Autosomal dominant limb-girdle muscular dystrophy type 1A (LGMD 1A), like other limb-girdle muscular dystrophies, is defined by slowly advancing muscle weakness in the pelvic and shoulder areas. Defects in a variety of proteins are found in the different subtypes of the disease, with the LGMD 1A condition caused by mutations in the myotilin gene. Diagnosis is made difficult by the symptoms overlapping with those of other ailments. Clinical features and epidemiological considerations, coupled with immunological tests for the affected proteins and molecular biology methods, especially next-generation sequencing, usually help in solidifying the diagnosis.
Autosomal dominant limb-girdle muscular dystrophy type 1A belongs to a group of relatively mild conditions that are distinct from the more serious Duchenne and Becker muscular dystrophies. Limb-girdle muscular dystrophies are autosomal diseases, either dominant (group 1) or recessive (group 2), with over 90% of people diagnosed with LGMD belonging to group 2 . The prevalence of LGMD in general, and of the specific subtypes, is variable among different populations . LGMD 1A is a rare variant that usually manifests in adults, but the age of onset can vary even in patients carrying the same mutation.
The shared attribute of LGMD is the proximal weakness in the muscles of the shoulder girdle and pelvic girdle. In LGMD 1A, the problem usually starts in the proximal pelvic muscles and spreads to other sites, including distal leg muscles, proximal and distal arm muscles. In a large family, the associated complaints were contractures at the heel, loss of ankle jerk reflex, and problems with articulation . The intensity of the features was highly variable: even asymptomatic carriers were discovered. Conversely, a woman with LGMD 1A who was diagnosed at age 40, became wheelchair-bound by age 50 and succumbed to pneumonia a few years later because of respiratory insufficiency . In addition to cases from the opposite ends of the spectrum of severity, unusual presentation in some victims has also been reported, such as muscle pseudo-hypertrophy .
LGMD 1A is caused by mutations in the myotilin gene . Myotilin is a protein mainly present in skeletal muscle, where it is associated with the Z line. Myotilin mutations can also result in myofibrillar myopathy, in addition to LGMD 1A  .
- Muscle Weakness
weakness.16 Weakness progresses over years to ultimately involve hip flexors, shoulder girdle, and hand muscles. [practicalneurology.com]
Muscle weakness and stiffness in the lower extremities were the patient's main complaints. [uniprot.org]
Weakness begins in ankle dorsiflexor muscles typically after age 40. In non-scandinavian cases, weakness may over time involve finger and wrist extensor muscles; later, proximal involvement can supervene. [ncbi.nlm.nih.gov]
The two patients with the ZASP mutation Ala147Thr described here showed only distal involvement of the legs without proximal weakness and involvement of the upper limb 6 and 19 years after onset of muscle weakness, respectively. [link.springer.com]
MFM associated with myotilin mutations, hereafter referred to as myotilinopathy, usually manifests between the 5th and 8th decade of life with progressive muscle weakness most often starting at distal lower limbs [4, 5, 11]. [actaneurocomms.biomedcentral.com]
Diagnosis is made difficult by some of the presenting symptoms of LGMD 1A being similar to those of other diseases (among them other LGMDs), and by the symptoms being heterogeneous among patients with LGMD 1A. For example, serum creatine kinase (CK) levels are elevated in most LGMD cases, although the dominant forms usually have lower CK levels than the recessive ones . Electrophysiology tests do not provide specific results for LGMDs but may be useful for differentiating them from other disorders, such as neuropathies .
Magnetic resonance imaging (MRI) is not as useful for the diagnosis of LGMDs as for myofibrillar myopathies. However, MRI can show which muscles are most affected  (for example, the semimembranosus muscle in the case of LGMD 1A ), which may help in the diagnosis and in selecting the location for muscle biopsy . In LGMD 1A, the histology images show rimmed vacuoles , which can contain inclusions, whereas the electron microscopic picture shows Z line streaming  . The histology is not characteristic enough to distinguish LGMD 1A from other LGMDs , but further tests with antibodies to different proteins can refine the diagnosis. Protein assays together with careful history collection (age of onset and other characteristics) are powerful tools for guiding the sequencing efforts and reaching a diagnosis  , while next-generation sequencing is best suited for the identification of the mutated genes .
