Spinal Muscular Atrophy, Lower Extremity-Predominant, 2a, Childhood Onset, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant childhood-onset lower extremity-predominant spinal muscular atrophy-2A (SMALED2A) is caused by heterozygous mutation in the BICD2 gene (609797) on chromosome 9q22.

Heterozygous mutation in the BICD2 gene can also cause SMALED2B (618291), a more severe disorder.

Description

SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013).

For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).

Clinical Features

Frijns et al. (1994) described a 3-generation Dutch family in which 7 individuals had nonprogressive muscular atrophy affecting the proximal and distal muscles mainly of the lower extremities. Affected individuals had contractures of the ankles and feet and difficulty walking. The index case began walking at 18 months with feet turned inward. At age 15 years, she was found to have atrophy of the thigh muscles, mild flexion contractures of the knees, pes equinovarus, and mild weakness of the adductor muscles of the thigh, knee extensors, and foot extensors, with only minimal involvement of the jaw muscles and neck flexors. Sensory examination and tendon reflexes were normal. Serum creatine kinase activity was marginally elevated. Nerve conduction tests and electromyography demonstrated giant motor unit potentials but normal motor and sensory nerve conduction velocities, sensory nerve action potentials, and H-reflex and F-wave latencies. Muscle biopsy demonstrated groups of atrophic fibers, predominantly type 1. The findings were consistent with a neurogenic process with likely involvement of lower motor neurons in the anterior horn of the spinal cord. Linkage to chromosome 5 markers for spinal muscular atrophy (SMA; 253300) was excluded.

Adams et al. (1998) reported a father and son with autosomal dominant slowly progressive spinal muscular atrophy with weakness and atrophy predominantly affecting the lower leg muscles, but with mild proximal lower limb weakness and weakness of the intrinsic hand muscles. Both were born with foot deformities, including pes equinovarus, overlapping toes, and Achilles tendon contractures, and both showed delayed walking. At age 7 years, the son could walk 1 block but used the railing for stairs. At age 41 years, the father used crutches and showed marked atrophy of the distal lower extremities. Reflexes were absent at the ankles and knees. The father also had mild weakness of the upper limbs. Muscle biopsy and EMG were consistent with a neurogenic process. Sural nerve biopsy was normal, suggesting a defect of the anterior horn cells.

Oates et al. (2012) reported a 4-generation Australian family with autosomal dominant congenital spinal muscular atrophy. Four members were studied in detail. One affected infant showed reduced fetal movements. All had congenital foot deformities and some developed early joint contractures. One had hip dysplasia. The patients showed delayed motor development with difficulty walking due to proximal and distal muscle weakness and atrophy predominantly affecting the lower limbs. Other features included hyporeflexia, Gowers sign, and hyperlordosis. Postmortem examination of an affected child who died from other causes at age 14 months showed decreased numbers of anterior horn cells in the lumbar and cervical spine with no peripheral nerve pathology. There was no evidence of ongoing loss or degeneration of anterior horn cells, suggesting that it had occurred in early life. These findings confirmed that the disorder in this family was a true form of spinal muscular atrophy.

Neveling et al. (2013) reported a 3-generation Dutch family with SMALED2A. Two patients, a mother and daughter, were studied in detail. They had shown delayed walking, mild weakness and atrophy of the proximal upper and lower limb muscles, waddling gait, inability to walk on their heels, and absent Achilles tendon reflexes. Both showed evidence of hyperreflexia and 1 had extensor plantar responses. Family history revealed similarly affected family members; some had congenital hip dysplasia and clubfeet. EMG and muscle biopsy studies in this family indicated a neurogenic disease process.

