Alternative titles; symbols
SNOMEDCT: 772129007; ORPHA: 209341, 363447; DO: 0070351;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q32.31 | Spinal muscular atrophy, lower extremity-predominant 1, AD | 158600 | Autosomal dominant | 3 | DYNC1H1 | 600112 |
A number sign (#) is used with this entry because autosomal dominant lower extremity-predominant spinal muscular atrophy-1 (SMALED1) is caused by heterozygous mutation in the DYNC1H1 gene (600112) on chromosome 14q32.
Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. SMALED shows autosomal dominant inheritance with muscle weakness predominantly affecting the proximal lower extremities (Harms et al., 2010).
The most common form of SMA (see, e.g., SMA1, 253300) shows autosomal recessive inheritance and is due to mutation in the SMN1 gene (600354) on chromosome 5q.
Genetic Heterogeneity of Lower Extremity-Predominant Spinal Muscular Atrophy
See also SMALED2A (615290) and SMALED2B (618291), both of which are caused by mutation in the BICD2 gene (609797) on chromosome 9q22. SMALED2A and SMALED2B differ in age at onset and severity, with SMALED2B being more severe.
Timme (1917) described a family with a dominant form of proximal 'muscular dystrophy' with onset at age 3 or 4 years, but with little if any effect on longevity and useful life. Gowers sign was noted early and the difficulty in getting up from the floor increased with age. Some affected individuals required lengthening of the Achilles tendon. Young (1972) provided follow-up of this family, which included 13 affected persons spanning 4 generations. The clinical picture was most consistent with an autosomal dominant childhood-onset spinal muscular atrophy. There were no additional features.
Saul and Meyer (1985) reported a family with 5 affected persons in 3 generations.
Harms et al. (2010) reported a large 6-generation North American family with early-onset spinal muscular atrophy affecting the proximal lower extremities. The disorder was manifest by prominent weakness and atrophy of the quadriceps muscles, moderate to severe atrophy of the hip abductors, and milder weakness in other leg muscles. Upper extremity strength and sensation were normal. Ten affected individuals were studied. Most patients had onset of symptoms in the first 2 years of life, although 3 had onset between 4 and 7 years of age. The disorder was static or only mildly progressive. None had arthrogryposis or contractures, but 5 had mild pes cavus. The 53-year-old proband reportedly had underdeveloped leg muscles in infancy, delayed motor development, and a lifelong history of difficulty running and climbing stairs. Examination at age 49 showed neurogenic weakness and atrophy of the lower limbs, most prominent in the quadriceps. There was also mild atrophy of distal leg muscles. Other muscles, including knee flexors, distal leg, face, neck, and upper extremity muscles showed normal strength. He had a waddling gait with excessive lumbar lordosis. No fasciculations were observed. This patient also showed mild, subclinical, chronic denervation in the hand, but his affected child did not, suggesting either that upper limb involvement may be related to length of disease or that there is intrafamilial variability. Other affected family members had a similar phenotype; none had arm or neck weakness, and all remained ambulatory into the sixth decade. Electromyographic (EMG) studies and skeletal muscle biopsies on 2 patients indicated chronic denervation. There was type II muscle fiber predominance, suggesting successive rounds of denervation and reinnervation.
Harms et al. (2012) reported a 3-generation family with SMALED confirmed by genetic analysis. The 3 affected individuals showed waddling gait from early childhood, with awkward running due to lower limb weakness; upper limbs were unaffected. Muscle atrophy and weakness confined to the lower limbs showed little progression throughout life. There was a notable strength discrepancy between knee extension and flexion, with the quadriceps showing significant weakness. Deep tendon reflexes were reduced at the knees, but normal elsewhere. Nerve conduction studies showed small motor responses and normal sensory responses; EMG showed chronic denervation. One patient had heel cord contractures and in-turning feet, whereas another had fasciculations of the calves. Another unrelated girl with the disorder showed delayed motor development, calcaneovalgus foot deformities, lower extremity weakness, and mild cognitive delay. At age 3.5 years, she could not run and had an unsteady gait. There was no sensory loss. EMG was consistent with nonlength-dependent motor neuron disease. A sister, who was not studied, reportedly had similar motor delay diagnosed as cerebral palsy, abnormal gait, and polymicrogyria on brain imaging.
