Late adult-onset spinal muscular atrophy with lower extremity predominance (SMALED)

Abstract

An elderly man in his early 80s presented with a 6-month history of worsening lower limb weakness on a background of a longer-standing waddling gait. Examination revealed bilateral scapular winging, and weakness in his proximal and distal lower limbs. Electromyography showed widespread chronic partial denervation changes, while sensory and motor nerve conduction parameters were preserved. After little progression over the course of 18 months, motor neuron disease was deemed less likely. Genetic testing revealed BICD2-related spinal muscular atrophy with lower extremity dominance (SMALED2), a disease that is usually of earlier onset. He is the oldest patient in the literature to be diagnosed with SMALED2 while maintaining ambulation, suggesting the milder spectrum of BICD2-related disease.

Background

Spinal muscular atrophy with lower extremity dominance (SMALED) is an autosomal dominant condition that occurs due to heterozygous mutations of the DYNC1H1 or BICD2 genes, causing SMALED1 and SMALED2, respectively.¹ It is part of a growing group of non-5q spinal muscular atrophy (SMA), traditionally constituting 5% cases of SMA. It is usually diagnosed at birth or in early childhood. BICD2 mutations that cause SMALED2 are heterozygous missense mutations, thought to cause a gain of function, altering interactions with the microtubule-transport machinery, and is associated with increased microtubule stability in motor neurons, leading to axonal aberrations and impaired neuromuscular junction development.² We present a case of very late adult-onset SMALED, with slow progression, and discuss the differential diagnoses in an elderly patient presenting with a motor neuropathy.

Case presentation

A man in his 80s with an active lifestyle presented with persistent weakness despite regular exercise therapy. He reported a 10-month history of severe pain above his left iliac crest unimproved by an L4/5 facet joint injection and a 6-month history of progressive lower limbs weakness, requiring arm support to climb stairs and using all four limbs to get up from the floor. He had a long-standing waddling gait of unclear onset that had been unchanged over many years, and he used a walking stick in his right hand. He denied voice changes, dysphagia or hand weakness. The patient had been attending weekly physical therapy sessions for 9 months without improvement. However, he remained active at home, mowed the lawn and was independent in driving. He reported occasions of urinary incontinence on a background of a radical prostatectomy for prostate cancer, diagnosed 10 years earlier. He had not received any radiotherapy. He saw a rheumatologist who wondered about facioscapulohumeral muscular dystrophy (FSHD).

On examination, the patient had wasting in his right sternocleidomastoid muscle, bilateral quadriceps, and left more than right tibialis anterior muscles and bilateral gastrocnemii. No fasciculation was observed. He had bilateral scapular winging (figure 1), more prominently on the right. He had mild 4 to 4+ weakness in shoulder abduction, finger abduction, hip flexion and ankle plantar flexion with the left hip extensor weaker than the right. He was able to stand on each heel but could only stand on his toes with both feet together (figures 2 and 3). The rest of his muscles was strong. Reflexes were present in the upper limbs except in the triceps, and just elicited at the knees, but absent at the ankles, with flexor plantar responses. The sensory examination was normal. Beevor’s sign was borderline positive. Trendelenburg test was positive, suggesting left hip extensor weakness.

Figure 1.

Prominent scapular winging.

Figure 2.

Mild weakness of the ankle plantar-flexors.

Figure 3.

Minimal weakness in the ankle dorsi-flexors.

Investigations

Nerve conduction studies (NCS) showed normal sensory and motor nerve conduction with mildly prolonged F-waves in the lower limb (right ulnar 31 ms, right tibial 65.9 ms), which suggest some proximal segment motor conduction delay. Needle electromyography (EMG) showed widespread chronic partial denervation changes in the upper and lower limb muscles, including the periscapular muscles. There was minimal change on repeat testing at 6 months and 1 year.

MRI of the spine showed multilevel spinal spondylotic changes with severe foraminal stenoses and probable irritation of bilateral C4, left C5 and left C6 nerve roots. There was no lumbar nerve root, spinal cord or cauda equina compression.

Respiratory function was within normal limits. Blood investigations showed normal creatine kinase (CK), blood counts, vitamin B₁₂, B₆ and folate, HbA1C of 5.7%, and normal plasma lead and mercury levels. Initial serum immunoelectrophoresis showed oligoclonal IgG with lambda light chains, with elevated kappa free light chains and a kappa:lambda light chain ratio of 3:1. Repeat testing a year later showed stable findings. Serum antineuronal antibodies, antiganglioside antibodies and C5N1A antibodies were negative. Cerebrospinal fluid examination was acellular with normal glucose and protein with matching oligoclonal IgG bands to serum. He subsequently had a small bowel biopsy diagnosing Coeliac disease and was started on a gluten-free diet. Gliadin IgG (21CU, Ref <20) and tissue transglutaminase antibodies (94CU, Ref <20) remained raised 3 months later.

