CMTX5 in Japanese Patient Linked to New PRPS1 Gene Mutation
A Japanese man was found to have a new mutation in the PRPS1 gene, which caused Charcot-Marie-Tooth disease type X- 5 (CMTX5), according to a recent case study.
The patient showed the classic symptoms of CMTX5, such as deafness and damage to multiple peripheral nerves — those outside the brain and spinal cord — yet with a lesser reduction in the activity of the affected PRPS1 protein, compared with other cases.
The study, “A Novel PRPS1 Mutation in a Japanese Patient with CMTX5,” was published in the Internal Medicine Journal.
Charcot-Marie-Tooth is a group of conditions of the peripheral nervous system, the nerves that supply movement and sensation to the arms and legs. Typically, people with CMT experience muscle weakness and have decreased sensation, specifically to touch, pain, or heat, in the lower legs, hands, and forearms.
CMTX5 is a very rare type of CMT, caused by a missense mutation — one that changes one amino acid in the resulting protein — in the PRPS1 gene located in the X chromosome. The PRPS1 gene codes for a protein of the same name that is involved in the synthesis of nucleotides, the building blocks of DNA and RNA.
The clinical presentation, or the symptoms that result from mutations in PRPS1, depends on the extent of the PRPS1 protein deficiency, with CMTX5 labeled as moderate deficiency.
This study reports the case of a 33-year-old man in Japan who had hearing loss in both ears from birth. His intellectual capabilities were normal at school, but he had trouble with handwriting and grasping chopsticks.
He did not walk until age 3 and then needed an ankle-foot orthosis to be able to walk. The man was able to walk until high school, but then subsequently became wheelchair-bound.
Vision problems began around age 11, with reduced sharpness, called visual acuity. He was able, however, to use a computer and cell phone until about age 30. According to the report, the man’s visual acuity slowly decreased and an ophthalmologist recognized bilateral optic atrophy — which refers to shrinkage of the optic nerve.
The patient was admitted to the hospital for a precise diagnosis. His family history did not include any other members with optic atrophy or polyneuropathy, which is the simultaneous damage of multiple peripheral nerves.
Neurological exams confirmed bilateral optic atrophy and hearing loss. Visual acuity was limited to perceiving variations in the degree of light or brightness.
He had severe thumb movement limitations, known as ape hand deformities, as well as claw hand — bent fingers — deformities. The patient also had pes cavus, a deformity of the feet characterized by a high arch that does not flatten with weight-bearing, and muscle wasting along with weakened muscles in both the arms and legs.
Additionally, he had reduced sensation in the lower extremities with no vibration sense in his ankles and reduced position sense — the ability to sense the location and movement of parts of the body — in his toes. Tendon reflexes also were reduced in both the lower and upper extremities.
Most of the patient’s blood work was normal. However, the level of creatine kinase, an indicator of muscle damage, was increased.
Nerve conduction studies showed severe motor sensory nerve damage. Imaging the brain showed no abnormalities, although auditory-evoked potentials, which are a means of measuring the functioning of auditory pathways, indicated no nerve responses.
Following patient and family consent, DNA tests for CMT were performed. Results showed a newly reported mutation in the PRPS1 gene (p.G28R), in which the amino acid glycine was changed to an ariginine at position 28.
“Since glycine at position 28 is strictly conserved from birds to humans, a substitution in this amino acid can have a significant impact on the protein function,” the investigators wrote.
PRS1 protein activity level was measured in the patient’s red blood cells. The team found a marked reduction to nearly 20% of normal values.
His mother was found to have one PRPS1 gene copy with the new mutation and reduced protein activity, although to a lesser extent than in her son.
“Given these findings, we concluded that the mutation causes CMTX5,” the scientists wrote.
The investigators mentioned that this patient had a milder reduction in protein activity than others with different mutations in the same gene, although he had typical CMTX5 symptoms.
“This indicates that the residual enzyme activity does not necessarily determine the clinical phenotype [presentation] of PRPS1 mutations,” the team wrote.
“In the future,” they concluded, “gathering more cases and examining the relationship between residual enzyme activity and phenotype will be necessary.”