Neurology: Case of the Month

Check Your Diagnosis — Patient 86

Larry Tran, M.D.

Diagnosis

Limb-Girdle Muscular Dystrophy: Fukutin-Related Protein (LGMD-2I)

Clinical Summary

The patient is a 55 year old gentleman reporting five years of progressive proximal lower greater than upper extremity weakness. He was diagnosed three months earlier with polymyositis after a muscle biopsy and underwent unsuccessful treatment with five days of intravenous immunoglobulin. His physical examination is notable for diffuse loss of muscle bulk especially involving leg adductors, bilateral scapular winging, proximal weakness of both upper and lower extremities, and weakness of his orbicularis oculi. Combined with his elevated creatine kinase (CK), our clinical suspicion was a muscular dystrophy in a limb girdle pattern. There may also be a hereditary component since the patient's father may have been misdiagnosed with polymyositis.

Differential Diagnosis

Facioscapulohumeral Muscular Dystrophy (FSHD): Admittedly, this was our initial clinical suspicion based on the distribution of weakness found on physical examination, especially with the orbicularis oculi weakness and pronounced scapular winging. There was also suspicion of an autosomal dominant mode of transmission based on the patient's father diagnosis. In retrospect, the patient's age was not typical for either the infantile or classic forms of FSHD. His facial weakness was minimal and he did not have the other typical features seen in patients with FSH such as horizontal clavicles and "poly-hill" sign. In light of the high sensitivity of genetic testing for FSHD (i.e., positive in 95-98% of typical FSHD cases), our patient's negative FSHD genetic test result further rules out this consideration.

Becker Muscular Dystrophy (BMD): Typically in BMD, the lower extremities proximal muscles are affected before the upper extremities and the CK was over 1,000 IU/L which can be suggestive of a dystrophinopathy. But classically, the age of onset is between 5-15. Patients with BMD may have cardiopulmonary complications that can lead to their death between the ages of 30-60 years. Mean age of death is in around mid-40s. Our patient is 55 years old, and while this age does not exclude him from BMD, it does lower this diagnosis on our differential. The mode of transmission in BMD is X-linked recessive.

Inflammatory Myopathies: Both dermatomyositis and polymyositis have patterns of weakness affecting proximal more than distal muscles. Also serum CK may be increased up to 50 times normal. However, a repeat muscle biopsy did not reveal an inflammatory component and the patient did not respond to intravenous immunoglobulin therapy administered three months earlier.

Discussion

The limb-girdle muscular dystrophies (LGMD) represent a heterogeneous group of disorders linked by their clinical presentation of predominantly proximal distribution of weakness, which early in the clinical course spares the distal musculature as well as facial and extra-ocular muscles.[2] Most cases are autosomal recessive, but autosomal dominant patterns of inheritance have been described as well. An international panel of neuromuscular experts at the European Neuromuscular Center Workshop coined the modern nomenclature in 1995, designating autosomal dominant variants as LGMD-1 and autosomal recessives as LGMD-2.[4] There are currently at least 19 forms of LGMD, seven being autosomal dominant and 14 autosomal recessive.

There is variable genotype-phenotype correlation where the same mutation might result in different phenotypes, some of which do not display the limb-girdle pattern. The age of onset varies from early childhood to adulthood. With a few exceptions, the clinical course is usually slowly progressive and the muscles affected may be the shoulder girdle or the pelvic-girdle or both. Neck flexors, extensor muscles, and facial weakness may be involved or totally absent. Scapular winging and pseudohypertrophy of the calves can be observed in several subtypes. Intellect is spared and cardiac or other systemic involvement is not as common as in the dystrophinopathies.[7]

Serum creatine kinase can be elevated, generally mild elevation in the autosomal dominant subtypes and significantly elevated in the autosomal recessive subtypes. The electromyography test shows features consistent with a generalized myopathy, and muscle biopsy reveals dystrophic changes with degeneration and regeneration of muscle fibers, fiber splitting, internal nuclei, fibrosis, moth-eaten and occasionally whorled fibers. Inflammatory myopathy should be excluded during the diagnostic process. In some LGMD (sarcoglycanopathy, dysferlinopathy, and calveolinopathy), the diagnosis can be established based on immunochemical staining on a muscle biopsy to determine if a specific protein is present or absent. Muscle biopsy can guide the genetic testing. In most cases, however, molecular genetic testing is very useful to identify a specific disease-causing mutation.[3]

LGMD-2I is an autosomal recessive disorder caused by mutations in the fukutin-related protein (FKRP) gene on chromosome 19, which encodes a putative Golgi-resident glycosyltransferase fukutin-related protein involved in alpha-dystroglycan glycosylation.[1] Missense, nonsense, and insertion and deletion mutations have been reported in the coding exon of FKRP. While most of the mutations are rare, the most common is the 826 C>A mutation.[1] The clinical phenotype of LGMD-2I is extremely heterogenous, including asymptomatic carriers, patients with severe early-onset type at times mistaken for a dystrophinophathy, and patients with mild late-onset varieties showing slow progression.[6]

Treatment for patients afflicted with a LGMD is supportive. Physical and occupation therapy services should be consulted for passive stretching exercise programs and prevention of contractures if there are concerns. Cardiology and pulmonary consultations are also warranted and genetic counseling should be offered.[5]

Clinical Course and Follow-up

After a repeat muscle biopsy did not demonstrate inflammatory changes, we proceeded with genetic testing which came back positive for a mutation in the FKRP gene. Clinically, the patient has been stable in regards to his weakness for the past two years and has not required assistance with ambulation. He is still employed full time, has been evaluated by physical therapy, and regularly sees his cardiologist for a mild dilated cardiomyopathy which has not caused him any clinical symptoms. None of his children were tested for the FKRP mutation.

References

  1. Boito CA, Melacini P, et al. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Arch Neurol. 2005;62(12):1894-9.
  2. Broglio L, Tentorio M, et al. Limb-girdle muscular dystrophy-associated protein diseases. Neurologist. 2010;16(6):340-52.
  3. Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain. 1999;122:1403-20.
  4. Bushby KM, Beckmann JS. The limb girdle muscular dystrophies – proposal for a new nomenclature. Neuromuscul Disord. 1995;5(4):337-43.
  5. Darras BT. Muscular dystrophies. Continuum. 2006;12(3):33-75.
  6. de Paula F, Vieira N, et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003;11:923?30.
  7. Wicklund MP, Mendell JR. The limb-girdle muscular dystrophies: our ever-expanding knowledge. J Clin Neuromuscul Dis. 2003;5(1):12-28.

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