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Differential Diagnosis of Distal MyopathiesThe era of clinical molecular genetics has refined diagnosis and will hopefully lead to disease-modifying treatments.

By Kevin J. Felice, DO

Distal myopathies comprise a rare and hetero-geneous group of disorders that present with weakness of the distal muscles of the hands, feet, or both.1 The term distal myopathy is usu-ally reserved for genetic disorders, although weakness of distal muscles is sometimes promi-

nent in the acquired muscle diseases.2 In addition, prominent distal muscle weakness is also a feature of several of the most common inherited myopathies including myotonic muscular dystrophy type 1 (DM1) and facioscapulohumeral muscular dystrophy (FSHD).2,3 The first description of a distal myopathy was provided in a series of cases from 1885 through 1893.4 Detailed clinicopathologic study of these cases documented distal muscular atrophy—or peripheral muscular tabes—in the absence of nervous system involvement. The term dis-tal myopathy was first mentioned in 1902 in a person with concurrent facial weakness, which may have been an early description of myotonic dystrophy type 1.5 In 1951, clinico-pathologic findings were reported for an adult-onset autoso-mal dominant disorder with weakness of long extensors in the hand; 249 people from 72 Swedish familieswere affected.6 The molecular genetic era for distal myopathies began in 1995 with mapping of Laing’s distal myopathy to chromosome 14 and the later discovery of causative MYH7 mutations.7,8 The Gene Table of Neuromuscular Disorders now lists 18 gene disorders under the heading distal myopathies and recent comprehen-sive review has added another 7 gene disorders.9,10 This review highlights classic distal myopathies, including genetic and clini-copathologic aspects and other categories of genetic myopa-thy associated with distal weakness, and provides a brief review of the evaluation and care of people with these disorders.

EvaluationFor most cases, EMG is an important initial test to confirm

the myopathic origin of weakness and search for other diag-nostic clues. For example , identifying symptom onset, family history, and pattern of muscle involvement are key to guid-ing further diagnostic studies (Figure 1). In clinical practice,

distal limb weakness of myopathic origin is uncommon and, therefore, other neuromuscular disorders must be consid-ered, including motor neuron diseases and polyneuropathies. Hereditary motor neuropathies and Charcot–Marie–Tooth neuropathies are particularly important to consider in familial cases presenting with bilateral foot drop, hand weakness, or both. Clinical clues, including preserved foot muscle bulk in the setting of bilateral foot drop, preservation of intrinsic hand muscle function in the setting of prominent finger extensor weakness, and concurrent neck or proximal limb muscle weak-ness, suggest primary muscle disease rather than neuropathy.

For most cases, EMG is an important initial test to confirm myopathic origin of weakness that may also give other clues. For example, myotonic discharges implicate a myotonic dys-trophy or, possibly, Pompe’s disease, and findings of fibrilla-tions and positive sharp waves focus further testing on dystro-phic myopathies. Creatine kinase (CK) values are helpful and may be normal or mildly elevated in most disorders, but highly elevated in dysferlinopathies and other muscular dystrophies.

Imaging upper and lower limb muscles with MRI provides valuable insight on patterns of involvement, especially if the clinical exam is limited (eg, in an individual who is obese).11 In this author’s experience, however, obtaining insurance carrier authorization for MRI testing in the evaluation of myopathy is challenging at best and often impossible.

Muscle biopsy findings vary and may give valuable diagnos-tic clues or show only nonspecific or nondiagnostic changes (Figure 2). Some characteristic findings are dystrophic changes (eg, Miyoshi myopathy, ANO5-related myopathy), rimmed vacuoles (eg, GNE-related myopathy, myofibrillar myopathies), and fiber type disproportion (eg, Laing’s myopathy, congenital myopathies).12 Muscle immunohistochemistry is helpful in identifying deficient structural proteins in recessive dystrophies (eg, Miyoshi’s myopathy) or abnormal protein accumulation in myofibrillar myopathies (eg, DES-related myopathy). Muscle biopsy is not always needed, given availability of next-generation DNA testing, but may be important if DNA test results are negative or report only variants of uncertain significance.

