Inherited Diseases of Skeletal Muscle

Slide 1 · Inherited Diseases of Skeletal Muscle

Congenital myopathies

Congenital muscular dystrophies

Genotype, morphology, and clinical phenotype

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish congenital myopathies from progressive muscular dystrophies.

Associate RYR1, nemaline, and centronuclear disorders with structural signatures.

Explain matrix and α-dystroglycan defects in congenital muscular dystrophy.

Integrate inheritance, course, phenotype, and morphology.

Slide 3 · Inherited myopathies form a heterogeneous disease spectrum

Inherited variant

Protein or pathway defect

Muscle / multisystem phenotype

Muscle dysfunction—with variable extracardiac and systemic involvement

Slide 4 · Skeletal muscle may not be the only affected organ

Predominantly skeletal muscle

Muscle + other organs

Anatomic extent varies among inherited myopathies.

Cardiac involvement is especially important because it may limit survival.

Slide 5 · Clinical classification uses several independent axes

Inheritance / pedigree

Age of onset

Pattern of weakness

Course of disease

Biopsy / molecular mechanism

Slide 6 · Major inherited skeletal-muscle disease categories

Group

Defining emphasis

Congenital myopathy

Structural abnormality; Often infancy onset

Muscular dystrophy

Progressive muscle injury

Congenital muscular dystrophy

Infancy onset + progressive injury

Channel / metabolic myopathy

Excitability or bioenergetics

Slide 7 · Age at onset and disease course are not interchangeable

Congenital onset ≠ invariably progressive

Progression must be assessed separately

Use onset and trajectory as distinct diagnostic descriptors.

Congenital muscular dystrophies generally combine early presentation with progressive injury.

Slide 8 · Mechanism and muscle compartment shape phenotype

Sarcomere / Z-disk

Nemaline

Calcium-release system

Central core

Myonuclear localization

Centronuclear

Extracellular matrix

Congenital dystrophy

Slide 9 · Congenital myopathy is primarily a structural concept

Many affected infants present with hypotonia and weakness.

Microscopy can reveal disease-defining alterations of fiber architecture.

The structural diagnosis should be interpreted alongside a molecular diagnosis.

Slide 10 · The “floppy infant” is a clinical presentation, not an etiologic diagnosis

Infant hypotonia

RYR1 core disease

Nemaline myopathy

MTM1 myotubular disease

Slide 11 · Congenital myopathies have different natural histories

Congenital presentation

Subtype / variant

Variable severity and course

Specific subtype and variant matter more than the umbrella label alone.

Slide 12 · Central core disease is linked to RYR1

RYR1

Central core disease

Autosomal dominant (table example)

The disorder may appear as early hypotonia and weakness.

Slide 13 · RYR1 couples excitation to intracellular calcium release

Muscle excitation

RYR1-mediated SR Ca²⁺ release

Contractile response

Disrupted calcium handling impairs coordinated contraction.

Slide 14 · The “central core” is a myofiber architectural lesion

Dashed core zones: Disrupted sarcomeres and reduced mitochondria.

Schematic — conceptual cross-sections, not a patient biopsy.

Slide 15 · Central cores combine contractile and mitochondrial abnormalities

Outside the core

Within the core

Organized sarcomeres

Disorganized sarcomeres

Usual mitochondria

Fewer mitochondria

Recognizable fiber architecture

Sharply demarcated central region

Slide 16 · Central core disease may affect the skeleton as well as muscle

Early-onset hypotonia and weakness are typical table entries.

Associated skeletal changes may include scoliosis.

Hip dislocation and foot deformities are also described.

Slide 17 · RYR1 variants produce overlapping disease phenotypes

Central core disease

Overlap possible

Malignant hyperthermia susceptibility

Some variants are associated with both phenotypes.

Slide 18 · Malignant hyperthermia is a relevant RYR1 safety association

Triggering anesthetic

Abnormal RYR1 Ca²⁺ efflux

Contracture + hypermetabolism

Context from the adjacent channelopathy section.

