Lama2 Muscular Dystrophy
Summary
Clinical characteristics.
The clinical manifestations of LAMA2 muscular dystrophy (LAMA2-MD) comprise a continuous spectrum ranging from severe congenital muscular dystrophy type 1A (MDC1A) to milder late-onset LAMA2-MD. MDC1A is typically characterized by neonatal profound hypotonia, poor spontaneous movements, and respiratory failure. Failure to thrive, gastroesophageal reflux, aspiration, and recurrent chest infections necessitating frequent hospitalizations are common. As disease progresses, facial muscle weakness, temporomandibular joint contractures, and macroglossia may further impair feeding and can affect speech.
In late-onset LAMA2-MD onset of manifestations range from early childhood to adulthood. Affected individuals may show muscle hypertrophy and develop a rigid spine syndrome with joint contractures, usually most prominent in the elbows. Progressive respiratory insufficiency, scoliosis, and cardiomyopathy can occur.
Diagnosis/testing.
The diagnosis of LAMA2 muscular dystrophy is established in a proband with suggestive findings and biallelic (homozygous or compound heterozygous) pathogenic variants in LAMA2 identified by molecular genetic testing.
Management.
Treatment of manifestations: It is recommended that multidisciplinary care be provided by specialists in neurology, gastroenterology, nutrition, orthopedics, occupational and physical therapy, speech and language therapy, education, psychiatry, pulmonary medicine, cardiology, ophthalmology, and social work.
Surveillance: Routine follow up of nutritional status and safety of oral intake, neurologic status, pulmonary function, developmental/educational progress, cognitive abilities, psychiatric issues, mobility and activities of daily living, cardiac status, vision, and social needs.
Agents/circumstances to avoid: Succinylcholine in induction of anesthesia because of risk of hyperkalemia and cardiac conduction abnormalities; statins, cholesterol-lowering medications, because of the risk of muscle damage.
Genetic counseling.
LAMA2-MD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a LAMA2 pathogenic variant each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the LAMA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
Diagnosis
The phenotypic spectrum of LAMA2 muscular dystrophy (LAMA2-MD) ranges from congenital muscular dystrophy type 1A (MDC1A) to LAMA2-MD with onset ranging from early childhood to adulthood (referred to as late-onset LAMA2-MD).
No consensus clinical diagnostic criteria for LAMA2-MD have been published.
Suggestive Findings
LAMA2-muscular dystrophy should be suspected in individuals with the following clinical findings by age of onset; laboratory and neuroimaging findings regardless of age; and family history.
Clinical Findings by Age of Onset
Congenital muscular dystrophy type 1A (MDC1A)
- Onset at birth or within the first six months of life: profound hypotonia with muscle weakness
- Poor spontaneous movements with contractures of the large joints
- Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections
- Delayed motor development milestones: the majority of affected individuals are able to sit but rarely achieve independent ambulation.
- Axial weakness, difficulties in head control (mainly due to flexor muscles of the neck); progressive scoliosis starting in childhood
- Absence of findings that could suggest lower motor neuron disease (i.e., tongue fasciculation and areflexia)
- Usually normal intellect
- Less common findings:
- Weak cry often associated with respiratory failure
- Epilepsy, including of a refractory nature
- Cardiac involvement
- Demyelinating progressive sensorimotor neuropathy
Late-onset LAMA2-MD (clinically heterogeneous group)
- Onset during childhood or even adulthood
- Proximal muscle weakness with or without muscle hypertrophy, as seen in limb-girdle muscular dystrophies
- Delayed motor milestones in childhood, but independent ambulation usually achieved
- Less common findings:
- Rigid spine syndrome with joint contractures usually most prominent in the elbows
- Childhood-onset seizures
- Progressive respiratory insufficiency and scoliosis
- Cardiomyopathy with or without conduction defect
Laboratory and Neuroimaging Findings
Serum creatine kinase (CK) concentration
- MDC1A. In the first years of life, serum CK concentration may be more than fourfold normal values [Hayashi et al 2001, Oliveira et al 2008]. In children with MDC1A who do not achieve walking, serum CK concentration is usually more than 1000 IU/L in the first two years of life, after which it progressively decreases.