Peeters et al. (2013) reported a 4-generation Bulgarian family of Turkish origin with autosomal dominant proximal SMA. The age at onset ranged between 1 and 6 years. Affected individuals presented with delayed motor milestones, Gowers sign, waddling gait, difficulty climbing stairs, and slow running. Neurologic examination showed muscle weakness and atrophy limited to the lower extremities with predominant involvement of the proximal leg muscles. Some patients had axial muscle weakness, and 1 older individual had distal leg muscle weakness. Bulbar and respiratory muscles were not affected. Most had decreased knee and ankle reflexes. Other features included hyperlordosis and scapular winging; 1 patient had fasciculations in the upper limb. EMG showed predominantly large-amplitude and long-duration motor unit potentials in the muscles of the lower and upper extremities, suggesting anterior horn cell damage. The disorder was not progressive; patients remained ambulatory even into the fifth decade. An additional unrelated woman with the disorder showed a similar clinical course, with delayed walking, waddling gait, Gowers sign, proximal and distal muscle weakness mostly affecting the lower limbs, and fasciculations in the upper limb.

Oates et al. (2013) described 3 unrelated families and 1 additional patient with sporadic occurrence of dominant congenital SMA. Affected individuals presented with congenital or early-onset hip dislocation, lower limb contractures, foot deformities, and predominantly distal leg wasting with proximal lower limb weakness. Some more severely affected individuals had upper motor neuron signs, such as brisk reflexes and extensor plantar responses. Some patients had weakness and atrophy of the upper limbs as well, including the shoulder and hand. Motor and sensory nerve conduction studies were normal apart from reduced or absent peroneal compound muscle action potentials representing secondary axonal loss in some individuals. EMG studies confirmed chronic denervation and reinnervation.

Unger et al. (2016) reported 2 unrelated German families with SMALED2A. Family 1 contained 5 affected individuals spanning 3 generations. The patients ranged in age from 3 to 84 years. Four patients had delayed motor development, and the proband had onset in early childhood. Features included distal muscle weakness and atrophy resulting in waddling gait and inability to walk on the toes. Some patients had Gowers sign and pes cavus. None of the patients had sensory, cardiac, or respiratory involvement. MRI of the lower extremities showed severe fatty degenerative changes in the affected muscles. Creatine kinase was normal in the children and moderately elevated in 2 adults. In family 2, the index patient was a 46-year-old man with a history of weakness and atrophy of the calf muscles since early childhood. The disease course was slowly progressive, and he remained ambulatory. Muscle biopsy as an adult showed complete lipofibromatosis with no detectable muscle tissue. Serum creatine kinase was increased, but EMG suggested a neurogenic process. Skeletal muscle biopsies from the proband of each family showed chronic myopathic alterations, including type 1 fiber predominance, fiber size variability, fiber splitting, necrotic fibers, and central nuclei, as well as increased fatty and fibrous tissue. There were also angular atrophic fibers, indicating neurogenic changes, and abnormalities of the mitochondria, Golgi apparatus, and endoplasmic reticulum. Unger et al. (2016) emphasized that the disorder includes a prominent myopathic component in addition to a neurologic component. Storbeck et al. (2017) reported follow-up of family 2 in the report of Unger et al. (2016), noting that the clinically unaffected 71-year-old mother of the proband was found to carry the same heterozygous BICD2 mutation as her son (T703M; 609797.0002). The mother was neurologically unaffected, but MRI showed myopathic changes and detailed examination showed mild distal weakness. Storbeck et al. (2017) suggested that other genetic or environmental factors may have influenced the clinical variability in this family.

Clinical Variability

Oates et al. (2013) reported a German family in which 4 patients developed features of hereditary spastic paraplegia, including lower limb spasticity and hyperreflexia between 20 and 70 years of age. Some of the patients had mild features of SMALED2A, such as foot deformities, Achilles tendon contractures, and proximal and distal muscle weakness and atrophy of the lower limbs. Two patients were wheelchair-bound. Affected members of this family carried a heterozygous mutation in the BICD2 gene (K508T; 609797.0006). However, since this was the only family with significant upper motor neuron features reported by Oates et al. (2013), the authors stated that it was premature to comment on possible genotype/phenotype correlations. Some patients in 1 of the families with SMALED2A reported by Neveling et al. (2013) also showed hyperreflexia and extensor plantar responses.