Slide 19 · Nemaline myopathy is a genetically heterogeneous congenital myopathy

Robbins Table 27.3 lists multiple sarcomere-related genes.

Patients may have childhood weakness or severe hypotonia at birth.

A common pathologic descriptor is the presence of nemaline rods.

Slide 20 · Nemaline disease implicates several contractile proteins

TPM3

TPM2

NEB

ACTA1

TNNT1

CFL2

A single “nemaline gene” does not explain this morphologic group.

Slide 21 · Nemaline rods are derived from Z-band material

Z-disk–associated material

Nemaline rod aggregates

Slide 22 · Nemaline rods have characteristic shape and fiber distribution

Red short rods: Z-band–derived nemaline aggregates.

Schematic — conceptual cross-sections, not a patient biopsy.

Slide 23 · Nemaline clinical severity varies

Infancy: Hypotonia may be severe

Childhood: Persistent weakness

Variable presentations within a shared rod-myopathy morphology.

The clinical spectrum is broader than any one gene–phenotype pairing.

Slide 24 · Nemaline rods require appropriate structural visualization

Red short rods: Z-band–derived nemaline aggregates.

Schematic fiber only — not an authentic stained section.

Slide 25 · Centronuclear myopathy features misplaced myonuclei

Blue nuclei positioned centrally in most modeled fibers.

Schematic — conceptual cross-sections, not a patient biopsy.

Slide 26 · Normal myonuclei provide the comparison standard

Expected mature fiber

Centronuclear phenotype

Peripheral myonuclei

Many centrally situated nuclei

Normal size distribution

Often small type I fibers

Nuclear location not dominant

Nuclear pattern is characteristic

Slide 27 · X-linked myotubular myopathy is associated with MTM1

MTM1

Myotubular myopathy

X-linked

A poor prognosis in the severe X-linked form.

Slide 28 · Autosomal dominant centronuclear disease can involve DNM2

DNM2

Centronuclear myopathy

Autosomal dominant

Weakness and hypotonia remain central clinical features.

Slide 29 · Autosomal recessive centronuclear disease can involve BIN1

BIN1

Centronuclear myopathy

Autosomal recessive

Clinical course and presentation differ from severe MTM1-associated disease.

Slide 30 · Type I fibers may be small in centronuclear myopathy

Blue nuclei positioned centrally in most modeled fibers.

Schematic fiber-type relationship; Not a biopsy.

Slide 31 · Central nuclei alone do not establish a molecular diagnosis

Centronuclear myopathy

Nonspecific myopathic regeneration

Many central myonuclei as core phenotype

Internal nuclei can accompany repair

Subtype-specific gene correlation

Necrosis/regeneration context

Family history supports inheritance

Other acquired causes are possible

Slide 32 · Structural signatures distinguish three congenital myopathies

Central core

Core zones

RYR1

Nemaline

Rod inclusions

Multiple sarcomeric genes

Centronuclear

Central myonuclei

MTM1 / DNM2 / BIN1

Slide 33 · Inheritance patterns narrow the congenital myopathy differential

Phenotype

Textbook gene examples

Inheritance

Central core

RYR1

AD

Nemaline rods

TPM3 / NEB / ACTA1 and others

AD or AR

Centronuclear

MTM1 / DNM2 / BIN1

XL / AD / AR

Slide 34 · A structural myopathy work-up integrates four domains

Phenotype + course

Pedigree + biopsy pattern

Genetic correlation

Molecular analysis can establish the specific etiology.

Slide 35 · Case 1: Neonatal hypotonia with central core morphology

An infant has generalized hypotonia and weakness.

Biopsy is reported to contain sharply defined central areas with disrupted sarcomeres and fewer mitochondria.

Which gene and additional safety association should be considered?

Formulate the most likely mechanistic diagnosis before revealing the discussion.