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Classic Distal MyopathiesLaing’s Myopathy

Laing’s myopathy is an early-onset disorder that begins with selective weakness of foot dorsiflexors and great toe extensors, followed by weakness of neck flexors and fin-ger extensors, and, in some cases, progresses to facial and proximal limb muscle weakness.13 Levels of CK are normal or mildly elevated. Muscle histopathology varies to include mild nonspecific changes, congenital fiber type dispropor-tion, cores and minicores, and dystrophic changes. Laing’s myopathy is an autosomal dominant disorder caused by MYH7 mutations affecting the b heavy chain of myosin. Other MYH7-allelic disorders include skeletal myopathies (congenital myopathies, late-onset myopathies, myosin stor-age myopathy, scapuloperoneal myopathies) and cardio-myopathies (dilated, hypertrophic, and left ventricular non-compaction).14 There are 1,010 MYH7 mutations reported, spanning the globular head region and rod domains of myo-sin.15 Mutations in MYH7 are likely to impair development of a normal coiled structure impacting myosin dimerization, which is required to form the thick filament.

GNE Myopathy

GNE myopathy (Nonaka’s myopathy, distal myopathy with rimmed vacuoles, hereditary inclusion myopathy type 2) is a primary skeletal myopathy usually presenting in late adolescence and early adulthood with bilateral foot drop and steppage-pattern gait caused by anterior tibialis muscle weakness.16 Weakness progresses over years to ulti-

mately involve hip flexors, shoulder girdle, and hand mus-cles. For most people, the quadriceps will be spared even in advanced disease. Loss of ambulation occurs 20 to 30 years after onset. Facial, oropharyngeal, cardiac, and respiratory muscles are usually spared with few exceptions. Levels of CK are mildly elevated, usually less than 5 times the upper normal limit. Characteristic muscle histopathology fea-tures include rimmed vacuoles and filamentous inclusions. GNE myopathy is an autosomal recessive disorder caused by GNE mutations affecting UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. There have been 224 mutations reported in GNE gene with founder muta-tions in individuals of Japanese and Middle Eastern ances-try.15 The pathophysiology is not entirely known but hypo-sialylation of muscle glycans is believed to play a major role. Extended-release sialic acid showed no benefit over placebo in improving muscle strength or function, however.17

Miyoshi’s MyopathyMiyoshi’s myopathy is a primary disorder of skeletal

muscle usually presenting with the triad of onset before age 20 years, early involvement of posterior foreleg muscles, and markedly elevated CK levels (20-50 times normal upper limit).18 Progression is slow but relentless, eventually involv-ing proximal muscles, and leading to wheelchair depen-dency 10 to 20 years after symptom onset. In addition to myopathic recruitment patterns, EMG shows fibrillations and positive sharp waves in resting muscle. Muscle biopsy shows varying degrees of dystrophic change including myo-

Figure 1. Distal myopathy gene disorders based on inheritance patterns, age of onset, and presenting muscle involvement.

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fiber necrosis and increased connective tissue. Immunostains show absent dysferlin. Diagnosis is confirmed with DNA testing that shows homozygous or compound heterozy-gous DYSF mutations. There are 599 reported mutations of DYSF.15 Other allelic disorders include limb-girdle muscular dystrophy (LGMD) type 2B and distal myopathy with anteri-or foreleg-onset weakness. The DYSF gene encodes dysferlin, which is located in the muscle membrane and plays a major role in sarcolemmal repair.