- Late-onset LAMA2-MD. Maximum serum CK concentrations range from 593 IU/L to 6987 IU/L (normal 200-400 depending on laboratory) [Oliveira et al 2008]. In adults, CK levels could be only mildly or slightly elevated [Rajakulendran et al 2011, Oliveira et al 2018].
Brain MRI findings (regardless of age)
- Abnormal white matter signals (in nearly all individuals with LAMA2-MD) include hyperintensity on T2-weighted and FLAIR MRI, and hypointensity on T1-weighted images in areas myelinated in the developing brain (i.e., subcortical and periventricular areas) with sparing of areas myelinated later in life (i.e., corpus callosum and internal capsule) [Geranmayeh et al 2010]. These findings, consistently documented in the first year of life, do not represent areas of demyelination but rather are likely secondary to leaky basal laminar connections giving rise to increased water content in the brain [Menezes et al 2014]. Although these white matter changes are mostly diffuse, focal and more subtle changes are seen in a small subset of affected individuals [Leite et al 2005, Chan et al 2014, Oliveira et al 2018]. Of note, two sibs with a late-onset phenotype were reported to have a nearly normal brain MRI [Saredi et al 2019].
- Structural brain abnormalities (secondary to neuronal migration defects) include cortical dysplasia [Mercuri et al 1999], lissencephaly (agyria or pachygyria) [Geranmayeh et al 2010], and polymicrogyria [Vigliano et al 2009].Polymicrogyria-like patterns (bilaterally in the temporal and occipital lobes) were reported in the majority of 25 individuals. When extensive, the polymicrogyria correlated with epilepsy [Natera-de Benito et al 2020].
Immunohistochemistry (IHC) of muscle or skin biopsy
- Complete or partial laminin α2 deficiency (muscle and skin)
- Increased expression of laminin α4 and α5
Muscle MRI findings. Muscle imaging, including whole-body MRI, is being increasingly used in the diagnostic workup of hereditary myopathies. Although the appearance of muscle on MRI in LAMA2-MD is similar to that of the collagen VI myopathies (see Differential Diagnosis), with bands of sparing and affected muscles [Nelson et al 2015, Harris et al 2017], the anterior thigh muscles are more frequently involved in LAMA2-MD. Sparing of the gracilis, sartorius, vastus medialis, and rectus femoris muscles has also been described [Nelson et al 2015]. Individuals with rigid spine syndrome had sparing of temporal muscles, except in those associated with biallelic LAMA2 pathogenic variants [Tordjman et al 2018].
Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of LAMA2 muscular dystrophy is established in a proband with suggestive findings and biallelic (homozygous or compound heterozygous) pathogenic variants in LAMA2 identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic LAMA2 variants of uncertain significance (or identification of one known LAMA2 pathogenic variant and one LAMA2 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, a variety of multigene panels) and comprehensive genomic testing (exome sequencing, exome array, chromosomal microarray (CMA), genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with later onset or with an atypical phenotype, in whom the diagnosis of LAMA2-muscular dystrophy has not been considered, are more likely to be diagnosed using a larger multigene panel (Option 2) or even comprehensive genomic testing (see Option 3).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of LAMA2-MD, molecular genetic testing approaches can include single-gene testing. Sequence analysis of LAMA2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis (e.g. multiplex-ligation dependent probe amplification or CMA) to detect intragenic large deletions or duplications that may be missed by Sanger sequencing.
Option 2
A muscular dystrophy multigene panel that includes LAMA2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 3
When the diagnosis of LAMA2-MD is not considered because an individual has atypical phenotypic findings, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is most likely to lead to diagnosis. Exome sequencing is most commonly used [Oliveira et al 2018, Saredi et al 2019]; genome sequencing may also be considered if clinically available.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in LAMA2 Muscular Dystrophy
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| LAMA2 | Sequence analysis 3 | ~80% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~20% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Oliveira et al [2018]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Oliveira et al [2014], Oliveira et al [2018]
Clinical Characteristics
Clinical Description
The clinical manifestations of LAMA2 muscular dystrophy (LAMA2-MD) comprise a continuous spectrum ranging from severe congenital muscular dystrophy type 1A (MDC1A) to milder late-onset LAMA2-MD.