Slide 36 · Case 2: Marked central nuclei in many fibers

A male newborn develops profound hypotonia.

Numerous small muscle fibers show nuclei in the geometric center.

Which congenital myopathy and gene fit this pattern?

Formulate the most likely mechanistic diagnosis before revealing the discussion.

Slide 37 · Congenital muscular dystrophies combine early onset and ongoing injury

These conditions present in infancy.

Unlike structurally defined, relatively static congenital myopathies, progressive damage is a key feature.

Developmental abnormalities of the central nervous system may accompany muscle disease.

Slide 38 · Myofiber–matrix attachments are necessary for tissue integrity

Myofiber interior

Sarcolemma

Extracellular matrix

Collagen VI

Perlecan

Merosin / laminin α2

Schematic of the myofiber–matrix interface

Slide 39 · Congenital muscular dystrophy has two matrix-related routes

Matrix protein deficiency

Matrix receptor dysfunction

Distinct molecular lesions can converge on impaired attachment.

Both routes disturb the myofiber–surrounding matrix interface.

Slide 40 · Ullrich congenital muscular dystrophy is a collagen VI disorder

Collagen VI

Ullrich congenital muscular dystrophy

Extracellular-matrix defect

Its phenotype combines weakness/hypotonia with joint abnormalities.

Slide 41 · Ullrich congenital muscular dystrophy has a characteristic joint pattern

Proximal joint contractures

Distal joint hyperextensibility

Both can coexist in Ullrich congenital muscular dystrophy.

Hypotonia accompanies the muscle disorder.

Slide 42 · Collagen VI and perlecan lose their normal spatial association in Ullrich disease

Myofiber interior

Sarcolemma

Extracellular matrix

Collagen VI

Perlecan

Merosin / laminin α2

Matrix components are separated in Ullrich disease.

Schematic of the myofiber–matrix interface

Slide 43 · Merosin deficiency reflects disruption of LAMA2

LAMA2

Merosin-deficient congenital muscular dystrophy

Matrix-protein defect

A defective matrix component causes a congenital muscular dystrophy phenotype.

Slide 44 · Laminin α2 is part of the myofiber’s extracellular support

Myofiber interior

Sarcolemma

Extracellular matrix

Collagen VI

Perlecan

Merosin / laminin α2

Schematic of the myofiber–matrix interface

Slide 45 · α-Dystroglycan is a matrix-facing receptor component

Myofiber interior

Sarcolemma

Extracellular matrix

Collagen VI

Perlecan

Merosin / laminin α2

α-Dystroglycan (glycosylated)

Schematic of the myofiber–matrix interface

Slide 46 · O-linked glycosylation enables normal α-dystroglycan function

Glycosylation pathway

Functional α-dystroglycan

Matrix attachment

A biochemical processing defect can therefore manifest as congenital muscular dystrophy.

Slide 47 · Dystroglycanopathy may involve muscle, brain, and eye

α-Dystroglycan dysfunction

Skeletal muscle

CNS development

Eye development

Slide 48 · Residual functional impairment helps explain disease severity

Very severe loss

Severe multisystem phenotype

Milder muscle-predominant disease

The phenotypic range extends from severe multisystem disease to muscle-predominant forms.

Slide 49 · Some dystroglycan defects overlap with limb-girdle dystrophy

Congenital dystrophy phenotype

Limb-girdle dystrophy phenotype

Shared pathway does not guarantee identical clinical onset.

Classification follows the phenotype and course as well as the molecular pathway.