Inheritance

The transmission pattern of SMALED2A in the families reported by Neveling et al. (2013) and Oates et al. (2013) was consistent with autosomal dominant inheritance.

Mapping

By genomewide linkage analysis of a Bulgarian family with proximal SMA, Peeters et al. (2013) found linkage to a 12.7-Mb region on chromosome 9q between D9S1812 and D9S176 (multipoint lod score of 2.71).

Molecular Genetics

In affected members of 3 unrelated families with autosomal dominant lower extremity-predominant spinal muscular atrophy-2A, Neveling et al. (2013) identified 3 different heterozygous missense mutations in the BICD2 gene (609797.0001-609797.0003). Two of the families had previously been reported by Frijns et al. (1994) and Adams et al. (1998), respectively. The mutation in the first family was found by linkage analysis combined with exome sequencing, and the additional 2 families were found by screening the BICD2 gene in a cohort of 23 families with autosomal dominant SMA. In vitro cellular expression assays and studies of patient fibroblasts showed that the BICD2 mutations caused fragmentation of the Golgi apparatus. In addition, patient cells showed decreased amounts of mutant BICD2 compared to wildtype, and the mutant proteins were trapped within the Golgi. The cellular defect was more apparent in cells from patients with a more severe phenotype.

In affected members of a Bulgarian family with SMALED2A, Peeters et al. (2013) identified the same heterozygous mutation in the BICD2 gene that had been identified by Neveling et al. (2013) (S107L; 609797.0001). The mutation was found by linkage analysis combined with exome sequencing. A different heterozygous missense mutation (609797.0004) was found in 1 (1.7%) of 199 individuals with SMA. Cellular studies showed that both mutations affected BICD2 binding with interacting proteins. The findings demonstrated that BICD2 is essential for motor neuron physiology.

In affected members of 6 unrelated families with SMALED2A, Oates et al. (2013) reported 4 different heterozygous mutations in the BICD2 gene (see, e.g., 609797.0001, 609797.0005-609797.0006). Three unrelated families carried the same mutation (S107L; 609797.0001) that had been identified by Neveling et al. (2013) and by Peeters et al. (2013). All mutations identified by Oates et al. (2013) occurred within the first 2 coiled-coil binding domains. In vitro functional expression studies showed that 2 of the mutations caused increased binding to dynein. Oates et al. (2013) suggested that the mutations interfered with neuronal anterograde trafficking, resulting in a block of neurite outgrowth and impaired embryonic development of motor neurons.

In affected members of a German family (family 1) with SMALED2A, Unger et al. (2016) identified a heterozygous S107L mutation in the BICD2 gene. The mutation, which was found by sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated German patient (family 2) with SMALED2A was found to be heterozygous for a T703M (609797.0002) mutation, which was later found to be inherited from his clinically unaffected mother (Storbeck et al., 2017). Unger et al. (2016) detected abnormal BICD2 localization in skeletal muscle biopsies from the 2 German probands, with the mutant protein showing partial localization within the myonuclei rather than associated with microtubules or vesicles as noted in control muscle. Patient muscle showed abnormal BICD2 aggregation and an altered endomembrane system, suggesting an aggregation-dependent loss of BICD2 function. In vitro functional expression studies in cultured muscle cells confirmed that the mutations caused the formation of abnormal aggregates and less cytosolic localization compared to controls.

Martinez Carrera et al. (2018) performed in vitro functional expression studies of several BICD2 missense mutations associated with SMALED2A (see, e.g., S107L; N188T, 609797.0003; and T703M). Patient-derived fibroblasts and murine motor neuron cells transfected with the mutations had increased microtubule stability associated with increased acetylation of microtubules compared to controls, regardless of the location of the mutation. Murine motor neurons transfected with the mutations showed variable axonal defects, including abnormal collateral long branching and overgrowth.