Udd’s MyopathyUdd’s myopathy (tibial muscular dystrophy) is a primary

skeletal myopathy causing weakness of ankle dorsiflexors lead-ing to bilateral foot drop and steppage-pattern gait usually beginning in adults more than age 35.19 Udd’s myopathy pro-gresses slowly, remains limited to foot and toe extensors, and is so insidious that some may remain unnoticed even in later years. Levels of CK are normal or mildly increased. Muscle biopsy shows nonspecific myopathic changes with dystrophic changes and rimmed vacuoles in some cases. Udd’s myopathy is an autosomal dominant disorder first described in Finnish

individuals; all reported cases with a founder variant in TTN associated with a unique 11-bp deletion/insertion that chang-es 4 amino acid residues in exon Mex6. Other pathogenic variants have been described in non-Finnish families. Other TTN-related allelic disorders include young adult-onset reces-sive distal titinopathy, LGMD type 2J, hereditary myopathy with early respiratory failure, early-onset myopathy with fatal cardiomyopathy, congenital centronuclear myopathy, multi-minicore disease with cardiomyopathy, and familial hypertro-phic and dilated cardiomyopathies.20 There are 352 mutations reported in TTN, which encodes the giant sarcomeric protein, titin that spans the Z-disc to the M-band.15 How TTN muta-tions cause myopathy is not entirely clear, but likely involves disruption of the scaffolding and elastic recoiling properties of titin in its support of the sarcomere.

Welander’s MyopathyWelander’s myopathy is a primary skeletal myopathy

presenting in adulthood with distal upper extremity weak-ness, typically affecting wrist and finger extensors at onset with later involvement of the intrinsic hand and distal leg

Figure 2. Photo examples of clinical exam and muscle histopathology in patients with hereditary distal myopathies—including finger

and wrist extensor weakness in Laing myopathy (A), marked gastrocnemius atrophy in Miyoshi myopathy (B), centralized nuclei in

centronuclear myopathy due to DMN2 mutation (H&E) (C), congenital fiber type disproportion in Laing myopathy (NADH-TR) (D), rimmed

vacuoles in GNE-related myopathy (Gomori trichrome) (E), and increased immunoreactivity to desmin in DES-related distal myopathy (F).

A

D

B

E

C

F

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muscles.12 Progression is typically slow with most remain-ing ambulatory. Levels of CK are normal or mildly increased. Muscle biopsy shows myopathic changes and rimmed vacu-oles. The causative gene in Welander’s myopathy is TIA1. The disorder is found predominantly in Sweden and parts of Finland with a founder mutation (E384K) common to all cases. Other allelic disorders due to TIA1 mutations include frontotemporal dementia and amyotrophic lateral sclero-sis.15 The coexistence of the TIA1 variant (N357S) combined with a pathogenic variant in SQSTM1 (digenic inheritance) causes a late-onset myopathy with involvement on the finger extensors and ankle dorsiflexors.10 The mechanism of muscle dysfunction in Welander’s myopathy is uncertain; however, reduced TIA1 activity may result in decreased response to oxi-dative stress, possibly leading to muscle cell atrophy.

Markesbery-Griggs MyopathyMarkesbery-Griggs myopathy (myofibrillar myopathy

type 4) is an autosomal dominant, late-onset disorder usu-ally presenting with bilateral anterior foreleg weakness and foot drop.12 Later, individuals develop weakness of finger and wrist extensors, and proximal leg weakness leading to loss of ambulatory function after 10 to 20 years of progres-sion. Concurrent cardiomyopathy and conduction system disease requiring pacemakers are features in some affected persons late in the disease. Levels of CK are normal or mildly elevated, usually less than 4 times the upper normal limit. An EMG shows myopathic changes. Muscle biopsy shows dystrophic changes, rimmed vacuoles, and extensive myofi-brillar changes. The disorder is caused by mutations in LDB3, which encodes protein Z-disc alternatively spliced PDZ-domain containing protein (ZASP). There are 14 mutations reported in LDB3 gene.15 Other LDB3 allelic disorders include various types of cardiomyopathy, including dilated, hyper-trophic, and left ventricular noncompaction. Mutant ZASP destabilizes the Z-disc, leading to streaming and myofibrillar disintegration and aggregation.