Those with congenital muscular dystrophy type 1A (MDC1A) typically have neonatal profound hypotonia, poor spontaneous movements, and respiratory failure [Jones et al 2001]. Failure to thrive, gastroesophageal reflux, aspiration, and recurrent chest infections necessitating frequent hospitalizations are common. As disease progresses, facial muscle weakness, temporomandibular joint contractures, and macroglossia may further impair feeding and can affect speech.
Late-onset LAMA2-MD is characterized by later onset of manifestations, ranging from early childhood to adulthood. Affected individuals may show muscle hypertrophy and develop a rigid spine syndrome with joint contractures, usually most prominent in the elbows. Progressive respiratory insufficiency and scoliosis can occur [He et al 2001] along with cardiomyopathy [Carboni et al 2011, Marques et al 2014].
Congenital Muscular Dystrophy Type 1A (MDC1A)
Respiratory involvement is caused by a progressively restrictive chest wall that first involves weakness of the intercostal and accessory muscles. Early in childhood, the thorax becomes stiff and chest wall compliance decreases, further contributing to alveolar hypoventilation, atelectasis, and mucous plugs with bronchial obstruction. These changes manifest as low lung volumes. Poor secretion clearance resulting from weak cough leads to recurrent chest infection. Swallowing difficulties and gastroesophageal reflux may increase the risk of aspiration. Chest infections may cause atelectasis, which along with limited pulmonary reserve, increases the risk of acute respiratory failure in the setting of infection.
The need for ventilatory support is most likely to occur during two time periods [Geranmayeh et al 2010]:
- Between birth and age five years in the most severely affected children mainly due to respiratory muscle weakness, hypotonia, and fatigue. Depending on age, total hours of ventilatory support required, frequency of hospitalizations, and institutional practice patterns, ventilatory support may be noninvasive or mechanical with tracheostomy. Respiratory issues in these infants and young children often stabilize in the first years, likely as a result of improved muscle tone.
- Between ages ten and 15 years due to progressive restrictive lung disease leading to respiratory insufficiency [Wallgren-Pettersson et al 2004]. Most children in this age group with the early-onset form do not have typical signs/symptoms of hypercapnia (i.e., headaches, attention difficulties, and drowsiness) but rather the more subtle findings including recurrent respiratory infections, failure to thrive, poor cough, and fatigue with feeding.
Feeding difficulties, consistent with poor weight gain, failure to thrive, and precipitous drop in weight with infections and hospitalizations are common. Philpot et al [1999a] reported weight below the third centile and feeding difficulties including swallowing abnormalities, difficulty chewing, and prolonged feeding time. In a study of 46 individuals with LAMA2-MD, 17 required enteral feeding, usually within the first year [Geranmayeh et al 2010]. Of note, children with early-onset LAMA2-MD do not attain normal weight (see Management, Treatment of Manifestations).
Joint contractures that are present in the first year of life progress slowly even in children receiving intensive daily physical therapy. Contractures tend to occur early in the shoulders, elbows, hips, and knees and later in the temporomandibular joints, distal joints, and cervical spine. Contractures often result in significant morbidity and interfere with activities of daily living.
Hyperlaxity of the distal phalanges of the fingers is observed in a number of affected children.
Motor developmental milestones are delayed and often arrested. Most affected children do not acquire independent walking; Geranmayeh et al [2010] reported that only 15% of individuals acquired independent ambulation. A smaller proportion gained the ability to walk with assistance but subsequently lost the ability.
Axial weakness
- Neck weakness, especially of the flexor muscles, impairs moving the head from the back to neutral position or performing neck flexion and lifting head from the lying position [Oliveira et al 2018]. This weakness may progress to a severe cervical lordosis in late adolescence, affecting the capacity to swallow and increasing the risk of food aspiration.
- Scoliosis is aggravated by thoracic and lumbar lordosis and frequently observed from the first decade of life [Bentley et al 2001]. It is often slowly progressive and may contribute to respiratory insufficiency due to thoracic restriction and airway compression.
Facial muscle weakness and macroglossia may become significant in toddlers and children, resulting in typical elongated myopathic facies, with an open mouth and tongue protrusion.