Tsurusaki et al. (2012) reported a Japanese mother and her 2 children with autosomal dominant spinal muscular atrophy with lower extremity predominance. Both children showed mildly delayed walking followed by persistently unstable gait due to muscle weakness in the proximal lower limbs. Imaging showed atrophy and lipid degeneration of the quadriceps femoris muscle. Muscle biopsy of 1 patient showed severe grouping atrophy of type 2 fibers, sparse enlarged type 1 fibers, and increased fibrous tissue. EMG of the other patient indicated a neurogenic pattern. The mother was only ascertained as being affected after her children were examined. The mother did not have a waddling gait, but had difficulty squatting and mild muscle atrophy in the hip. Imaging showed quadriceps-dominant muscle atrophy and lipid degeneration. None of the patients had upper limb involvement, and sensation and intellectual function were normal.
Tsukagoshi et al. (1966) reported autosomal dominant inheritance of the disorder, but quasidominance due to consanguinity may have been possible in at least 1 family.
Garvie and Woolf (1966) and Magee and DeJong (1960), among others, also described autosomal dominant transmission of proximal spinal muscular atrophy.
Pearn (1978) estimated that autosomal dominant SMA with childhood onset accounts for less than 2% of all childhood onset SMA.
Hausmanowa-Petrusewicz et al. (1985) noted that proximal spinal muscular atrophy of childhood and adolescence is a heterogeneous condition, and suggested that some cases may be due to new dominant mutations.
Rudnik-Schoneborn et al. (1994) presented 3 pieces of evidence for the existence of an autosomal dominant form of childhood-onset proximal spinal muscular atrophy distinct from the more common forms of autosomal recessive SMA (253300). First, segregation analysis performed in 333 families with proximal SMA affecting only individuals in 1 generation showed a deviation from autosomal recessive inheritance. Second, they reported 3 pedigrees with proximal SMA in 2 generations with the disorder apparently starting as a de novo mutation in the affected parent. Third, they reported data on 5 of 93 informative SMA families who did not show linkage with 5q markers.
By genomewide linkage analysis of a North American family with autosomal dominant spinal muscular atrophy affecting the lower limbs, Harms et al. (2010) found significant linkage to chromosome 14q32 (maximum 2-point lod score of 5.10 at rs17679127). Linkage to 14q32 was further supported by multipoint parametric lod scores of 3.00 between rs2615453 and rs10143250. Haplotype analysis identified a 6.1-Mb disease-associated interval, containing 73 known or predicted genes.. Harms et al. (2010) proposed the designation spinal muscular atrophy-lower extremity, dominant (SMALED) for this disorder.
In affected members of a large family with autosomal dominant lower extremity spinal muscular atrophy originally reported by Harms et al. (2010), Harms et al. (2012) identified a heterozygous 1750A-C mutation in the DYNC1H1 gene (I584L; 600112.0004). The mutation was identified by sequencing all exons of 73 annotated genes in the 14q32 linkage interval using custom target capture followed by next-generation sequencing. Patient skin fibroblasts showed normal binding to microtubules in the absence of ATP, but markedly decreased binding to microtubules in the presence of ATP. The mutant dynein also appeared to disrupt the stability of the dynein complex. Sequencing of this gene in 32 additional probands with a similar disorder identified 2 additional families with a heterozygous DYNC1H1 mutation (600112.0005 and 600112.0006). The findings were similar to those observed in Loa homozygous mice, who have a mutation in the Dync1h1 gene (Hafezparast et al., 2003; Ori-McKenney et al., 2010).
