Muscle & peripheral nerve nontumor

• Overall prevalence of congenital myopathy in the U.S. is estimated at 1 in 26,000; core myopathies represent the most common subgroup (Ann Neurol 2011;70:662)
• Most have infant or early childhood onset, although some variants can have adult onset

• Common features of multiminicore myopathy are similar to other congenital myopathies, include neonatal hypotonia, delayed motor development, generalized muscle weakness and atrophy and normal intelligence; weakness usually remains stable (nonprogressive)
• Gene specific clinical features
  • SELENON: autosomal recessive; classical severe clinical phenotype of axial myopathy, scoliosis and respiratory failure
    • Significant subset shows rigid spine syndrome (Am J Hum Genet 2002;71:739)
  • RYR1: autosomal recessive (dominant RYR1 mutations usually cause central core myopathy); weakness, malignant hyperthermia, external ophthalmoplegia and ligament laxity in distal upper extremity (Neurology 2005;65:1930)
  • MYH7: autosomal dominant and recessive; hypertrophic or dilated cardiomyopathy, distal weakness and respiratory impairment (Neuromuscul Disord 2012;22:1096)
  • TTN: autosomal recessive: cardiomyopathies (dilated cardiomyopathy, septal defects, noncompaction), arthrogryposis (Hum Mol Genet 2014;23:980)
  • ACTN2: autosomal recessive; adult onset, progressive proximal and distal low extremity weakness, with facial, respiratory and ocular muscle involvement in a subset (Ann Clin Transl Neurol 2024;11:629, Acta Neuropathol 2019;137:501)
  • MEGF10: autosomal recessive; pediatric or adult onset respiratory insufficiency, scoliosis and distal joint hyperlaxity (Nat Genet 2011;43:1189, Muscle Nerve 2016;53:984)

• SELENON mutant patients show severe wasting of sternocleidomastoid muscle and atrophy of semimembranosus, paraspinal, gluteus maximus and thigh muscle (Muscle Nerve 2015;52:728)
• In RYR1 mutant patients, quadriceps are usually diffusely involved with relative sparing of rectus femoris; sartorius is more severely affected than gracilis (Neurology 2005;65:1930)
• In MYH7 mutant patients, there is more prominent involvement of distal compared to proximal muscle groups and more prominent involvement of the posterior compared to the anterior compartment in the lower extremities (Neuromuscul Disord 2012;22:1096)
• ACTN2 mutant patients demonstrate selective involvement of the hamstrings and adductors in the thigh and anterior tibial group and soleus in the lower leg (Ann Clin Transl Neurol 2024;11:629)

Contributed by Chunyu Cai, M.D., Ph.D.

Case 1: Muscle biopsy from a 7 year old boy with clinical phenotype of congenital myopathy
and pathology finding of multiminicore disease; genetic analysis was denied


Case 2: Muscle biopsy from a 12 year old boy with multiple heterozygous RYR1 mutations


Case 3: Muscle biopsy from a 2 year old girl with 2 heterozygous TTN mutations

Contributed by Chunyu Cai, M.D., Ph.D.

Case 2: Muscle biopsy from a 12 year old boy with multiple heterozygous RYR1 mutations


Case 3: Muscle biopsy from a 2 year old girl with 2 heterozygous TTN mutations

• Skeletal muscle, left thigh, biopsy:
  • Congenital myopathy with multiminicore formation (see comment)
  • Comment: The morphologic changes of this biopsy include type I myofiber predominance and multiminicores on oxidative stains. Electron microscopy examination identified multiple small areas of Z disk streaming involving 1 to 3 sarcomeres; rare fibers demonstrate areas of myofibrillar disarray oriented along the longitudinal axis of the fiber. In this case, the biopsy features may best be categorized as multiminicore myopathy. A congenital myopathy genetic panel analysis is recommended to confirm the diagnosis. Precautions should be taken if this patient undergoes general anesthesia because patients with central core disease and some with multiminicore disease are at increased risk for malignant hyperthermia.

A 7 year old boy presented with generalized weakness. Per his mother, he had an onset of symptoms at birth but has since been stable. Serum creatine kinase (CK) was normal. A left quadriceps muscle biopsy was performed and appeared unremarkable on H&E stained cryostat sections. However, on NADH stain, the muscle showed changes represented by the image above. What is the most likely diagnosis?

1. Congenital muscular dystrophy
2. Congenital myasthenic syndrome
3. Juvenile dermatomyositis
4. Multiminicore myopathy
5. Nemaline rod myopathy

D. Multiminicore myopathy. The history is most consistent with a congenital myopathy. The NADH shows multiple irregular pale areas involving both type I (darker fibers) and type II (lighter fibers) muscle fibers, characteristic of multiminicore myopathy. Answer A is incorrect because congenital muscular dystrophy is usually progressive and has high CK. Answer B is incorrect because congenital myasthenic syndrome is not associated with core-like changes in muscle fibers. Answer C is incorrect because juvenile dermatomyositis is characterized by perifascicular myofiber damage and atrophy, which is not present in the image. Answer E is incorrect because nemaline rod myopathy is another type of congenital myopathy characterized by the presence of nemaline rods, best visualized in Gomori trichrome stain.

Comment Here

Reference: Multiminicore myopathy

A 7 year old boy presented with generalized weakness. Per his mother, he had an onset of symptoms at birth but has since been stable. Serum creatine kinase (CK) was normal. A left quadriceps muscle biopsy was performed and appeared unremarkable on H&E stained cryostat sections. However, on NADH stain, the muscle showed changes represented by the image above. Subsequent genetic analysis identified a homozygous RYR1 mutation in this patient. Which of the following is indicated in this patient?

1. Avoid succinylcholine or inhaled anesthetics
2. Cardiac evaluation and monitoring
3. Chest CT and respiratory support
4. CNS evaluation

A. Avoid succinylcholine or inhaled anesthetics. The history is most consistent with a congenital myopathy. The NADH shows multiple irregular pale areas involving both type I (darker fibers) and type II (lighter fibers) muscle fibers, characteristic of multiminicore myopathy. Genetic analysis identified RYR1 mutation, which is commonly associated with central core myopathy or multiminicore myopathy. Patients with RYR1 mutations are at high risk for malignant hyperthermia and thus need to avoid trigging anesthetics including succinylcholine or inhaled anesthetics. Answers B and D are incorrect because RYR1 mutations typically do not cause cardiomyopathy or CNS abnormality. Answer C is incorrect because respiratory muscle weakness is common in multiminicore myopathy caused by SELENON but not common in RYR1 mutant patients. Therefore, chest CT and respiratory support are not indicated.

Comment Here

Reference: Multiminicore myopathy