Limitation of eye movements (ophthalmoparesis) may be evident as early as age two years.
Central nervous system. Cognitive abilities are normal in the majority of affected individuals and do not correlate with brain MRI abnormalities [Messina et al 2010]; however, in a small proportion of individuals, intellectual disability and epilepsy were associated with bilateral occipital pachygyria [Jones et al 2001] or dysplastic cortical changes affecting predominantly the occipital and temporal regions [Sunada et al 1995, Pini et al 1996, Philpot et al 1999b, Leite et al 2005, Geranmayeh et al 2010, Natera-de Benito et al 2020].
Cognitive impairment, reported in fewer than 7% of individuals [Jones et al 2001, Geranmayeh et al 2010], ranged from mild intellectual disability to communication difficulties.
Epilepsy occurs in 8%-35% of affected individuals. Epilepsy is more prevalent in persons with more extensive cortical malformation. Seizures are mainly focal and visual aura; autonomic signs are common. Atypical absence, atonic, motor, and focal seizures with clonic bilateralization can also occur. In some individuals epilepsy is controlled with mono- or polytherapy, whereas in others epilepsy can be refractory, leading to a progressive deterioration of cognition [Vigliano et al 2009, Geranmayeh et al 2010, Natera-de Benito et al 2020].
A progressive sensorimotor neuropathy with signs of dysmyelinization may be detected in childhood [Di Muzio et al 2003]. These abnormalities are usually mild or clinically not significant. In contrast, needle EMG, even when performed early in infancy, shows myopathic signs in a majority of individuals [Quijano-Roy et al 2004].
Cardiac involvement has been described in persons with late-onset LAMA2-MD. There are only a few reports of cardiac involvement in individuals with MDC1A [Abdel Aleem et al 2020]; however, as improved medical care prolongs life expectancy, cardiac involvement may become more prevalent, and thus a management concern [Nelson et al 2015].
Secondary pulmonary hypertension may be observed as a complication of respiratory insufficiency [Geranmayeh et al 2010].
Late-Onset LAMA2 Muscular Dystrophy
The onset of this milder phenotype ranges from early childhood to adulthood. Although children may have delayed motor milestones, they acquire independent ambulation. Proximal muscle weakness is slowly progressive in a pattern similar to that of other limb-girdle muscular dystrophies. Long-term consequences include wheelchair dependence, scoliosis, and respiratory problems [Oliveira et al 2018].
Weakness is also associated with marked contractures (mainly in the elbows and Achilles tendon) [Harris et al 2017, Saredi et al 2019] and heart involvement that can be clinically significant (particularly in individuals with phenotypes resembling Emery-Dreifuss muscular dystrophy or collagen VI diseases); however, subclinical abnormal echocardiograms and/or ECG-Holter findings are more common [Nelson et al 2015, Harris et al 2017].
Some individuals have rigid spine syndrome and/or muscle pseudohypertrophy [Nelson et al 2015].
Peripheral nerve demyelination may be detected with nerve conduction studies; however, most commonly there are no significant clinical consequences [Chan et al 2014].
Severe epilepsy and intellectual disability are described in some individuals.
Genotype-Phenotype Correlations
Prognostication of clinical severity depends on several variables including age at onset of first manifestations, LAMA2 pathogenic variant type, and, if known, the effect of the variant on protein function [Geranmayeh et al 2010, Oliveira et al 2018]. See Table 6 for the phenotypes associated with several commonly reported pathogenic variants.
Complete absence of laminin α2 and the phenotype of congenital muscular dystrophy type 1A (MDC1A) in general are caused by loss-of-function LAMA2 variants [Pegoraro et al 1998, Oliveira et al 2008, Oliveira et al 2018]; however, exceptions occur, including an individual homozygous for a pathogenic nonsense LAMA2 variant who achieved ambulation [Geranmayeh et al 2010]. Intrafamilial variation has also been observed [Geranmayeh et al 2010, Oliveira et al 2018].