LGMD 1A has to be separated from a large number of diseases, including rheumatological conditions, several types of myopathy, dystrophinopathies, and other LGMDs. It is especially challenging to distinguish between LGMD 1A and myofibrillar myopathy caused by myotilin mutations since there is considerable overlap between the symptoms of these two groups. The age of onset, the loss of deep tendon reflexes, and the presence of rimmed vacuoles are similar in both groups. Dysarthric speech has only been observed in LGMD 1A, whereas peripheral neuropathy and hyaline and non-hyaline lesions appear unique to the group presenting with myofibrillar myopathy  .
Pages 145-200 Number of pages 56 ISBN (Print) 9781626184602 Publication status Published - 2013 Diagnosis LGMD Limb girdle muscular dystrophy Treatment Medicine(all) Neuroscience(all) APA Standard Harvard Vancouver Author BIBTEX RIS [moh-it.pure.elsevier.com]
Other muscular dystrophies and inherited myopathies presenting with distal weakness include the dysferlinopathies, myotilinopathies, anoctaminopathy, caveolinopathies, and telethoniopathies.12 Care and Treatment No effective disease-modifying treatments [practicalneurology.com]
Since these proteins are potential therapeutic targets, this may be relevant for the development of new treatment strategies. [actaneurocomms.biomedcentral.com]
Corticosteroid treatment was associated with a partial but significant improvement in two patients. [ncbi.nlm.nih.gov]
There have been 224 mutations reported in GNE gene with founder mutations in individuals of Japanese and Middle Eastern ancestry.15 The pathophysiology is not entirely known but hyposialylation of muscle glycans is believed to play a major role. [practicalneurology.com]
Pathophysiology of protein aggregation and extended phenotyping in filaminopathy. Brain. 2012;135(Pt 9):2642–60. doi:10.1093/brain/aws200. Article PubMed Central PubMed Google Scholar Neill T, Schaefer L, Iozzo RV. [actaneurocomms.biomedcentral.com]
The pathophysiology of the mutations in MYH7 was not well understood, however some introduced proline, which is incompatible with coiled coils. [ncbi.nlm.nih.gov]
Only peptides that were unique within the complete data set were considered for final analysis to prevent an assignment to different proteins due to sequence homologies. [actaneurocomms.biomedcentral.com]
Oral supplementation with sialic acid metabolites in GNE knockout mice results in an increase of sialic acid in muscle to a nearly normal level and prevents development of the muscle phenotype (59). [ncbi.nlm.nih.gov]
- Bastian A, Mageriu V, Micu G, Manole E. The Growing Family of Limb-Girdle Muscular Dystrophies: Old and Newly Identified Members. Rom J Intern Med. 2015 Jan-Mar;53(1):13-24.
- Gilchrist JM, Pericak-Vance M, Silverman L, Roses AD. Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy. Neurology. 1988 Jan;38(1):5-9.
- Reilich P, Krause S, Schramm N, et al. A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A). J Neurol. 2011 Aug;258(8):1437-1444.
- Gamez J, Armstrong J, Shatunov A, et al. Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype? J Neurol Sci. 2009 Feb 15;277(1-2):167-171
- Hauser MA, Horrigan SK, Salmikangas P, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet. 2000 Sep 1;9(14):2141-2147.
- Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology. 2004; 62: 1363-1371.
- Olivé M, Goldfarb LG, Shatunov A, Fischer D, Ferrer I. Myotilinopathy: refining the clinical and myopathological phenotype. Brain. 2005 Oct;128(Pt 10):2315-2326.
- Murphy AP, Straub V. The Classification, Natural History and Treatment of the Limb Girdle Muscular Dystrophies. J Neuromuscul Dis. 2015 Jul 22;2(s2):S7-S19.
- Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014 May;33(1):1-12.
- Barresi R. From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies. Skelet Muscle. 2011 Jun 24;1(1):24.
- Guglieri M, Bushby K. How to go about diagnosing and managing the limb-girdle muscular dystrophies. Neurol India. 2008 Jul-Sep;56(3):271-280.