In 2 Japanese sibs with autosomal dominant lower extremity spinal muscular atrophy and no sensory symptoms, Tsurusaki et al. (2012) identified a heterozygous missense mutation in the DYNC1H1 gene (H306R; 600112.0001). The mutation, which was found by exome sequencing, was inherited from their mother, who had mild symptoms. The same mutation had previously been found by Weedon et al. (2011) in a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; 614228).
Young (1972) provided follow-up of the family reported by Timme (1917), noting that the disorder did not prevent productive life, as indicated by the biography of one of the affected persons (Young, 1967), William Stewart Young, a cofounder of Occidental College. An autopsy report by Butt et al. (1939), who wrongly labeled the disorder as dystrophia myotonica (160900), a distal myopathy, also noted that affected persons could maintain a productive life. There were no additional features, such as cataract, myotonia, diabetes, or mental retardation in the family. One of the affected members of the family, son of William Stewart Young, gave a useful description of mechanical aids for patients with muscular disability (Young, 1949).
Baraitser, M. The Genetics of Neurological Disorders. Oxford: Oxford Univ. Press (pub.) 1982.
Butt, E. M., Hall, E. M., Courville, C. B. Progressive muscular dystrophy (dystrophia myotonica). Bull. Los Angeles Neurol. Soc. 4: 58-68, 1939.
Garvie, J. M., Woolf, A. L. Kugelberg-Welander syndrome (hereditary proximal spinal muscular atrophy). Brit. Med. J. 1: 1458-1461, 1966. [PubMed: 5933049] [Full Text: https://doi.org/10.1136/bmj.1.5501.1458]
Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300: 808-812, 2003. [PubMed: 12730604] [Full Text: https://doi.org/10.1126/science.1083129]
Harms, M. B., Allred, P., Gardner, R., Jr., Fernandes Filho, J. A., Florence, J., Pestronk, A., Al-Lozi, M., Baloh, R. H. Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32. Neurology 75: 539-546, 2010. [PubMed: 20697106] [Full Text: https://doi.org/10.1212/WNL.0b013e3181ec800c]
Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78: 1714-1720, 2012. [PubMed: 22459677] [Full Text: https://doi.org/10.1212/WNL.0b013e3182556c05]
Hausmanowa-Petrusewicz, I., Zaremba, J., Borkowska, J. Chronic proximal spinal muscular atrophy of childhood and adolescence: problems of classification and genetic counselling. J. Med. Genet. 22: 350-353, 1985. [PubMed: 2370051] [Full Text: https://doi.org/10.1007/BF00193198]
Magee, K. R., DeJong, R. N. Neurogenic muscular atrophy simulating muscular dystrophy. Arch. Neurol. 2: 677-682, 1960. [PubMed: 14419782] [Full Text: https://doi.org/10.1001/archneur.1960.03840120083009]
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Timme, W. Progressive muscular dystrophy as an endocrine disease. Arch. Intern. Med. 19: 79-104, 1917.
Tsukagoshi, H., Sugita, H., Furukawa, T., Tsubaki, T., Ono, E. Kugelberg-Welander syndrome with dominant inheritance. Arch. Neurol. 14: 378-381, 1966. [PubMed: 5906462] [Full Text: https://doi.org/10.1001/archneur.1966.00470100034004]
Tsurusaki, Y., Saitoh, S., Tomizawa, K., Sudo, A., Asahina, N., Shiraishi, H., Ito, J., Tanaka, H., Doi, H., Saitsu, H., Miyake, N., Matsumoto, N. A DYNC1H1 mutation causes a dominant spinal muscular atrophy with lower extremity predominance. Neurogenetics 13: 327-332, 2012. [PubMed: 22847149] [Full Text: https://doi.org/10.1007/s10048-012-0337-6]
Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 89: 308-312, 2011. [PubMed: 21820100] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.002]
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Young, P. T. Personal Communication. Claremont, Calif. 1972.
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