OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: CAPN3

Calpainopathy
Leyden-Moebius muscular dystrophy
LGMD2A
Pelvofemoral muscular dystrophy

Muscle weakness
Muscle wasting
Muscle contractures
Muscle atrophy
Respiratory insufficiency

Limb-Girdle Muscular Dystrophy, Type 2A

Clinical Characteristics

General description (for patients):

This is one of two types of muscular dystrophy, primarily of the limbs, found among the Amish. The severity varies widely both within and between families.  The average age of onset is 13.5 years but may be as early as three.  Outstanding symptoms are difficulty walking, climbing stairs, and frequent falls due to lower limb involvement.  Approximately 2-5 years later, weakness is noted in the upper extremities.  Some swaying of the back may be noted at this time as well.  Wasting of muscles becomes evident.  Neck and facial muscles are relatively spared while eye movements and swallowing are not affected.  Sometime in the 3rd decade of life, walking and getting up from a sitting position are no longer possible.  Contractures of the elbows, hips and knees are often seen in late stages. Involvement of the diaphragm can make breathing difficult.

Medical description:  

This type (2A) of limb-girdle muscular dystrophy closely resembles the other type (2E) also found in the Amish.  Onset in 2A may be slightly later and the lower limb involvement predominates earlier.  Diaphragm function may beome impaired resulting in respiratory insufficiency, sometimes severely.  Cardiac, extraocular, and velopharyngeal muscles seem to be spared.  The earlier the onset (3-30, mean 13.5 years), the more rapid the progression of weakness with most being confined to a wheelchair in the third decade.  Muscle atrophy is most pronounced in the limbs although serum creatinine kinase is markedly elevated even in the youngest before much weakness is noted.  Contractures at the elbow, hip and knees are often seen late in the disease.

Genetics:

Type 2A autosomal recessive LMGD was first identified on the island of Reunion in the Indian Ocean in 1991. The mutation was localized to chromosome 15 at that time, and then confirmed in 1992 in Amish cases in northern Indiana and then again in Brazilians in 1993.  Thirty years previously, Amish individuals with LGMD had been identified in southern Indiana, which subsequently was determined to be type 2E with a mutation in SGCB on chromosome 4.  The community in Daviess County was established by settlers from northern Indiana, among others, and consanguineous connections between the two populations have been documented.  Therefore, the Amish in southern Indiana were restudied which ruled out any mutation on chromosome 15 leading to the conclusion that two mutations causing LGMD were indeed segregating in one large population, with a curious geographic distribution in the two communities.  One might speculate that since the type 2E mutation arose in Switzerland (see #604286), the mutation in CAPN3 causing type 2A arose later in the Northern Indiana Amish after founders with the Swiss mutation from the Northern Indiana community left to establish the southern community in 1869.  The mutation for type 2A (2306G>A) is in the CAPN3 gene (15q15.1-q21.1) encoding the proteolytic enzyme calpain-3.

Treatment:

No treatment other than physical therapy is available.

Prognosis:

Most patients live into adulthood but progression is inevitable and all individuals eventually become totally disabled.

Ancillary treatments and support:

Respiratory therapy is important when diaphragmatic weakness becomes prominent.

Specialists and specialty centers:

Neurologist, physical therapy, respiratory therapy.

References:

Young, K., Williams, P., Foroud, T., Jackson, C.E., Beckmann, J., Cohen, D., Conneally, P.M., Tischfield, J., and Hodes, M.E.:  Confirmation of linkage of limb-girdle muscular dystrophy, type 2, to chromosome 15. Genomics 13(4):1370-1, 1992. PubMed ID: 1505977

Allamand, V., Broux, O., Bourg, N., Richard, I., Tischfield, J.A., Hodes, M.E., Conneally, P.M., Fardeau, M., Jackson, C.E., and Beckmann, J.S.:  Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus.  Hum. Molec. Genet. 4: 459-465, 1995.   PubMed ID: 7795603

Jackson, C.E., and Carey, J.H.:  Progressive muscular dystrophy: autosomal recessive type.  Pediatrics 28: 77-84, 1961. PubMed ID: 13718465

Resources:

Muscular Dystrophy Association

Associated Graphics