Congenital Myopathy

Definition And Concept

Congenital myopathies are a heterogeneous group of genetically determined muscle disorders presenting at birth or in early infancy.
They are characterized by nonprogressive or slowly progressive weakness and hypotonia.
The underlying pathology involves structural or histochemical abnormalities of muscle fibers visible only on muscle biopsy, using histochemistry, immunocytochemistry, or electron microscopy.
Muscle biopsy shows no necrosis, inflammation, or true dystrophy, but rather specific subcellular defects or fiber-type disproportion.
These disorders spare the central and peripheral nervous systems, distinguishing them from spinal muscular atrophies and neuropathies.

Most congenital myopathies result from identified genetic variants.
Pathogenesis involves defects in sarcomeric proteins, excitation-contraction coupling, thin or thick filament assembly, membrane remodeling, or oxidative stress.
Many genes affect multiple phenotypes, and significant overlap exists with myofibrillar myopathies, congenital muscular dystrophies, and metabolic myopathies.

Gene	Subtype	Inheritance	Primary Subcellular Involvement	Pathogenesis
ACTA1	Nemaline myopathy; cap/zebra body	AD/AR	Thin filament	Abnormal thin filament structure.
NEB	Nemaline myopathy; core-rod	AR	Thin filament	Defective remodeling and stability.
RYR1	Central core; multiminicore; centronuclear	AD/AR	Triad	Abnormal excitation-contraction coupling.
MTM1, DNM2	Centronuclear (myotubular)	XR/AD/AR	T-tubule/sarcoplasmic reticulum	Defective membrane remodeling.
SEPN1	Multiminicore	AR	Unspecified	Oxidative defects.
MYH7	Myosin storage; fiber-type disproportion	AD/AR	Thick filament	Defective ATPase/actin binding.

Patients consistently present with neonatal or infantile hypotonia, and proximal weakness greater than distal weakness.
Common features include facial weakness, bulbar and respiratory involvement, a high-arched palate, thin muscle mass, and delayed motor milestones.
Alertness is preserved, which distinguishes this group from central causes of hypotonia.
Infants exhibit a frog-leg posture, slip through the examiner’s hands when held in axillary suspension, and display reduced antigravity movements.
Extraocular muscles are typically spared, except in specific centronuclear forms.
Fasciculations are strictly absent, differentiating them from Spinal Muscular Atrophy.
Severe forms present with contractures at birth (arthrogryposis).

Myopathy	Severe Form With Neonatal Death	Facial Weakness	Ptosis	Extraocular Weakness
Central Core Disease	Absent	Present	Absent	Absent.
Nemaline Myopathy	Present	Present	Absent	Absent.
Myotubular/Centronuclear	Present	Present	Present	Present.
Fiber-Type Disproportion	Variable	Variable	Absent	Present.

The X-linked form (MTM1 gene) is the most common and severe variant affecting males.
Presents with severe neonatal hypotonia, respiratory failure, ptosis, ophthalmoplegia, thin muscle mass, and a high palate.
Undescended testes are a common physical finding.
Muscle biopsy reveals large vesicular, centrally placed nuclei in >90% of fibers with perinuclear sarcoplasm and mitochondria.
Prognosis is poor in the severe X-linked form, with 75% mortality early in life.

The most common congenital myopathy, predominantly involving the ACTA1 and NEB genes.
Clinical spectrum ranges from fatal neonatal respiratory failure with arthrogryposis to mild juvenile and adult forms.
Common findings include dolichocephaly, high-arched or cleft palate, jaw weakness, and thin muscles.
Biopsy demonstrates nemaline rods, which are composed of excessive Z-band material such as actin, alpha-actinin, and nebulin.

Includes central core and multiminicore disease.
Central core disease is frequently associated with RYR1 mutations and presents with proximal weakness, hip dislocation, and joint laxity.
Multiminicore disease (associated with SEPN1) presents with a rigid spine, scoliosis, and early respiratory failure disproportionate to limb weakness.
Cores are amorphous central areas within the myofibrils lacking mitochondria and oxidative enzyme activity.
RYR1 mutations carry a high risk for Malignant Hyperthermia Susceptibility (MHS).

Characterised by nonprogressive hypotonia and weakness.
Muscle biopsy reveals type I fibers that are uniformly small and hypotrophic, outnumbering hypertrophic type II fibers.
Associated with facial weakness, dolichocephaly, and mild respiratory weakness.

Serum Creatine Kinase (CK): Normal or only mildly elevated, rarely exceeding 4 times the upper limit of normal.
Electrophysiology (EMG/NCV): Shows a myopathic pattern or remains normal, distinctly lacking denervation features seen in neuropathies.
Muscle Biopsy: Traditionally diagnostic, revealing specific structural changes such as central cores, nemaline rods, central nuclei, or fiber-type disproportion.
Genetic Testing: Targeted next-generation sequencing (NGS) panels on blood samples are preferred and can confirm many variants without the need for an invasive biopsy.

Spinal Muscular Atrophy (SMA): Distinguished by the presence of tongue fasciculations and early areflexia.
Congenital Muscular Dystrophies: Characterised by early contractures, potential structural brain involvement, and significantly elevated CK levels.
Congenital Myotonic Dystrophy: Differentiated by a history of maternal myotonia and generalized neonatal weakness.
Metabolic Myopathies: Examples like Pompe disease present with systemic findings, hepatomegaly, or cardiomegaly.
Central Hypotonia: Differentiated by the presence of brisk deep tendon reflexes, seizures, and dysmorphic features.

Currently, no definitive curative therapies exist; management relies on multidisciplinary supportive care.
Respiratory Management: Noninvasive ventilation, cough assist devices, and routine monitoring for nocturnal hypoventilation.
Nutritional Support: Gavage or gastrostomy feeding following thorough swallowing assessments.
Orthopedic Intervention: Physiotherapy, passive stretching for contracture prevention, and surgical correction for progressive scoliosis.
Anesthesia Precautions: Strictly avoid specific anesthetic triggers in patients with RYR1 mutations due to MHS risk; dantrolene must be readily available.
Emerging Therapies: Gene therapy trials for MTM1 myotubular myopathy are showing promising potential.
Prognosis: Highly variable. Most forms are nonprogressive, but severe neonatal forms can be rapidly fatal without continuous mechanical ventilation. With optimal supportive care, survival and ambulation rates improve dramatically.