Differential diagnosis

This elderly male’s history of progressive lower limbs weakness with clinical findings of limb girdle atrophy on a background of longer-standing waddling gait could be suggestive of a late adult-onset muscular dystrophy. But, his CK was normal, and EMG instead suggested a widespread axonal motor neuropathy rather than a myopathy. Given his age and deterioration over 6 months, a more slowly progressive form of motor neuron disease, such as progressive muscular atrophy or the flail-leg variant, was considered. Coeliac disease has been described to uncommonly cause a pure motor neuropathy³ but has not been associated with scapular winging.

Because of lack of progression of the disease over 18 months, we proceeded to genetic testing. survival motor neuron 1 gene (SMN1) testing was normal, and testing for FSHD1 was done using Southern blot analysis after double digestion with EcoRI/BlnI, with no abnormal fragment detected in the patient to suggest FSHD1.

A massively parallel sequencing custom gene capture panel for motor neuron disorders/SMA, which included 50 genes, found a heterozygous, likely pathogenic missense variant in the BICD2 (bicaudal D homolog 2) gene c.2108C>T, p.(Thr703Met), which is associated with SMALED2, a condition which is usually of early onset, with static or slow progression, of autosomal dominant inheritance. The panel also screened for an additional 119 genes associated with the Charcot-Marie-Tooth phenotype and 277 genes associated with other neurological disorders, including those that can have neuropathy as a manifestation.

Treatment

The patient was encouraged to continue exercising regularly, and although this did not improve his strength, it improved his back pain. He adhered to a gluten-free diet, but this did not help his neuropathy.

Outcome and follow-up

There was little progression to his distal lower limb weakness over 3 years. He remains ambulant at age 83. The patient was counselled about the finding of the likely pathogenic variant in the BICD2 gene, but his sister and children have not yet decided to proceed with testing.

Discussion

Our patient presented with the phenotype of spinal muscular atrophy with lower extremity predominance (SMALED). SMALED describes the non-length dependent nature of weakness in what would otherwise be counted as part of the distal hereditary motor neuropathies or distal SMA.⁴ Electrophysiological studies show a motor axonopathy/neuronopathy in these conditions, and patients may have upper motor neuron signs.⁵ SMALED can be noted at birth or during infancy with delayed motor milestones and joint contractures,⁶ including ankle contractures, scoliosis and hip dysplasia.¹ However, there have been case reports of late adult-onset disease. Synofzik et al⁷ and Rudnik-Schöneborn et al⁸ have reported cases with onset in the fourth and fifth decades of life. Wan et al⁹ describes a Chinese pedigree with the index patient presenting in her 50s and a family member presenting with onset in their 60s.

Families reported in the literature with SMALED2 due to BICD2 gene mutation have distal lower limb weakness and nearly all have gait difficulties.⁶ Upper limb involvement is reported in the majority but is milder, and affected later than the lower limbs.⁶ NCS can reveal no abnormalities and EMG shows signs of chronic denervation.¹ The diagnosis is often delayed because of mild, long-standing symptoms of slow progression, with family history often unclear, possibly due to reduced penetrance. We are suspicious that our patient’s sister’s hip dysplasia, and his son and grandson’s described thin legs could be manifestation of the condition.

Our patient’s mutation, c.2108C>T, p.(Thr703Met), has been reported in a Canadian family, with subsequent study of BICD2 levels found to be lower in the fibroblasts of affected individuals.^{10 11} Similar to our patient, normal NCS, chronic neurogenic change on EMG and normal CK were also described in the Canadian adult at age 41. However, our patient had an even later presentation, with no history of congenital deformities, still intact knee reflexes and prominent scapular winging. This could suggest variable expressivity with this disorder. There may be other genetic modifiers that are yet unknown, that makes this a milder, later onset presentation in our patient. A limitation of the study rest in that a custom gene capture panel was done rather than whole genome sequencing to exclude other possible genetic contributors to the phenotype.

SMALED2 being a rare condition, our initial investigation for the patient’s axonal motor neuropathy aimed at checking for paraneoplastic causes including for a monoclonal gammopathy, autoimmune causes including for motor predominant chronic inflammatory demyelinating polyneuropathy (CIDP) and Coeliac disease, as well as motor neuron disease. The lack of progression over time, including lack of active denervation on EMG, in addition to laboratory investigations, and a suggestive family history helped eventually point to the possibility of a genetic cause.

Learning points.

• The differential diagnoses of an adult presenting with a motor neuropathy include paraneoplastic and autoimmune causes, motor neuron disease and also rarer hereditary causes; the latter two conditions can be associated with scapular winging and more prominent muscle wasting.

• Although SMALED usually manifests early in life, it may also present in late adulthood.

• Stepwise investigations with neurophysiological testing, laboratory investigation, imaging studies and follow-up of the disease progression can help lead us to consider rarer genetic causes for motor neuropathies, including SMALED2, and allow appropriate advice on prognosis, and cascade testing.

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