Giant axonal neuropathy (GAN) in an 8‐year‐old girl caused by a homozygous pathogenic splicing variant in GAN gene

Abstract

Giant axonal neuropathy (GAN) is a progressive disease that involves the peripheral and central nervous systems. This neurodegenerative disease is caused by variants in the GAN gene encoding gigaxonin, and is inherited in an autosomal recessive manner. Herein, we performed whole‐exome sequencing on a 8‐year‐old child with dense, curly hair, weakness in both lower limbs, and abnormal MRI. The child was born to consanguineous parents. Our results revealed that the child carried the c.1373+1G>A homozygous pathogenic variant of the GAN gene, while both parents were heterozygous carriers. According to the validation at the cDNA levels, the splicing variant led to the skipping of exon 8 and affected the Kelch domain's formation. Unlike the previously reported cases of GAN, the child's clinical manifestations revealed peripheral nervous system involvement, no vertebral signs, cerebellar signs, and spasticity, but only MRI abnormalities. These results suggested that the patient's central nervous system was mildly involved, which may be related to the genotype. In order to further clarify the correlation between GAN genotype and phenotype, combined with this patient, 54 cases of reported homozygous variants of the GAN gene were merged for the analysis of genotype and phenotype. The results revealed a certain correlation between the GAN gene variant domain and the patient's clinical phenotype, such as central nervous system involvement and age of onset.

Giant Axonal Neuropathy: A Case Report of Subclinical Childhood Manifestations

“…This is confirmed by studies that reviewed over 63 reported cases of the GAN variant [9]. These findings were echoed by Guo et al [10] who also investigated 55 cases of the GAN variant showing clinical features that are compatible with the clinical presentation of our cases. Moreover, determining the severity and prognosis of patients remains an active area of research.…”

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

“…Data analysis of 55 cases of GAN was published by Guo et al ( 2022 ) show that hypo/areflexia, muscle weakness, curly hair, and cerebellar dysfunction were the most detected clinical findings that are compatible with the clinical presentation of our cases. The most commonly reported electrodiagnostic and neuroimaging findings in GAN include sensorimotor neuropathy and nonspecific supra and infratentorial white matter signal changes, respectively.…”

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

“…Progressive distal motor weakness is the initial symptom in all cases. Diffused muscle atrophy, most predominantly in distal muscles, flaccid, paralysis, severely decreased muscle strength, low muscle tone, and loss of reflexes (areflexia) may be observed as the disease advances ( Table 2 ) [ 3 , 22 , 23 , 24 , 25 , 26 , 37 , 38 ]. Diagnosis of PNS degeneration in early infancy and sensorimotor pathway involvement in teens resemble more commonly inherited peripheral neuropathy called Charcot-Marie-Tooth (CMT) diseases [ 27 ].…”