Hypotonic Syndrome as a Manifestation of an Ultra-Rare Disease of Genetic Origin

Background: Congenital hypotonia is a condition that encompasses heterogeneous neuromuscular disorders. Patients have impaired consciousness, feeding difficulties, seizures, abnormal postures, abnormal eye movements, and brainstem reflexes. Genetic disorders account for about 60% of the causes of hypotonia. These include infantile neuroaxonal dystrophy (INAD), an ultra-rare neurodegenerative disorder and according to the Orphanet Reports Series database of unknown prevalence, with reports of more than 150 cases.

Case report: The 2-year-old patient was born without complications and no genetic family history but had severe global neurodevelopmental delay, regression of acquired milestones, generalised hypotonia, left horizontal nystagmus, and strabismus. The brain MRI revealed cerebellar atrophy. Genetic sequencing using NGS (New Generation Sequencing) + CNV (Copy Number Variants) for genes related to congenital hypotonia (1621 genes) identified a compound heterozygous variant in the PLA2G6 gene associated with INAD.

Results: Two variants were identified in a heterozygous state (double heterozygous for the PLA2G6 gene), the first probably pathogenic variant of the PLA2G6 gene, duplication of 5 nucleobases between positions 1914 of the cDNA, in exon 14. A second pathogenic heterozygous variant was also identified in the PLA2G6 gene, a guanine to adenine substitution at position 2081 in exon 15.

Discussion/conclusion: Congenital hypotonia is related to several disorders, such as INAD, and is difficult to diagnose with conventional tools, hence the importance of implementing genomic technologies.

The PLA2G6 gene is identified as the only gene committed so far to the generation of INAD and it is located on chromosome 22 at 22q13.1. Variants that disrupt the PLA2G6 gene fail to repair oxidative damage to phospholipid membranes, leading to changes in membrane permeability.

INAD with an autosomal recessive pattern of inheritance begins between 6 months and 3 years with regression or psychomotor retardation, hypotonia, and progressive spastic tetraparesis. Strabismus, nystagmus, and optic atrophy may also occur. The disease course ends in mortality in the first decade, and most have cerebellar atrophy appreciable on magnetic resonance imaging. At the moment, there is no specific treatment for the disease, only palliative and supportive.