Myofibrillar MyopathiesThe myofibrillar myopathies are a heterogeneous group of

genetic disorders characterized pathologically by disruption of myofibrils and accumulation of degradation products in intracellular inclusions.21 Most people present with progres-sive limb muscle weakness—distal, proximal or both. Dilated or hypertrophic cardiomyopathy can be an isolated feature or may develop concurrently with the skeletal myopathy. Other common phenotypic features include length-depen-dent sensorimotor axonal polyneuropathy and chest wall/diaphragmatic muscle weakness leading to chronic respira-tory insufficiency. There are 10 genes—DES, CRYAB, SEPN1, LDB3, MYOT, FLNC, BAG3, TRIM54, KY, TRIM63—implicated in myofibrillar myopathy. Other gene disorders—PLEC, TTN,

FHL1, ACTA1, HSPB8, DNAJB6—have also been associated with myofibrillar histopathology, and upwards of 50% of reported cases have eluded a specific genetic diagnosis.22

Congenital MyopathiesCongenital myopathies comprise a heterogeneous group of

genetic muscle disorders causing static or slowly progressive weakness. Onset is usually in infancy or childhood but some-times delayed into adulthood. Diagnosis is made initially with clinical features, patterns of inheritance, and characteristic muscle pathologic features.23 Recent genetic discoveries have implicated 32 disease-associated genes and, coupled with histopathologic and ultrastructural findings, have subclassified the congenital myopathies into 5 major groups: nemaline, core, centronuclear, myosin storage, and congenital fiber type disproportion. Distal-onset weakness has been associated with several congenital myopathy disorders, including ACTA1, MYH7, RYR1, and NEB gene disorders.

Complex Neuromyopathy DisordersAdvances in DNA testing have facilitated discovery of sev-

eral complex neuromyopathies and multisystem proteinopa-thies that combine multiple phenotypes including distal myopathy, hereditary motor neuropathy, Charcot–Marie–Tooth neuropathy, amyotrophic lateral sclerosis, frontotem-poral dementia, and Paget’s disease of bone. Several genes are implicated in these rare disorders including DNM2, HNRNPA1, HNRNPA2, HSPB1, HSPB8, MATR3, SQSTM1, TIA, and VCP.10

Muscular Dystrophies and Other Inherited Myopathies

Some more common muscular dystrophies (eg, myotonic dystrophy type 1 and FSHD) may present with distal limb muscle weakness. Other muscular dystrophies and inherited myopathies presenting with distal weakness include the dys-ferlinopathies, myotilinopathies, anoctaminopathy, caveo-linopathies, and telethoniopathies.12

Care and TreatmentNo effective disease-modifying treatments for distal

myopathies exist yet. The hope is that some or all of the potential therapies under development, including oligonucleotide-based therapies, small molecule therapies, genome editing, gene replacement, and stem cell therapy, will provide future benefit to people with these progressive neuromuscular disorders. Until then, disease monitoring, rehabilitative support, physical therapy and exercise pro-grams, and symptomatic treatments are the mainstay of care for individuals with distal myopathy. This author rec-ommends referral to neuromuscular centers with experience in diagnosis and care for genetic neuromuscular disorders.

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Periodic assessments by a team of providers—including neuromuscular neurologists, physical medicine specialists, cardiologists, pulmonologists, sleep disorder specialists, neuropsychologists, physical and occupational therapists, speech and language pathologists, dietitians, social workers, and respiratory therapists help maximize functional abilities, monitor for potential cardiopulmonary complications, navi-gate insurance and home care issues, provide psychosocial counseling, and, ultimately, improve the quality of life for individuals with distal myopathy and caregivers.24 In the US, Muscular Dystrophy Association (MDA) Care Centers are particularly suited for such care. n

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Kevin J. Felice, DOProfessor of NeurologyUniversity of Connecticut School of MedicineFarmington, CTThe Charles H. Kaman Foundation Neuromuscular and Muscular Dystrophy Association Care CenterHospital for Special CareNew Britain, CT

DisclosureKJF reports no disclosures.

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