Slide 50 · Congenital dystrophy: Three molecular-pathologic comparisons

Disease mechanism

Affected feature

Helpful clue

Collagen VI (Ullrich)

Extracellular matrix

Proximal contractures, distal hyperextensibility

LAMA2 (merosin)

Extracellular-matrix laminin

Congenital dystrophy

α-DG glycosylation

Matrix receptor processing

Variable CNS / ocular abnormalities

Slide 51 · Congenital myopathy and congenital dystrophy should not be conflated

Feature

Congenital myopathy

Congenital muscular dystrophy

Unifying clue

Core, rod, or nuclear pattern

Progressive muscle damage

Typical onset

Often infancy

Infancy

Systemic findings

Variable by subtype

CNS / eye possible in select forms

Disease course

May be relatively static or severe

Usually progressive

Slide 52 · Progressive muscular dystrophy usually appears beyond infancy

Congenital muscular dystrophy: Infancy

Other muscular dystrophies: Often later

Timing is informative but does not replace molecular classification.

Congenital muscular dystrophies are the infancy-onset exception to this clinical pattern.

Slide 53 · Dystrophic injury can overwhelm regenerative capacity

Fiber injury

Necrosis + myophagocytosis

Regeneration or cumulative loss

Over time, repeated injury may exceed regenerative capacity.

Slide 54 · Chronic dystrophy remodels muscle architecture

Repeated injury

Fibrosis + fatty replacement

Distorted muscle architecture

Marked fiber-size variation reflects ongoing injury, loss, and adaptation.

Slide 55 · Clinical progression and fiber pathology should be interpreted together

Structural congenital myopathy

Progressive dystrophy

Core / rod / centronuclear signature

Necrosis and regeneration

May be relatively static

Accumulating tissue loss

Genotype clarifies subtype

Genotype confirms disease group

Slide 56 · Serum creatine kinase indicates damage, not a specific genotype

Damaged fibers release creatine kinase into blood.

CK elevation can accompany dystrophic muscle injury.

Interpret the value with weakness distribution, age, biopsy and molecular data.

Slide 57 · Myopathic regeneration can complicate morphology

Segmental necrosis

Removal of debris

Repair and regeneration

Therefore an isolated internal nucleus cannot identify MTM1, DNM2, or BIN1 disease.

Slide 58 · A structured inherited-myopathy assessment reduces category errors

Inheritance / pedigree

Age of onset

Pattern of weakness

Course of disease

Biopsy / molecular mechanism

Slide 59 · Not every inherited myopathy is captured by these three groups

Related group

Dominant concept

Channelopathy

Muscle excitability / ion channels

Lipid or glycogen metabolism

Energy substrate handling

Mitochondrial myopathy

ATP generation / mitochondrial genetics

Slide 60 · Case 3: Contractures with distal hyperextensibility

An infant has hypotonia and proximal joint contractures.

Examination also shows marked distal joint hyperextensibility.

Which extracellular-matrix protein family best fits this combination?

Formulate the most likely mechanistic diagnosis before revealing the discussion.

Slide 61 · Case 4: Congenital dystrophy with eye and brain anomalies

An infant has progressive muscle weakness and developmental abnormalities affecting the brain and eyes.

The suspected lesion impairs posttranslational modification of a matrix receptor.

Which receptor-associated pathway should be prioritized?

Formulate the most likely mechanistic diagnosis before revealing the discussion.

Slide 62 · Integrate phenotype, lesion, and inheritance in the final diagnosis

Phenotype

Morphology

Molecular etiology

Genetics links these phenotypes to RYR1, sarcomeric genes, MTM1/DNM2/BIN1, matrix genes, or glycosylation pathways.

Slide 63 · Core distinctions to retain

Core + RYR1: Consider a variant-dependent malignant hyperthermia association.

Nemaline rods: Sarcomeric/Z-band phenotype with genetic heterogeneity.

Central nuclei: MTM1, DNM2, or BIN1 depending on inheritance and course.

Congenital dystrophy: Matrix or receptor dysfunction; Some forms involve brain and eye.

Slide 64 · Selected textbook source

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Inherited Diseases of Skeletal Muscle, Chapter 27.

Contextual passages: Myopathic Changes; Muscular Dystrophies; Ion Channel Myopathies; Mitochondrial Myopathies.