patients with a myofibrillar myopathy, the causative gene mutation is unknown.

Age at onset varies from 7–77 years, with a mean of 54 years, except for patients with mutations in selenoprotein N who have onset at birth and the 1 described patient with a lamin A/C mutation who presented at age 3 years. Patients with desminopathy often present in early adulthood, while patients with myotilinopathy and filaminopathy often present after age 50 years.

Clinically, this group of disorders is heterogeneous, with slowly progressive weakness affecting the proximal and distal muscles in most patients, but about 25% present with distal predominant weakness (common in myotilinopathy), and 25% present with only proximal weakness (common in filaminopathy). They are included in this article because some mutations are in the same genes that cause LGMD phenotypes.

Muscle MRI may help to distinguish distinct subtypes. [50] In patients with desminopathy, the semitendinosus was as least equally affected as the biceps femoris and the peroneal muscles were never less involved than the tibialis anterior. In patients with myotilinopathy, the adductor magnus was more affected than the gracilis and the sartorius was as least equally affected as the semitendinosus. In patients with filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius, the medial gastrocnemius was more affected than the lateral gastrocnemius and the semimembranosus was more affected than the adductor magnus.

Rare findings include the following:

  • Facial weakness

  • Asymmetric weakness

  • Severe atrophy

  • Respiratory failure, which may be severe or at presentation

  • Contractures

  • Distal sensory deficits (neuropathy diagnosed in about 20%)

Cardiac disease (especially common in desmopathy) may be present either as cardiomyopathy or arrhythmias and conduction block, and is present in about 50%.

Specific mutations include the following:

  • Desminopathy (MFM1): Onset is generally in the 20s or 30s with slow progression. Patients often present with distal weakness that progresses proximally, but limb-girdle, scapuloperoneal, and distal weakness combined with proximal weakness have all been described. Inter- and intrafamilial variability exists. Those with autosomal recessive disease may have an early onset. Cardiac disease (cardiomyopathy or atrioventricular conduction abnormalities) occurs in about 60% and may follow or precede myopathy, may be isolated, and may be severe. Respiratory failure may be severe and may be present at presentation. Facial and bulbar weakness may occur late. About 75% of patients eventually need assistance with ambulation.

  • αβ-crystallinopathy (MFM2): Onset varies from early to mid adulthood. Patients present with proximal more often than distal weakness. They may also present with respiratory failure. Patients may have neuropathy, cardiac failure, conduction abnormality, and congenital posterior polar cataracts.

  • Myotilinopathy (MFM3): The first mutations described were in 2 patients with an LGMD phenotype (see LGMD1A). Since then, several patients have been found with a myofibrillar myopathy. Onset is usually in mid-to-late adulthood. Most patients present with distal greater than proximal weakness, often with early foot drop. Neuropathy occurs in about 50%. Cardiomyopathy affects about 50%. Dysarthria, joint contractures and myalgias are present in about 33%. One family with spheroid body myopathy, a congenital myopathy, has been found with a mutation in the myotilin gene.

  • Z-band alternatively spliced PDZ motif-containing protein (ZASPopathy) (MFM4): Onset is at age 44-73 years, and patients most often present with distal more than proximal weakness, though proximal weakness can occur alone. Cardiac disease occurs in about 25% of patients and may be the presenting or predominant feature. Neuropathy affects approximately 45% of patients. Mutations are allelic with Markesbery distal myopathy, and dilated cardiomyopathy +/- isolated noncompaction of left ventricular myocardium.

  • Filamin C (γ-filamin) myopathy (MFM5): Age at onset is 24-57 years, with proximal greater than distal weakness. Respiratory failure occurs in about 50% of patients. Neuropathy affects about 40%. Cardiac disease may be present in up to 33%.

  • BCL2-associated athanogene 3 (BAG3) myopathy (MFM6): Age of onset is from childhood to early teens with proximal and distal weakness with progression that often causes respiratory failure and wheelchair dependency. [51, 52] Other features include contractures, scoliosis, and rigid spine. Peripheral neuropathy may be present. Cardiomyopathy is common and often severe, requiring transplantation in some patients.

  • Selenoprotein N myopathy: Selenoprotein N mutations were originally found in patients with congenital muscular dystrophy with rigid spine syndrome or minicore congenital myopathy. A study has shown that some patients with Mallory-body desmin-related myopathy also have a mutation in the selenoprotein N gene. Onset is at birth with hypotonia as well as axial and proximal weakness. Contractures and scoliosis are common and cardiac disease may occur. Death or the need for ventilatory support occurs before adulthood due to progressive respiratory failure.

  • Laminopathy: Besides presenting with a limb girdle phenotype (see LGMD1B), a case was described with a myofibrillar myopathy. The patient presented at age 3 years with difficulty running and at age 5 years was noted to have limb-girdle weakness.


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