Mutation Newly Linked to Adult-Onset Distal SMA in Spanish Siblings, Case Study Reports

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A mutation in the KIF5A gene, found in four Spanish siblings, causes a rare form of spinal muscular atrophy (SMA) known as adult-onset distal SMA (DSMA), according to a case report. DSMA mainly affects the distal muscles, or those further from the center of the body.

The report, “Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations,” was published as a letter to the editor in the journal Brain.

Spinal muscular atrophy (SMA) is a group of heritable neuromuscular disorders that result in the loss of lower motor neurons — nerve cells that connect the spinal cord with skeletal muscles, regulating voluntary movement — and consequently is marked by muscle weakness and atrophy.

The distal form of SMA is rare, and characterized by slow progression of muscle weakness that starts in distal muscles of the upper and lower limbs (such as hands, feet, lower arms, and lower legs) and later extends to other muscle groups.

Distal SMA usually does not significantly affect sensory neurons — those responsible for transmitting sensory information — or a person’s lifespan.

More than 10 distal SMAs with varying symptoms and severities have been reported, each associated with a different gene. Some of these disorders resemble another neurodegenerative disease called Charcot-Marie-Tooth disease (CMT), which greatly affects not only motor but also sensory neurons.

Researchers discuss four people in a Spanish family with an adult-onset form of distal SMA caused by a mutation in the KIF5A gene.

These siblings (three men and one woman) had two healthy sisters and a brother who died of leukemia at age 12. They were all born to the same parents, who were from the Andalusia region in southern Spain. Their father, who died at 65, began showing similar muscle symptoms at age 40.

These four adults (ages 48 to 59) reported the first signs of muscle weakness between 44 and 50 years of age. All showed a slowly progressive weakness in the lower legs and feet, which became moderate to severe, and eventually progressed to muscles in the upper legs.

Later, one sister and two brothers developed mild-to-moderate muscle weakness in the lower arms, hands, and fingers. One of these two men also showed mild involvement of the upper arms, which the researchers noted was probably related to his cervical myelitis – inflammation in the cervical area of the spinal cord – due to primary progressive multiple sclerosis.

While the sister and one of the brothers were able to walk without help, the other two required aids — a cane, a walker, ankle foot orthotics, or a motorized wheelchair — for long distances.

Further examination of leg muscles in all four siblings showed signs of muscle atrophy, fat accumulation, denervation (loss of nerve supply), and impaired motor neuron function.

Genetic analysis discarded SMA linked to SMN1 mutations, finding instead these siblings all carried the same mutation in the KIF5A gene (c.G802A, p.A268T), which was not present in the two unaffected sisters. This mutation was predicted to be disease-causative, leading to a switch of an amino-acid — the building blocks of proteins — in the resulting protein.

Mutations in the KIF5A gene have been linked to several neurodegenerative diseases, including spastic paraplegia, Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS).

But clinical data on the siblings were not consistent with any of these, and more indicative of a lower motor neuron disorder.

Their age at onset of slowly progressive muscle weakness and atrophy, predominantly affecting the lower legs and without sensory impairment, suggested an adult-onset form of distal SMA.

The KIF5A protein is involved in the transport of molecules in neurons through their axons — nerve cell extensions that allow signal to be transmitted to other cells. Interestingly, one of these molecules is VAPB, and mutations in the VAPB gene have been identified in people with Finkel type SMA (FSMA) — an adult-onset SMA form that primarily affects the proximal muscles — those closest to the center of the body — and ALS.

Animal studies have shown that mice lacking the KIF5A gene have poorer motor neuron growth and survival, but sensory neurons are unaffected. Since no signs of reinnervation (restoration of nerve supply; often a compensation seen in people with a motor neuron disease) was detected in the affected muscles of these siblings, the researchers hypothesized that this KIF5A mutation may limit motor neurons’ ability to effectively reinnervate the affected muscles.

“This work expands the [disease] spectrum of KIF5A mutations and indicates that mutations in KIF5A should be considered in the differential diagnosis of a distal spinal muscular atrophy,” the researchers wrote.