Partial deficiency of laminin α2. The phenotypes associated with partial deficiency of laminin α2 tend to be less severe, with slower disease progression [Allamand & Guicheney 2002, Tezak et al 2003, Oliveira et al 2018]. Some missense, splice site, and in-frame variants have been associated with partial deficiency as well as pathogenic missense variants in conserved cysteine residues on the short arm of the laminin α2 protein [Allamand & Guicheney 2002, Tezak et al 2003, Oliveira et al 2018]. Late-onset LAMA2-MD has been observed in multiple individuals with the variant c.2461A>C (p.Thr821Pro) in homozygosity or compound heterozygosity with another variant [Oliveira et al 2018].
Nomenclature
Individuals with early-onset LAMA2-MD were often categorized in the past as having complete or partial laminin α2 deficiency (or complete or partial merosin deficiency before it was known that the defect was laminin α2 deficiency) based on immunochemistry (IHC) staining of muscle. These IHC-based terms are less relevant now, given that the diagnosis of LAMA2 muscular dystrophy can be made with certainty by the detection of biallelic LAMA2 pathogenic variants. Moreover, laminin α2 deficiency can be secondary to defects in other proteins involved in the dystroglycan complex or pathway (e.g., in dystroglycanopathies; see Differential Diagnosis) [Bönnemann et al 2014, Endo 2015].
The abbreviation MDC1A is derived from the designation merosin-deficient congenital muscular dystrophy type 1A.
Based on a nomenclature system that describes which chains are present in each laminin isoform, merosin was given the name laminin-211 because it comprises chains α2, β1, and γ1.
Late-onset LAMA2 muscular dystrophy may also be referred to as LGMDR23 [Straub et al 2018].
Prevalence
Exact prevalence of congenital muscular dystrophy type 1A (MDC1A) is still unknown. The prevalence of congenital muscular dystrophies (CMD) has been estimated between 0.563:100,000 (in Italy [Graziano et al 2015]) and 2.5:100,000 (in western Sweden [Darin & Tulinius 2000]).
Geographic prevalence of MDC1A is also quite variable:
- In Europe it accounts for about 30% of CMD, whereas in Japan it accounts for only 6% [Allamand & Guicheney 2002].
- In the United Kingdom it accounts for 37.4% of CMD, making it the most common cause [Sframeli et al 2017].
- In Italy it accounts for 24.1% of CMD, making it the second most common cause [Graziano et al 2015].
- In Australia it accounts for 16% of CMD, making it the third most common cause [O'Grady et al 2016].
Differential Diagnosis
Congenital muscular dystrophy type 1A (MDC1A) must be distinguished from other disorders that may present with profound hypotonia (with frog leg posture of the legs), chest deformity, and breathing and feeding problems. The disorders included in the differential diagnosis are other congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, and spinal muscular atrophy. Of note, these disorders are not typically associated with: (1) laminin-α2 deficiency detected by immunohistochemical staining of muscle or skin biopsy, or (2) white matter changes on brain MRI. Additional distinguishing features include:
- Progressive improvement of tone and strength (in some affected individuals), CK levels near normal range values, diagnostic structural abnormalities on muscle biopsy (by light and electron microscopy), and an absence of joint contractures (even when the disease is severe) in the congenital myopathies;
- Multisystemic presentation (e.g., liver and cardiac involvement besides muscle weakness) in congenital metabolic myopathies.
Table 2a.
