Researchers Identify Gene Causing Atypical SMA With Brain Degeneration in Infants

Japanese researchers have identified a new gene that likely gives rise to spinal muscular atrophy (SMA) with severe brain degeneration.

The team at the University of Miyazaki studied two sisters who developed atypical SMA shortly after birth. Atypical SMA involves muscle atrophy that is accompanied by other neurological symptoms, such as seizures or atrophy of the brain’s cerebellum.

The study, “TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy,” was published in the Journal of Human Genetics.

The girls were born to healthy parents. Doctors noticed problems with the older sister when she was only a month old. She had poor muscle tone, but was alert and reacted to light and visual stimuli. She could swallow, but not lift her arms and legs, and she had weak hands and feet movement. She had some reflexes but not others.

In their first examination of the girl, doctors noted no abnormal values on laboratory tests, and brain scans were normal. The team excluded the possibility of typical infantile SMA since they did not find mutations of the SMN gene.

But the girl’s condition deteriorated rapidly. At three months, she had lost the ability to smile and react to visual cues, and she had muscle twitching in the tongue — a feature indicating lower-motor-neuron injury.

At seven months, brain scans showed tissue loss in the larger part of her brain, but not in the cerebellum or brain stem. She developed seizures, and had difficulty swallowing and breathing. At one year she had lost all means of communication, relied on mechanical ventilation for breathing, and was tube fed. The girl died of aspiration pneumonia when she was 6.

Her younger sister had a similar course of illness, needing a tracheostomy with mechanical ventilation at seven months. Now 7, the girl is still alive.

Since tests for mitochondrial disease and other suspected conditions were negative, researchers sequenced the parents’ genomes in their search for explanations.

They noted that the girls shared two unusual mutations. Both gene variants were homozygous, meaning they were found in both gene copies. A computer analysis suggested that one was likely harmless. Researchers believe the other, in the TBCD (tubulin-folding cofactor D) gene, is connected to the damage.

Each parent carried the mutation in one of their gene copies. This gene codes for a factor that is crucial for normal muscle function, but also important to nerve cells.

Other reports of patients with symptoms similar to the girls’ have been published recently, the Japanese team said. Although the patients also had TBCD mutations, none had conditions as severe as the girls’. Based on this, the researchers concluded that homozygous mutations in the TBCD gene are likely responsible for a new and severe neurodegenerative disorder.