Two brothers with X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), who carried newly identified mutations in the PRPS1 gene, experienced temporary but recurrent symptoms of muscle weakness after taking ill with fever, a case study notes.
According to the study’s authors, this is the first report of such symptoms associated with CMTX5. Researchers recommend that children with these transient neurological signs should be evaluated for peripheral neuropathy (nerve disease) and considered for genetic screens of PRPS1.
The report, “X-linked Charcot–Marie–Tooth disease type 5 with recurrent weakness after febrile illness,” was published in the journal Brain and Development.
Clinical and neurophysiological manifestations of pediatric CMTX5 are poorly defined, with less than 20 cases reported in the literature to date.
The condition is caused by genetic defects on the X chromosome, one of the sex chromosomes. It can arise due to mutations in the PRPS1 gene, which provides instructions for the production of an enzyme called phosphoribosyl pyrophosphate synthetase 1 (PRS-I).
Mutations in PRPS1, resulting in loss of enzyme activity, can manifest in multiple conditions, ranging in type and severity of symptoms: X-linked nonsyndromic sensorineural deafness (DFN2), CMTX5 and Arts syndrome.
Art syndrome is the most severe, marked by intellectual disability, poor muscle strength and coordination, and immune system impairment. DFN2 is characterized by prelingual hearing loss, or hearing loss evident at birth or which develops before a child has learned to speak.
Both Art syndrome and DFN2 show some overlap in disease manifestations with CMTX5.
This study describes two Japanese brothers, ages 13 and 8. Both had hearing loss either since birth or in the first year of life, a symptom often associated with CMTX5.
They had experienced recurrent, sudden-onset episodes of muscle weakness, the older between 8 and 11 years of age and the younger after age 2. All such episodes occurred with illnesses marked by fever, such as respiratory infections.
During these episodes, neurological evaluation noted reduced reflexes in the ankles and knees, and severe muscle weakness in their upper legs — including Gowers’ sign, marked by difficulty in getting up after laying down; walking the hands up the legs in order to stand again, and a waddling gait.
In the two brothers, all episodes resolved within one month of onset.
Nerve conduction studies revealed weaker muscle action potential — electrical impulses that allow muscles to contract — in their lower legs.
Visual impairment, a predominant features of CMTX5, was not observed, but this symptom usually appears later in these patients.
A genetic screen for 72 peripheral neuropathy-related genes identified a novel PRPS1 mutation (c.319A>G) as the cause of the disease. As expected, the mutation had been inherited from the mother (mother’s transmit their X chromosome where PRPS1 lies to male children); the woman did not have any neurological or hearing deficits.
Based on their symptoms of sensorineural hearing loss (rooted in the inner, sensory organ of the ear), peripheral neuropathy, and genetic results, the siblings were diagnosed with CMTX5.
“Proximal muscle weakness usually occurs in patients with myogenic [muscle origin] diseases. In the present case study, it was unknown whether the exact mechanism of proximal muscle weakness in our patients was myogenic or neurogenic [neurological origin],” the researchers wrote.
The cause of recurrent weakness might be due to the high-energy demand of neuronal cells during infection, combined with the fact that PRS-I deficiency reduces energy supply, particularly in the brain, muscle, and retina, they added.
Similar transient episodes of proximal muscle weakness have been reported in a boy with Art syndrome, which also worsened after episodes of fever related to infections.
But to date, such muscle manifestations have not been reported in CMTX5. “The transient weakness presenting in both CMTX5 and Arts syndrome suggests an overlap of signs” and a continuous spectrum of disease associated with PRS-I deficiency, the researchers said.
“Thus, children presenting with transient neurological signs should be evaluated for peripheral neuropathy,” they concluded. “Genetic analysis for CMTX is advised even without clinical evidence of neuropathy.”
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