Selected Genes of Interest in the Differential Diagnosis of MDC1A
| Gene(s) | Disorder | MOI | Distinguishing Clinical Features 1 |
|---|---|---|---|
| B3GALNT2 B4GAT1 CRPPA DAG1 FKRP FKTN GMPPB LARGE1 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 | Dystroglycanopathies, congenital (OMIM PS236670) | AR | Wide variety of brain & eye structural & functional abnormalities (may be more severe in Walker Warburg syndrome & muscle-eye-brain disease) |
| COL6A1 COL6A2 COL6A3 | Collagen type VI disorders (Ullrich CMD) 2 | AR 3 | Characterized by triad of myopathic features, hyperlaxity, & typical skin changes (keratosis pilaris, keloids, striae) |
| BIN1 CCDC78 DNM2 MAP3K20 MTM1 MTMR14 SPEG | Centronuclear/myotubular myopathy 4 (see X-Linked Myotubular Myopathy) | XL AR AD | Ophthalmoplegia; facial bulbar weakness |
| ACTA1 CFL2 KBTBD13 KLHL40 KLHL41 LMOD3 NEB TNNT1 TPM2 TPM3 | Nemaline myopathy 4 (OMIM PS161800) | AR AD | Facial & bulbar weakness |
| RYR1 | Central core disease (OMIM 117000) & multiminicore disease (OMIM 255320) 4 | AR AD 5 | Malignant hyperthermia in some affected individuals |
| SELENON | Congenital myopathy w/fiber-type disproportion | AD AR | Insulin resistance |
| Rigid spine (congenital) muscular dystrophy (OMIM 602771) | AR | Restrictive respiratory syndrome (nocturnal hypoventilation) | |
| CHAT CHRNE COLQ DOK7 GFPT1 RAPSN 6 | Congenital myasthenic syndromes | AR AD | Facial & bulbar weakness; striking motor variability; decremental EMG response or abnormal single-fiber EMG |
| SMN1 7 | Spinal muscular atrophy | AR | Relatively rapid motor impairment & tongue fasciculations; EMG & muscle biopsy findings suggest denervation-reinnervation profile; normal nerve conduction studies |
AD = autosomal dominant; AR = autosomal recessive; CMD = congenital muscular dystrophy; MOI = mode of inheritance; XL = X-linked
- 1.
In addition to absence of brain white matter changes
- 2.
Immunohistochemical analysis of muscle or skin biopsies can be diagnostically useful, showing variable reduction of antibody labeling against collagen VI or glycosylated α-dystroglycan.
- 3.
The Ullrich congenital muscular dystrophy phenotype is usually inherited in an autosomal recessive manner; however, exceptions occur.
- 4.
Selected examples of congenital myopathies are included in Table 2a; other congenital myopathies may also be relevant to the differential diagnosis of MDC1A.
- 5.
Minicore disease is most often inherited in an autosomal recessive manner. The report of minicore disease in two generations in a few families also suggested autosomal dominant inheritance.
- 6.
Most commonly associated of ~30 known genes; pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of congenital myasthenic syndromes.
- 7.
The detection of the genetic defect causing spinal muscular atrophy (deletion involving SMN1 exons 7 and 8) requires specific methodologies.
Late-onset LAMA2 muscular dystrophy (LAMA2-MD) is in the differential diagnosis of childhood-onset weakness of the limb-girdle type.
Table 2b.
Genes of Interest in the Differential Diagnosis of Late-Onset LAMA2-MD
| Genes | Disorder | MOI | Clinical Features of the Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/LAMA2-MD | Distinguishing from LAMA2-MD | |||
| EMD FHL1 LMNA | Emery-Dreifuss muscular dystrophy 1 | XL AR AD | Elbow contractures, high serum CK concentrations, prominent spinal rigidity |
|
| COL6A1 COL6A2 COL6A3 | Collagen type VI disorders (Bethlem myopathy) 2 | AR AD | Elbow or Achilles tendon contractures; mildly ↑ serum CK concentrations |
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
- 1.
Immunofluorescence and/or western blot in fresh muscle biopsies (or from other affected tissues) can be used to detect changes in emerin or FHL1 proteins.
- 2.
Immunohistochemical (IHC) analysis of muscle or skin biopsies can be diagnostically useful, showing variable reduction of antibody labeling against collagen VI.
Management
Published consensus clinical practice guidelines for congenital muscular dystrophies list recommendations for the following six clinical care areas: neurology, pulmonary, gastrointestinal/nutritional/oral care, orthopedics and rehabilitation, cardiology, and palliative care [Wang et al 2010] (full text).
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of a child diagnosed with LAMA2 muscular dystrophy (LAMA2-MD), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with LAMA2 Muscular Dystrophy
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Height, weight, & nutritional status | |
| Neurologic | Complete exam by experienced neurologist | To incl assessment of strength |
| For seizures or unexplained fainting or loss of consciousness | To incl EEG | |
| Musculoskeletal | Multidisciplinary neuromuscular clinic assessment by orthopedist, physical medicine, OT/PT | To incl assessment of:
|