The case was reported in the study, “A novel homozygous variant extending the peripheral myelin protein 22 by 9 AMino acids causes early‐onset Charcot‐Marie‐Tooth disease with predominant severe sensory ataxia,” published in the Journal of the Peripheral Nervous System.
CMT1A is normally associated with genetic mutations that cause a duplication in the DNA sequence of the PMP22 gene, which provides instructions to make a protein that is one of the components of myelin, the fatty substance that wraps around nerve fibers to ensure proper neuron communication.
Mutations causing deletions in the DNA sequence of PMP22 have been associated with another neuropathic disease, called hereditary neuropathy with liability to pressure palsies (HNPP), while point mutations have been linked to both CMT1A and HNPP.
Point mutations are those in which a single nucleotide (DNA building blocks) is modified in a gene’s DNA sequence, which may or may not lead to alterations in the composition of the protein it encodes.
“Bi-allelic mutations [mutations found in both copies of a gene] are exceptionally rare and have been associated with early onset and prominent ataxia [loss of movement control],” the investigators wrote.
Researchers described the rare case of a girl who carried a mutation in both copies of the PMP22 gene and developed a severe and early-onset form of CMT1A.
The 9-year-old girl was the second child of a consanguineous (family-related) Afghani couple. She was born after an uneventful pregnancy and did not require respiratory support at birth. There was no history of any neuromuscular or developmental disorder in the family.
Parents started noticing problems in their daughter’s motor development by the time she reached 1 year. She had floppy movements and only started crawling at age 2. The girl started showing signs of abnormal posture in her hands and feet. However, lab tests, chromosomal analyses, and brain magnetic resonance imaging (MRI) scans were normal.
By age 3 she was able to stand and walk with support. However, she never gained the ability to walk independently.
When she reached the age of 3-and-a-half, a neurological examination found signs of low muscle tone in her legs, which initially were attributed to lack of physical exercise.
Her gait was severely impaired, she lacked body reflexes, and had a mild speech delay, which later improved.
Nerve conduction studies performed when she reached age 7 revealed the speed at which electrical signals traveled through her sensory and motor nerves was abnormally low, which was indicative of a motor-sensory neuropathy.
Sensory nerves are those that are responsible for detecting and carrying information from different types of stimuli to the central nervous system (CNS, composed by the brain and spinal cord). Motor nerves are those that are responsible for controlling voluntary movements.
A re-assessment performed when she reached age 9 showed that despite requiring support for standing and walking, her muscle power and tone were close to normal in all segments tested.
Genetic tests performed afterward showed the girl carried a new mutation (c.483A>G) in both copies of the PMP22 gene that led to the addition of nine amino acids (the building blocks of proteins) to the PMP22 protein sequence.
Analyses also revealed her parents were both carriers of the mutation — carrying one copy each — and had abnormalities in nerve conduction tests that were consistent with the diagnosis of HNPP.
“PMP22‐deficient human models are rare but important to decipher the physiological [normal] function of the PMP22 protein,” the researchers wrote.
They also added the type of abnormalities observed in sensory nerves in this and other patients may indicate the PMP22 protein plays a key role during the development of the dorsal root ganglia, a region that contains the cell bodies of sensory nerves.
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